From a1007c09a40db247032e2cbb9d58e7e98d68994a Mon Sep 17 00:00:00 2001 From: Ryan Whaley Date: Wed, 17 Jul 2024 22:41:58 -0700 Subject: [PATCH] fix(data): fix downloading new guidance data --- .../pharmgkb/pharmcat/util/DataManager.java | 17 +- .../reporter/prescribing_guidance.json | 77257 ++++++++-------- .../org/pharmgkb/pharmcat/PipelineTest.java | 5 +- 3 files changed, 40200 insertions(+), 37079 deletions(-) diff --git a/src/main/java/org/pharmgkb/pharmcat/util/DataManager.java b/src/main/java/org/pharmgkb/pharmcat/util/DataManager.java index a795d512..eae81062 100644 --- a/src/main/java/org/pharmgkb/pharmcat/util/DataManager.java +++ b/src/main/java/org/pharmgkb/pharmcat/util/DataManager.java @@ -139,8 +139,8 @@ public static void main(String[] args) { PgkbGuidelineCollection pgkbGuidelineCollection; if (!skipGuidelines) { Path drugsDir = cliHelper.getValidDirectory("g", true); - Path guidanceFile = drugsDir.resolve(PRESCRIBING_GUIDANCE_FILE_NAME); - pgkbGuidelineCollection = new PgkbGuidelineCollection(guidanceFile); + Path updatedGuidancePath = manager.transformGuidelines(downloadDir, drugsDir); + pgkbGuidelineCollection = new PgkbGuidelineCollection(updatedGuidancePath); } else { // if we're skipping new drug data, then use the default data pgkbGuidelineCollection = new PgkbGuidelineCollection(); @@ -209,6 +209,19 @@ public static void main(String[] args) { } } + private Path transformGuidelines(Path downloadDir, Path guidelinesDir) throws IOException { + if (!Files.exists(guidelinesDir)) { + Files.createDirectories(guidelinesDir); + } + + Path downloadedGuidanceFile = downloadDir.resolve(PRESCRIBING_GUIDANCE_FILE_NAME); + Path destinationGuidanceFile = guidelinesDir.resolve(PRESCRIBING_GUIDANCE_FILE_NAME); + System.out.println("Saving guidelines to " + destinationGuidanceFile); + + FileUtils.copyFile(downloadedGuidanceFile.toFile(), destinationGuidanceFile.toFile()); + return destinationGuidanceFile; + } + private DefinitionFile[] parseDefinitionFiles(Path downloadDir) throws IOException { Path definitionsFile = downloadDir.resolve(ALLELES_FILE_NAME); diff --git a/src/main/resources/org/pharmgkb/pharmcat/reporter/prescribing_guidance.json b/src/main/resources/org/pharmgkb/pharmcat/reporter/prescribing_guidance.json index 63299ca4..b83637a6 100644 --- a/src/main/resources/org/pharmgkb/pharmcat/reporter/prescribing_guidance.json +++ b/src/main/resources/org/pharmgkb/pharmcat/reporter/prescribing_guidance.json @@ -212,7 +212,7 @@ "id" : "PA165987830", "symbol" : "HLA-B*57:01", "name" : "*57:01", - "version" : 6 + "version" : 21 } ], "relatedChemicals" : [ @@ -220,7 +220,7 @@ "objCls" : "Chemical", "id" : "PA448004", "name" : "abacavir", - "version" : 11 + "version" : 41 } ], "relatedGenes" : [ @@ -229,23 +229,23 @@ "id" : "PA35056", "symbol" : "HLA-B", "name" : "major histocompatibility complex, class I, B", - "version" : 40 + "version" : 2920 } ], "source" : "CPIC", "summaryMarkdown" : { "id" : 1447982036, "html" : "

In individuals with the HLA-B*57:01 variant allele ("HLA-B*57:01-positive"), abacavir is not recommended and should be considered only under exceptional circumstances. See full guideline for disclaimers, further details and supporting evidence.

\n", - "version" : 0 + "version" : 1 }, "terms" : [], "textMarkdown" : { "id" : 1451433650, "html" : "

This annotation is based on the CPIC® guideline for abacavir and HLA-B.

\n

May 2014 Update

\n

Accepted article preview online 21 February 2014; Advance online publication 12 March 2014

\n

The 2014 update of CPIC guidelines regarding abacavir has been published in Clinical Pharmacology and Therapeutics. Literature published between April 2011-November 2013 was reviewed and there is no new evidence that would change the original guidelines. Therefore, the dosing recommendations in the original publication remain clinically current.

\n\n

April 2012

\n

Advance online publication February 2012

\n\n

Excerpt from the abacavir dosing guidelines:

\n
\n

We agree with others* that HLA-B*57:01 screening should be performed in all abacavir-naive individuals before initiation of abacavir-containing therapy (see Table 1 below); this is consistent with the recommendations of the FDA, the US Department of Health and Human Services, and the European Medicines Agency. In abacavir-naive individuals who are HLA-B*57:01-positive, abacavir is not recommended and should be considered only under exceptional circumstances when the potential benefit, based on resistance patterns and treatment history, outweighs the risk.

\n
\n

*[Articles:18826546, 19640227, 21174626, 21412232] Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents (PDF)

\n\n

Adapted from Tables 1 and 2 of the 2012 guideline manuscript.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Likely phenotypeGenotypesExamples of diplotypesImplications for phenotypic measuresRecommendations for abacavir therapyClassification of recommendation for abacavir therapy a
Very low risk of hypersensitivity (constitutes ~94% b of patients)Absence of *57:01 alleles (reported as "negative" on a genotyping test)*X/*X cLow or reduced risk of abacavir hypersensitivityUse abacavir per standard dosing guidelinesStrong
High risk of hypersensitivity (~6% of patients)Presence of at least one *57:01 allele (reported as "positive" on a genotyping test)*57:01/*X c *57:01/*57:01Significantly increased risk of abacavir hypersensitivityAbacavir is not recommendedStrong
\n

a Rating scheme described in the 2012 Supplement

\n

b See the 2012 Supplement for estimates of genotype frequencies among different ethnic/geographic groups

\n

c *X = any HLA-B genotype other than *57:01.

\n

HLA-B = human leukocyte antigen B

\n

Listen to an interview with the lead author: podcast

\n", - "version" : 2 + "version" : 4 }, "userId" : "carrillo", - "version" : 49 + "version" : 108 }, "recommendations" : [ { @@ -274,21 +274,21 @@ "objCls" : "Chemical", "id" : "PA448004", "name" : "abacavir", - "version" : 11 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104997", "name" : "Annotation of CPIC Guideline for abacavir and HLA-B", - "version" : 49 + "version" : 108 }, "text" : { "id" : 1452059560, "html" : "

Use abacavir per standard dosing guidelines

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -316,14 +316,14 @@ "objCls" : "Chemical", "id" : "PA448004", "name" : "abacavir", - "version" : 11 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104997", "name" : "Annotation of CPIC Guideline for abacavir and HLA-B", - "version" : 49 + "version" : 108 }, "text" : { "id" : 1452059561, @@ -557,7 +557,7 @@ "id" : "PA165987831", "symbol" : "HLA-B*58:01", "name" : "*58:01", - "version" : 4 + "version" : 21 } ], "relatedChemicals" : [ @@ -565,7 +565,7 @@ "objCls" : "Chemical", "id" : "PA448320", "name" : "allopurinol", - "version" : 9 + "version" : 35 } ], "relatedGenes" : [ @@ -574,30 +574,30 @@ "id" : "PA35056", "symbol" : "HLA-B", "name" : "major histocompatibility complex, class I, B", - "version" : 40 + "version" : 2920 } ], "source" : "CPIC", "summaryMarkdown" : { "id" : 1447981950, "html" : "

Allopurinol is contraindicated in individuals with the HLA-B*58:01 variant allele ("HLA-B*58:01-positive") due to significantly increased risk of allopurinol-induced SCAR.

\n", - "version" : 0 + "version" : 1 }, "terms" : [], "textMarkdown" : { "id" : 1451433640, "html" : "

This annotation is based on the CPIC® guideline for allopurinol and HLA-B.

\n

January 2016 Update

\n

Accepted article preview online June 2015

\n

The 2015 update of CPIC guidelines regarding allopurinol has been published in Clinical Pharmacology and Therapeutics. Recent literature was reviewed and there is no new evidence that would change the original guidelines. Therefore, the dosing recommendations in the original publication remain clinically current.

\n\n

February 2013

\n

Advanced online publication December 2012

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Likely PhenotypeGenotypesExamples of diplotypesImplications for phenotypic measuresRecommendations for allopurinol therapyClassification of recommendation for allopurinol therapy
Low or reduced risk of allopurinol SCARAbsence of *58:01 alleles (reported as "negative" on a genotyping test)*X/*X aLow or reduced risk of allopurinol SCARUse allopurinol per standard dosing guidelinesStrong
Significantly increased risk of allopurinol SCARPresence of at least one *58:01 allele (reported as "positive" on a genotyping test)*58:01/*X a *58:01/*58:01Significantly increased risk of allopurinol SCARAllopurinol is contraindicatedStrong
\n

Adapted from Table 2 of the 2013 Guideline Manuscript

\n

a *X = any HLA-B genotype other than *58:01.

\n

HLA-B = human leukocyte antigen B

\n", - "version" : 2 + "version" : 3 }, "userId" : "carrillo", - "version" : 43 + "version" : 92 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166296961", - "name" : "Recommendation PA166296961", - "alternateDrugAvailable" : true, + "id" : "PA166296760", + "name" : "Recommendation PA166296760", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, "parents" : [], @@ -609,9 +609,9 @@ }, "dosingInformation" : false, "implications" : [ - "HLA-B: Significantly increased risk of allopurinol-induced SCAR" + "HLA-B: Low or reduced risk of allopurinol-induced SCAR" ], - "lookupKey" : {"HLA-B": "*58:01 positive"}, + "lookupKey" : {"HLA-B": "*58:01 negative"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -619,27 +619,27 @@ "objCls" : "Chemical", "id" : "PA448320", "name" : "allopurinol", - "version" : 9 + "version" : 35 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105003", "name" : "Annotation of CPIC Guideline for allopurinol and HLA-B", - "version" : 43 + "version" : 92 }, "text" : { - "id" : 1452059563, - "html" : "

Allopurinol is contraindicated

\n", + "id" : 1452059562, + "html" : "

Use allopurinol per standard dosing guidelines

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166296760", - "name" : "Recommendation PA166296760", - "alternateDrugAvailable" : false, + "id" : "PA166296961", + "name" : "Recommendation PA166296961", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, "parents" : [], @@ -651,9 +651,9 @@ }, "dosingInformation" : false, "implications" : [ - "HLA-B: Low or reduced risk of allopurinol-induced SCAR" + "HLA-B: Significantly increased risk of allopurinol-induced SCAR" ], - "lookupKey" : {"HLA-B": "*58:01 negative"}, + "lookupKey" : {"HLA-B": "*58:01 positive"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -661,18 +661,18 @@ "objCls" : "Chemical", "id" : "PA448320", "name" : "allopurinol", - "version" : 9 + "version" : 35 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105003", "name" : "Annotation of CPIC Guideline for allopurinol and HLA-B", - "version" : 43 + "version" : 92 }, "text" : { - "id" : 1452059562, - "html" : "

Use allopurinol per standard dosing guidelines

\n", + "id" : 1452059563, + "html" : "

Allopurinol is contraindicated

\n", "version" : 0 }, "version" : 0 @@ -822,7 +822,7 @@ "id" : "PA166158908", "symbol" : "rs267606618", "name" : "rs267606618", - "version" : 6 + "version" : 7 }, { "objCls" : "Variant", @@ -837,43 +837,43 @@ "objCls" : "Chemical", "id" : "PA164744372", "name" : "amikacin", - "version" : 7 + "version" : 22 }, { "objCls" : "Chemical", "id" : "PA449753", "name" : "gentamicin", - "version" : 8 + "version" : 30 }, { "objCls" : "Chemical", "id" : "PA450137", "name" : "kanamycin", - "version" : 6 + "version" : 22 }, { "objCls" : "Chemical", "id" : "PA164784023", "name" : "paromomycin", - "version" : 6 + "version" : 15 }, { "objCls" : "Chemical", "id" : "PA166228921", "name" : "plazomicin", - "version" : 3 + "version" : 4 }, { "objCls" : "Chemical", "id" : "PA451512", "name" : "streptomycin", - "version" : 7 + "version" : 23 }, { "objCls" : "Chemical", "id" : "PA451704", "name" : "tobramycin", - "version" : 8 + "version" : 27 } ], "relatedGenes" : [ @@ -882,114 +882,30 @@ "id" : "PA31274", "symbol" : "MT-RNR1", "name" : "mitochondrially encoded 12S RNA", - "version" : 8 + "version" : 12 } ], "source" : "CPIC", "summaryMarkdown" : { "id" : 1451330800, "html" : "

Administration of aminoglycoside antibiotics should be avoided in patients carrying certain MT-RNR1 variants due to the increased risk of developing aminoglycoside-induced hearing loss (AIHL).

\n", - "version" : 0 + "version" : 1 }, "terms" : [], "textMarkdown" : { "id" : 1451330801, "html" : "

This annotation is based on the CPIC® Guideline for Aminoglycosides and MT-RNR1.

\n

June 2021

\n

The CPIC® guideline for aminoglycosides and MT-RNR1 has been published in Clinical Pharmacology and Therapeutics. The authors of the guideline evaluated the available evidence for the use of aminoglycoside antibiotics in patients carrying certain MT-RNR1 variants.

\n\n\n

Adapted from Tables 1 and 2 of the guideline.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
PhenotypeGenotypeExample genotypesImplicationsRecommendationsClassification of
recommendationa		Considerations
MT-RNR1 increased risk of aminoglycoside-induced hearing lossIndividuals with an MT-RNR1 variant with an increased risk of aminoglycoside-induced hearing lossm.1095T>C
m.1494C>T
m.1555A>G		Very high risk of developing hearing loss if administered an aminoglycoside antibioticAvoid aminoglycoside antibiotics unless the high risk of permanent hearing loss is outweighed by the severity of infection and lack of safe or effective alternative therapies.StrongIf no effective alternative to an aminoglycoside antibiotic is available, evaluate for hearing loss frequently during therapy and ensure that all appropriate precautions are utilized (e.g., lowest possible dose and duration, utilization of therapeutic drug monitoring, hydration, renal function monitoring).
MT-RNR1 normal risk of aminoglycoside-induced hearing lossIndividuals with no detectable MT-RNR1 increased risk variant or a MT-RNR1 variant associated with normal risk of aminoglycoside-induced hearing lossm.827A>GNormal risk of developing hearing loss if administered an aminoglycoside antibiotic.Use aminoglycoside antibiotics at standard doses for the shortest feasible course with therapeutic dose monitoring. Evaluate regularly for hearing loss in line with local guidance.StrongIndividuals without MT-RNR1 aminoglycoside-induced hearing loss increased risk variants are still at risk of aminoglycoside-associated hearing loss, especially with high drug levels or prolonged courses.
MT-RNR1 uncertain risk of aminoglycoside-induced hearing lossIndividuals with a MT-RNR1 variant associated with an uncertain risk of aminoglycoside-induced hearing lossm.663A>G
m.669T>C
m.747A>G
m.786G>A
m.807A>G
m.807A>C
m.839A>G
m.896A>G
m.930A>G
m.951G>A
m.960C>del
m.961T>G
m.961T>del
m.961T>del+Cn
m.988G>A
m.1189T>C
m.1243T>C
m.1520T>C
m.1537C>T
m.1556C>T		Weak or no evidence for an increased risk of MT-RNR1-associated hearing loss if administered an aminoglycoside antibiotic.Use aminoglycoside antibiotics at standard doses for the shortest feasible course with therapeutic drug monitoring. Evaluate regularly for hearing loss in line with local guidance.OptionalIndividuals without MT-RNR1 aminoglycoside-induced hearing loss increased risk variants are still at risk of aminoglycoside-associated hearing loss, especially with high drug levels or prolonged courses.
\n

a Rating scheme described in the Strength of Recommendations section in the guideline supplement.

\n", - "version" : 2 + "version" : 4 }, "userId" : "rachel", - "version" : 6 + "version" : 53 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166296970", - "name" : "Recommendation PA166296970", + "id" : "PA166296963", + "name" : "Recommendation PA166296963", "alternateDrugAvailable" : false, - "classification" : { - "id" : 981565059, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "MT-RNR1: Weak or no evidence for an increased risk of MT-RNR1 associated hearing loss if administered an aminoglycoside antibiotic." - ], - "lookupKey" : {"MT-RNR1": "uncertain risk of aminoglycoside-induced hearing loss"}, - "otherPrescribingGuidance" : true, - "population" : "general", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA450137", - "name" : "kanamycin", - "version" : 6 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166229081", - "name" : "Annotation of CPIC Guideline for amikacin, gentamicin, kanamycin, paromomycin, plazomicin, streptomycin, tobramycin and MT-RNR1", - "version" : 6 - }, - "text" : { - "id" : 1452059572, - "html" : "

Use aminoglycoside antibiotics at standard doses for the shortest feasible course with therapeutic dose monitoring. Evaluate regularly for hearing loss in line with local guidance.

\n

Other Considerations

\n

Individuals without MT-RNR1 aminoglycoside-induced hearing loss increased risk variants are still at risk of aminoglycoside-associated hearing loss, especially with high drug levels or prolonged courses.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166296974", - "name" : "Recommendation PA166296974", - "alternateDrugAvailable" : true, - "classification" : { - "id" : 981501930, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "MT-RNR1: Very high risk of developing hearing loss if administered an aminoglycoside antibiotic." - ], - "lookupKey" : {"MT-RNR1": "increased risk of aminoglycoside-induced hearing loss"}, - "otherPrescribingGuidance" : false, - "population" : "general", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA166228921", - "name" : "plazomicin", - "version" : 3 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166229081", - "name" : "Annotation of CPIC Guideline for amikacin, gentamicin, kanamycin, paromomycin, plazomicin, streptomycin, tobramycin and MT-RNR1", - "version" : 6 - }, - "text" : { - "id" : 1452059576, - "html" : "

Avoid aminoglycoside anitbiotics unless the high risk of permanent hearing loss is outweighed by the severity of infection and lack of safe or effective alternative therapies.

\n

Other Considerations

\n

If no effective alternative to an aminoglycoside antibiotic is available, evaluate for hearing loss frequently during therapy and ensure that all appropriate precautions are utilized (e.g., lowest possible dose and duration, utilization of therapeutic drug monitoring, hydration, renal function monitoring).

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166296965", - "name" : "Recommendation PA166296965", - "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, "parents" : [], @@ -1001,36 +917,36 @@ }, "dosingInformation" : false, "implications" : [ - "MT-RNR1: Very high risk of developing hearing loss if administered an aminoglycoside antibiotic." + "MT-RNR1: Normal risk of developing hearing loss if administered an aminoglycoside antibiotic." ], - "lookupKey" : {"MT-RNR1": "increased risk of aminoglycoside-induced hearing loss"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"MT-RNR1": "normal risk of aminoglycoside-induced hearing loss"}, + "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA449753", - "name" : "gentamicin", - "version" : 8 + "id" : "PA164744372", + "name" : "amikacin", + "version" : 22 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166229081", "name" : "Annotation of CPIC Guideline for amikacin, gentamicin, kanamycin, paromomycin, plazomicin, streptomycin, tobramycin and MT-RNR1", - "version" : 6 + "version" : 53 }, "text" : { - "id" : 1452059567, - "html" : "

Avoid aminoglycoside anitbiotics unless the high risk of permanent hearing loss is outweighed by the severity of infection and lack of safe or effective alternative therapies.

\n

Other Considerations

\n

If no effective alternative to an aminoglycoside antibiotic is available, evaluate for hearing loss frequently during therapy and ensure that all appropriate precautions are utilized (e.g., lowest possible dose and duration, utilization of therapeutic drug monitoring, hydration, renal function monitoring).

\n", + "id" : 1452059565, + "html" : "

Use aminoglycoside antibiotics at standard doses for the shortest feasible course with therapeutic dose monitoring. Evaluate regularly for hearing loss in line with local guidance.

\n

Other Considerations

\n

Individuals without MT-RNR1 aminoglycoside-induced hearing loss increased risk variants are still at risk of aminoglycoside-associated hearing loss, especially with high drug levels or prolonged courses.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166296978", - "name" : "Recommendation PA166296978", + "id" : "PA166296972", + "name" : "Recommendation PA166296972", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -1051,23 +967,23 @@ "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA451512", - "name" : "streptomycin", - "version" : 7 + "id" : "PA164784023", + "name" : "paromomycin", + "version" : 15 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166229081", "name" : "Annotation of CPIC Guideline for amikacin, gentamicin, kanamycin, paromomycin, plazomicin, streptomycin, tobramycin and MT-RNR1", - "version" : 6 + "version" : 53 }, "text" : { - "id" : 1452059580, + "id" : 1452059574, "html" : "

Use aminoglycoside antibiotics at standard doses for the shortest feasible course with therapeutic dose monitoring. Evaluate regularly for hearing loss in line with local guidance.

\n

Other Considerations

\n

Individuals without MT-RNR1 aminoglycoside-induced hearing loss increased risk variants are still at risk of aminoglycoside-associated hearing loss, especially with high drug levels or prolonged courses.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", @@ -1095,68 +1011,26 @@ "objCls" : "Chemical", "id" : "PA450137", "name" : "kanamycin", - "version" : 6 + "version" : 22 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166229081", "name" : "Annotation of CPIC Guideline for amikacin, gentamicin, kanamycin, paromomycin, plazomicin, streptomycin, tobramycin and MT-RNR1", - "version" : 6 + "version" : 53 }, "text" : { "id" : 1452059571, "html" : "

Use aminoglycoside antibiotics at standard doses for the shortest feasible course with therapeutic dose monitoring. Evaluate regularly for hearing loss in line with local guidance.

\n

Other Considerations

\n

Individuals without MT-RNR1 aminoglycoside-induced hearing loss increased risk variants are still at risk of aminoglycoside-associated hearing loss, especially with high drug levels or prolonged courses.

\n", "version" : 0 }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166296982", - "name" : "Recommendation PA166296982", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 981565059, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "MT-RNR1: Weak or no evidence for an increased risk of MT-RNR1 associated hearing loss if administered an aminoglycoside antibiotic." - ], - "lookupKey" : {"MT-RNR1": "uncertain risk of aminoglycoside-induced hearing loss"}, - "otherPrescribingGuidance" : true, - "population" : "general", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA451704", - "name" : "tobramycin", - "version" : 8 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166229081", - "name" : "Annotation of CPIC Guideline for amikacin, gentamicin, kanamycin, paromomycin, plazomicin, streptomycin, tobramycin and MT-RNR1", - "version" : 6 - }, - "text" : { - "id" : 1452059584, - "html" : "

Use aminoglycoside antibiotics at standard doses for the shortest feasible course with therapeutic dose monitoring. Evaluate regularly for hearing loss in line with local guidance.

\n

Other Considerations

\n

Individuals without MT-RNR1 aminoglycoside-induced hearing loss increased risk variants are still at risk of aminoglycoside-associated hearing loss, especially with high drug levels or prolonged courses.

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Use aminoglycoside antibiotics at standard doses for the shortest feasible course with therapeutic dose monitoring. Evaluate regularly for hearing loss in line with local guidance.

\n

Other Considerations

\n

Individuals without MT-RNR1 aminoglycoside-induced hearing loss increased risk variants are still at risk of aminoglycoside-associated hearing loss, especially with high drug levels or prolonged courses.

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Use aminoglycoside antibiotics at standard doses for the shortest feasible course with therapeutic dose monitoring. Evaluate regularly for hearing loss in line with local guidance.

\n

Other Considerations

\n

Individuals without MT-RNR1 aminoglycoside-induced hearing loss increased risk variants are still at risk of aminoglycoside-associated hearing loss, especially with high drug levels or prolonged courses.

\n", + "id" : 1452059564, + "html" : "

Avoid aminoglycoside anitbiotics unless the high risk of permanent hearing loss is outweighed by the severity of infection and lack of safe or effective alternative therapies.

\n

Other Considerations

\n

If no effective alternative to an aminoglycoside antibiotic is available, evaluate for hearing loss frequently during therapy and ensure that all appropriate precautions are utilized (e.g., lowest possible dose and duration, utilization of therapeutic drug monitoring, hydration, renal function monitoring).

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166296977", - "name" : "Recommendation PA166296977", + "id" : "PA166296965", + "name" : "Recommendation PA166296965", "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, @@ -1261,19 +1135,19 @@ "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA451512", - "name" : "streptomycin", - "version" : 7 + "id" : "PA449753", + "name" : "gentamicin", + "version" : 30 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166229081", "name" : "Annotation of CPIC Guideline for amikacin, gentamicin, kanamycin, paromomycin, plazomicin, streptomycin, tobramycin and MT-RNR1", - "version" : 6 + "version" : 53 }, "text" : { - "id" : 1452059579, + "id" : 1452059567, "html" : "

Avoid aminoglycoside anitbiotics unless the high risk of permanent hearing loss is outweighed by the severity of infection and lack of safe or effective alternative therapies.

\n

Other Considerations

\n

If no effective alternative to an aminoglycoside antibiotic is available, evaluate for hearing loss frequently during therapy and ensure that all appropriate precautions are utilized (e.g., lowest possible dose and duration, utilization of therapeutic drug monitoring, hydration, renal function monitoring).

\n", "version" : 0 }, @@ -1305,14 +1179,14 @@ "objCls" : "Chemical", "id" : "PA450137", "name" : "kanamycin", - "version" : 6 + "version" : 22 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166229081", "name" : "Annotation of CPIC Guideline for amikacin, gentamicin, kanamycin, paromomycin, plazomicin, streptomycin, tobramycin and MT-RNR1", - "version" : 6 + "version" : 53 }, "text" : { "id" : 1452059570, @@ -1323,9 +1197,9 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166296981", - "name" : "Recommendation PA166296981", - "alternateDrugAvailable" : false, + "id" : "PA166296971", + "name" : "Recommendation PA166296971", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, "parents" : [], @@ -1337,36 +1211,162 @@ }, "dosingInformation" : false, "implications" : [ - "MT-RNR1: Normal risk of developing hearing loss if administered an aminoglycoside antibiotic." + "MT-RNR1: Very high risk of developing hearing loss if administered an aminoglycoside antibiotic." ], - "lookupKey" : {"MT-RNR1": "normal risk of aminoglycoside-induced hearing loss"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"MT-RNR1": "increased risk of aminoglycoside-induced hearing loss"}, + "otherPrescribingGuidance" : false, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA164784023", + "name" : "paromomycin", + "version" : 15 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166229081", + "name" : "Annotation of CPIC Guideline for amikacin, gentamicin, kanamycin, paromomycin, plazomicin, streptomycin, tobramycin and MT-RNR1", + "version" : 53 + }, + "text" : { + "id" : 1452059573, + "html" : "

Avoid aminoglycoside anitbiotics unless the high risk of permanent hearing loss is outweighed by the severity of infection and lack of safe or effective alternative therapies.

\n

Other Considerations

\n

If no effective alternative to an aminoglycoside antibiotic is available, evaluate for hearing loss frequently during therapy and ensure that all appropriate precautions are utilized (e.g., lowest possible dose and duration, utilization of therapeutic drug monitoring, hydration, renal function monitoring).

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Avoid aminoglycoside anitbiotics unless the high risk of permanent hearing loss is outweighed by the severity of infection and lack of safe or effective alternative therapies.

\n

Other Considerations

\n

If no effective alternative to an aminoglycoside antibiotic is available, evaluate for hearing loss frequently during therapy and ensure that all appropriate precautions are utilized (e.g., lowest possible dose and duration, utilization of therapeutic drug monitoring, hydration, renal function monitoring).

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Avoid aminoglycoside anitbiotics unless the high risk of permanent hearing loss is outweighed by the severity of infection and lack of safe or effective alternative therapies.

\n

Other Considerations

\n

If no effective alternative to an aminoglycoside antibiotic is available, evaluate for hearing loss frequently during therapy and ensure that all appropriate precautions are utilized (e.g., lowest possible dose and duration, utilization of therapeutic drug monitoring, hydration, renal function monitoring).

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Use aminoglycoside antibiotics at standard doses for the shortest feasible course with therapeutic dose monitoring. Evaluate regularly for hearing loss in line with local guidance.

\n

Other Considerations

\n

Individuals without MT-RNR1 aminoglycoside-induced hearing loss increased risk variants are still at risk of aminoglycoside-associated hearing loss, especially with high drug levels or prolonged courses.

\n", + "id" : 1452059582, + "html" : "

Avoid aminoglycoside anitbiotics unless the high risk of permanent hearing loss is outweighed by the severity of infection and lack of safe or effective alternative therapies.

\n

Other Considerations

\n

If no effective alternative to an aminoglycoside antibiotic is available, evaluate for hearing loss frequently during therapy and ensure that all appropriate precautions are utilized (e.g., lowest possible dose and duration, utilization of therapeutic drug monitoring, hydration, renal function monitoring).

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166296972", - "name" : "Recommendation PA166296972", + "id" : "PA166296975", + "name" : "Recommendation PA166296975", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -1387,28 +1387,28 @@ "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA164784023", - "name" : "paromomycin", - "version" : 6 + "id" : "PA166228921", + "name" : "plazomicin", + "version" : 4 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166229081", "name" : "Annotation of CPIC Guideline for amikacin, gentamicin, kanamycin, paromomycin, plazomicin, streptomycin, tobramycin and MT-RNR1", - "version" : 6 + "version" : 53 }, "text" : { - "id" : 1452059574, + "id" : 1452059577, "html" : "

Use aminoglycoside antibiotics at standard doses for the shortest feasible course with therapeutic dose monitoring. Evaluate regularly for hearing loss in line with local guidance.

\n

Other Considerations

\n

Individuals without MT-RNR1 aminoglycoside-induced hearing loss increased risk variants are still at risk of aminoglycoside-associated hearing loss, especially with high drug levels or prolonged courses.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166296963", - "name" : "Recommendation PA166296963", + "id" : "PA166296966", + "name" : "Recommendation PA166296966", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -1429,28 +1429,28 @@ "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA164744372", - "name" : "amikacin", - "version" : 7 + "id" : "PA449753", + "name" : "gentamicin", + "version" : 30 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166229081", "name" : "Annotation of CPIC Guideline for amikacin, gentamicin, kanamycin, paromomycin, plazomicin, streptomycin, tobramycin and MT-RNR1", - "version" : 6 + "version" : 53 }, "text" : { - "id" : 1452059565, + "id" : 1452059568, "html" : "

Use aminoglycoside antibiotics at standard doses for the shortest feasible course with therapeutic dose monitoring. Evaluate regularly for hearing loss in line with local guidance.

\n

Other Considerations

\n

Individuals without MT-RNR1 aminoglycoside-induced hearing loss increased risk variants are still at risk of aminoglycoside-associated hearing loss, especially with high drug levels or prolonged courses.

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166296976", - "name" : "Recommendation PA166296976", + "id" : "PA166296973", + "name" : "Recommendation PA166296973", "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, @@ -1471,28 +1471,28 @@ "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA166228921", - "name" : "plazomicin", - "version" : 3 + "id" : "PA164784023", + "name" : "paromomycin", + "version" : 15 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166229081", "name" : "Annotation of CPIC Guideline for amikacin, gentamicin, kanamycin, paromomycin, plazomicin, streptomycin, tobramycin and MT-RNR1", - "version" : 6 + "version" : 53 }, "text" : { - "id" : 1452059578, + "id" : 1452059575, "html" : "

Use aminoglycoside antibiotics at standard doses for the shortest feasible course with therapeutic dose monitoring. Evaluate regularly for hearing loss in line with local guidance.

\n

Other Considerations

\n

Individuals without MT-RNR1 aminoglycoside-induced hearing loss increased risk variants are still at risk of aminoglycoside-associated hearing loss, especially with high drug levels or prolonged courses.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166296967", - "name" : "Recommendation PA166296967", + "id" : "PA166296976", + "name" : "Recommendation PA166296976", "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, @@ -1513,29 +1513,29 @@ "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA449753", - "name" : "gentamicin", - "version" : 8 + "id" : "PA166228921", + "name" : "plazomicin", + "version" : 4 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166229081", "name" : "Annotation of CPIC Guideline for amikacin, gentamicin, kanamycin, paromomycin, plazomicin, streptomycin, tobramycin and MT-RNR1", - "version" : 6 + "version" : 53 }, "text" : { - "id" : 1452059569, + "id" : 1452059578, "html" : "

Use aminoglycoside antibiotics at standard doses for the shortest feasible course with therapeutic dose monitoring. Evaluate regularly for hearing loss in line with local guidance.

\n

Other Considerations

\n

Individuals without MT-RNR1 aminoglycoside-induced hearing loss increased risk variants are still at risk of aminoglycoside-associated hearing loss, especially with high drug levels or prolonged courses.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166296980", - "name" : "Recommendation PA166296980", - "alternateDrugAvailable" : true, + "id" : "PA166296978", + "name" : "Recommendation PA166296978", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, "parents" : [], @@ -1547,121 +1547,121 @@ }, "dosingInformation" : false, "implications" : [ - "MT-RNR1: Very high risk of developing hearing loss if administered an aminoglycoside antibiotic." + "MT-RNR1: Normal risk of developing hearing loss if administered an aminoglycoside antibiotic." ], - "lookupKey" : {"MT-RNR1": "increased risk of aminoglycoside-induced hearing loss"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"MT-RNR1": "normal risk of aminoglycoside-induced hearing loss"}, + "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA451704", - "name" : "tobramycin", - "version" : 8 + "id" : "PA451512", + "name" : "streptomycin", + "version" : 23 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166229081", "name" : "Annotation of CPIC Guideline for amikacin, gentamicin, kanamycin, paromomycin, plazomicin, streptomycin, tobramycin and MT-RNR1", - "version" : 6 + "version" : 53 }, "text" : { - "id" : 1452059582, - "html" : "

Avoid aminoglycoside anitbiotics unless the high risk of permanent hearing loss is outweighed by the severity of infection and lack of safe or effective alternative therapies.

\n

Other Considerations

\n

If no effective alternative to an aminoglycoside antibiotic is available, evaluate for hearing loss frequently during therapy and ensure that all appropriate precautions are utilized (e.g., lowest possible dose and duration, utilization of therapeutic drug monitoring, hydration, renal function monitoring).

\n", + "id" : 1452059580, + "html" : "

Use aminoglycoside antibiotics at standard doses for the shortest feasible course with therapeutic dose monitoring. Evaluate regularly for hearing loss in line with local guidance.

\n

Other Considerations

\n

Individuals without MT-RNR1 aminoglycoside-induced hearing loss increased risk variants are still at risk of aminoglycoside-associated hearing loss, especially with high drug levels or prolonged courses.

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Avoid aminoglycoside anitbiotics unless the high risk of permanent hearing loss is outweighed by the severity of infection and lack of safe or effective alternative therapies.

\n

Other Considerations

\n

If no effective alternative to an aminoglycoside antibiotic is available, evaluate for hearing loss frequently during therapy and ensure that all appropriate precautions are utilized (e.g., lowest possible dose and duration, utilization of therapeutic drug monitoring, hydration, renal function monitoring).

\n", + "id" : 1452059581, + "html" : "

Use aminoglycoside antibiotics at standard doses for the shortest feasible course with therapeutic dose monitoring. Evaluate regularly for hearing loss in line with local guidance.

\n

Other Considerations

\n

Individuals without MT-RNR1 aminoglycoside-induced hearing loss increased risk variants are still at risk of aminoglycoside-associated hearing loss, especially with high drug levels or prolonged courses.

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Use aminoglycoside antibiotics at standard doses for the shortest feasible course with therapeutic dose monitoring. Evaluate regularly for hearing loss in line with local guidance.

\n

Other Considerations

\n

Individuals without MT-RNR1 aminoglycoside-induced hearing loss increased risk variants are still at risk of aminoglycoside-associated hearing loss, especially with high drug levels or prolonged courses.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166296962", - "name" : "Recommendation PA166296962", - "alternateDrugAvailable" : true, + "id" : "PA166296981", + "name" : "Recommendation PA166296981", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, "parents" : [], @@ -1673,78 +1673,78 @@ }, "dosingInformation" : false, "implications" : [ - "MT-RNR1: Very high risk of developing hearing loss if administered an aminoglycoside antibiotic." + "MT-RNR1: Normal risk of developing hearing loss if administered an aminoglycoside antibiotic." ], - "lookupKey" : {"MT-RNR1": "increased risk of aminoglycoside-induced hearing loss"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"MT-RNR1": "normal risk of aminoglycoside-induced hearing loss"}, + "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA164744372", - "name" : "amikacin", - "version" : 7 + "id" : "PA451704", + "name" : "tobramycin", + "version" : 27 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166229081", "name" : "Annotation of CPIC Guideline for amikacin, gentamicin, kanamycin, paromomycin, plazomicin, streptomycin, tobramycin and MT-RNR1", - "version" : 6 + "version" : 53 }, "text" : { - "id" : 1452059564, - "html" : "

Avoid aminoglycoside anitbiotics unless the high risk of permanent hearing loss is outweighed by the severity of infection and lack of safe or effective alternative therapies.

\n

Other Considerations

\n

If no effective alternative to an aminoglycoside antibiotic is available, evaluate for hearing loss frequently during therapy and ensure that all appropriate precautions are utilized (e.g., lowest possible dose and duration, utilization of therapeutic drug monitoring, hydration, renal function monitoring).

\n", + "id" : 1452059583, + "html" : "

Use aminoglycoside antibiotics at standard doses for the shortest feasible course with therapeutic dose monitoring. Evaluate regularly for hearing loss in line with local guidance.

\n

Other Considerations

\n

Individuals without MT-RNR1 aminoglycoside-induced hearing loss increased risk variants are still at risk of aminoglycoside-associated hearing loss, especially with high drug levels or prolonged courses.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166296966", - "name" : "Recommendation PA166296966", + "id" : "PA166296964", + "name" : "Recommendation PA166296964", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "MT-RNR1: Normal risk of developing hearing loss if administered an aminoglycoside antibiotic." + "MT-RNR1: Weak or no evidence for an increased risk of MT-RNR1 associated hearing loss if administered an aminoglycoside antibiotic." ], - "lookupKey" : {"MT-RNR1": "normal risk of aminoglycoside-induced hearing loss"}, + "lookupKey" : {"MT-RNR1": "uncertain risk of aminoglycoside-induced hearing loss"}, "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA449753", - "name" : "gentamicin", - "version" : 8 + "id" : "PA164744372", + "name" : "amikacin", + "version" : 22 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166229081", "name" : "Annotation of CPIC Guideline for amikacin, gentamicin, kanamycin, paromomycin, plazomicin, streptomycin, tobramycin and MT-RNR1", - "version" : 6 + "version" : 53 }, "text" : { - "id" : 1452059568, + "id" : 1452059566, "html" : "

Use aminoglycoside antibiotics at standard doses for the shortest feasible course with therapeutic dose monitoring. Evaluate regularly for hearing loss in line with local guidance.

\n

Other Considerations

\n

Individuals without MT-RNR1 aminoglycoside-induced hearing loss increased risk variants are still at risk of aminoglycoside-associated hearing loss, especially with high drug levels or prolonged courses.

\n", "version" : 0 }, - "version" : 0 + "version" : 4 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166296979", - "name" : "Recommendation PA166296979", + "id" : "PA166296967", + "name" : "Recommendation PA166296967", "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, @@ -1765,23 +1765,23 @@ "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA451512", - "name" : "streptomycin", - "version" : 7 + "id" : "PA449753", + "name" : "gentamicin", + "version" : 30 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166229081", "name" : "Annotation of CPIC Guideline for amikacin, gentamicin, kanamycin, paromomycin, plazomicin, streptomycin, tobramycin and MT-RNR1", - "version" : 6 + "version" : 53 }, "text" : { - "id" : 1452059581, + "id" : 1452059569, "html" : "

Use aminoglycoside antibiotics at standard doses for the shortest feasible course with therapeutic dose monitoring. Evaluate regularly for hearing loss in line with local guidance.

\n

Other Considerations

\n

Individuals without MT-RNR1 aminoglycoside-induced hearing loss increased risk variants are still at risk of aminoglycoside-associated hearing loss, especially with high drug levels or prolonged courses.

\n", "version" : 0 }, - "version" : 0 + "version" : 4 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166229081" @@ -2029,7 +2029,7 @@ "pediatricMarkdown" : { "id" : 1451266620, "html" : "

Guideline excerpt: "There are scarce studies focusing solely on CYP2D6 or CYP2C19 genotype and association with pharmacokinetic parameters or treatment outcomes of TCAs in pediatric patients. CYP2D6 activity is fully mature by early childhood, but CYP2C19 activity may be increased in children relative to adults. Although further genomic ontogeny studies are needed, there is a lack of evidence suggesting that this guideline cannot be extrapolated to pediatric patients."

\n", - "version" : 0 + "version" : 1 }, "recommendation" : true, "relatedAlleles" : [], @@ -2038,7 +2038,7 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "relatedGenes" : [ @@ -2047,21 +2047,21 @@ "id" : "PA124", "symbol" : "CYP2C19", "name" : "cytochrome P450 family 2 subfamily C member 19", - "version" : 7210 + "version" : 7266 }, { "objCls" : "Gene", "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "CPIC", "summaryMarkdown" : { "id" : 1447982032, "html" : "

The CPIC Dosing Guideline update for amitriptyline recommends an alternative drug for CYP2D6 ultrarapid or poor metabolizers and CYP2C19 ultrarapid, rapid or poor metabolizers. If amitriptyline is warranted, consider a 50% dose reduction in CYP2D6 or CYP2C19 poor metabolizers. For CYP2D6 intermediate metabolizers, a 25% dose reduction should be considered.

\n", - "version" : 1 + "version" : 4 }, "terms" : [], "textMarkdown" : { @@ -2070,14 +2070,14 @@ "version" : 0 }, "userId" : "whaleyr", - "version" : 58 + "version" : 939 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166297055", - "name" : "Recommendation PA166297055", - "alternateDrugAvailable" : true, + "id" : "PA166297127", + "name" : "Recommendation PA166297127", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -2089,10 +2089,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -2100,305 +2100,227 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059657, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059729, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297152", - "name" : "Recommendation PA166297152", - "alternateDrugAvailable" : true, - "classification" : { - "id" : 981565059, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : true, - "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" - ], - "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Likely Poor Metabolizer"}, + "id" : "PA166301333", + "name" : "Recommendation Annotation PA166301333", + "alternateDrugAvailable" : false, + "dosingInformation" : false, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, - "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059754, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452095652, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297108", - "name" : "Recommendation PA166297108", + "id" : "PA166301334", + "name" : "Recommendation Annotation PA166301334", "alternateDrugAvailable" : false, - "classification" : { - "id" : 1448526251, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", - "valid" : true, - "version" : 0 - }, "dosingInformation" : false, - "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Normal metabolism of TCAs" - ], - "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Indeterminate"}, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, - "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059710, - "html" : "

No recommendation

\n", + "id" : 1452095653, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166296983", - "name" : "Recommendation PA166296983", + "id" : "PA166301335", + "name" : "Recommendation Annotation PA166301335", "alternateDrugAvailable" : false, - "classification" : { - "id" : 981565059, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : true, - "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" - ], - "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Intermediate Metabolizer"}, + "dosingInformation" : false, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, - "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059585, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452095654, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", "version" : 0 }, - "version" : 1 + "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297187", - "name" : "Recommendation PA166297187", - "alternateDrugAvailable" : true, - "classification" : { - "id" : 981501930, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : true, - "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" - ], - "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "No Result"}, + "id" : "PA166301336", + "name" : "Recommendation Annotation PA166301336", + "alternateDrugAvailable" : false, + "dosingInformation" : false, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, - "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059789, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452095655, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297042", - "name" : "Recommendation PA166297042", - "alternateDrugAvailable" : true, - "classification" : { - "id" : 981565059, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : true, - "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" - ], - "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Poor Metabolizer"}, + "id" : "PA166301337", + "name" : "Recommendation Annotation PA166301337", + "alternateDrugAvailable" : false, + "dosingInformation" : false, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, - "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059644, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452095656, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166296996", - "name" : "Recommendation PA166296996", - "alternateDrugAvailable" : true, - "classification" : { - "id" : 981565059, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : true, - "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" - ], - "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Intermediate Metabolizer"}, + "id" : "PA166301338", + "name" : "Recommendation Annotation PA166301338", + "alternateDrugAvailable" : false, + "dosingInformation" : false, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, - "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059598, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452095657, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301338", - "name" : "Recommendation Annotation PA166301338", + "id" : "PA166301339", + "name" : "Recommendation Annotation PA166301339", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452095657, + "id" : 1452095658, "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", "version" : 0 }, @@ -2406,94 +2328,68 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297077", - "name" : "Recommendation PA166297077", - "alternateDrugAvailable" : true, - "classification" : { - "id" : 981565059, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : true, - "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: n/a" - ], - "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Rapid Metabolizer"}, + "id" : "PA166301340", + "name" : "Recommendation Annotation PA166301340", + "alternateDrugAvailable" : false, + "dosingInformation" : false, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, - "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059679, - "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. If a tertiary amine is warranted, utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452095659, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297174", - "name" : "Recommendation PA166297174", + "id" : "PA166301341", + "name" : "Recommendation Annotation PA166301341", "alternateDrugAvailable" : false, - "classification" : { - "id" : 981501931, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : true, - "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" - ], - "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "No Result"}, + "dosingInformation" : false, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, - "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059776, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452095660, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297064", - "name" : "Recommendation PA166297064", + "id" : "PA166297049", + "name" : "Recommendation PA166297049", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -2506,10 +2402,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -2517,27 +2413,27 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059666, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059651, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297161", - "name" : "Recommendation PA166297161", - "alternateDrugAvailable" : true, + "id" : "PA166296984", + "name" : "Recommendation PA166296984", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -2549,10 +2445,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -2560,42 +2456,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059763, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059586, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297156", - "name" : "Recommendation PA166297156", - "alternateDrugAvailable" : true, + "id" : "PA166296983", + "name" : "Recommendation PA166296983", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -2603,42 +2499,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059758, - "html" : "

Avoid amitriptyline use. If amitripyline is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452059585, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297011", - "name" : "Recommendation PA166297011", - "alternateDrugAvailable" : false, + "id" : "PA166296992", + "name" : "Recommendation PA166296992", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -2646,26 +2542,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059613, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452059594, + "html" : "

Avoid amitriptyline use. If a amitripyline is warranted, consider a 50% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297059", - "name" : "Recommendation PA166297059", + "id" : "PA166296993", + "name" : "Recommendation PA166296993", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -2678,10 +2574,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -2689,42 +2585,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059661, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452059595, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166296987", - "name" : "Recommendation PA166296987", - "alternateDrugAvailable" : false, + "id" : "PA166296994", + "name" : "Recommendation PA166296994", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Normal metabolism of TCAs" + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -2732,26 +2628,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059589, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452059596, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297143", - "name" : "Recommendation PA166297143", + "id" : "PA166296996", + "name" : "Recommendation PA166296996", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -2767,7 +2663,7 @@ "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -2775,17 +2671,17 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059745, + "id" : 1452059598, "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, @@ -2793,24 +2689,24 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297090", - "name" : "Recommendation PA166297090", + "id" : "PA166296997", + "name" : "Recommendation PA166296997", "alternateDrugAvailable" : true, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Normal metabolism of tertiary amines", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -2818,26 +2714,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059692, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452059599, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297046", - "name" : "Recommendation PA166297046", + "id" : "PA166296998", + "name" : "Recommendation PA166296998", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -2850,10 +2746,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -2861,72 +2757,85 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059648, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059600, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301334", - "name" : "Recommendation Annotation PA166301334", - "alternateDrugAvailable" : false, - "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Intermediate Metabolizer"}, + "id" : "PA166296999", + "name" : "Recommendation PA166296999", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981565059, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + ], + "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, + "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452095653, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "id" : 1452059601, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297178", - "name" : "Recommendation PA166297178", - "alternateDrugAvailable" : false, + "id" : "PA166297000", + "name" : "Recommendation PA166297000", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -2934,42 +2843,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059780, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452059602, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297033", - "name" : "Recommendation PA166297033", + "id" : "PA166297001", + "name" : "Recommendation PA166297001", "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -2977,42 +2886,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059635, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452059603, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297130", - "name" : "Recommendation PA166297130", - "alternateDrugAvailable" : false, + "id" : "PA166297003", + "name" : "Recommendation PA166297003", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Normal metabolism of TCAs" + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -3020,26 +2929,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059732, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452059605, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297165", - "name" : "Recommendation PA166297165", + "id" : "PA166297004", + "name" : "Recommendation PA166297004", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -3052,10 +2961,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -3063,26 +2972,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059767, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059606, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297020", - "name" : "Recommendation PA166297020", + "id" : "PA166297016", + "name" : "Recommendation PA166297016", "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, @@ -3098,7 +3007,7 @@ "CYP2C19: Normal metabolism of tertiary amines", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -3106,17 +3015,17 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059622, + "id" : 1452059618, "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", "version" : 0 }, @@ -3124,24 +3033,24 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297068", - "name" : "Recommendation PA166297068", - "alternateDrugAvailable" : true, + "id" : "PA166297005", + "name" : "Recommendation PA166297005", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -3149,26 +3058,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059670, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452059607, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297100", - "name" : "Recommendation PA166297100", + "id" : "PA166296995", + "name" : "Recommendation PA166296995", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -3181,10 +3090,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -3192,26 +3101,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059702, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452059597, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297095", - "name" : "Recommendation PA166297095", + "id" : "PA166297002", + "name" : "Recommendation PA166297002", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -3224,10 +3133,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -3235,26 +3144,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059697, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452059604, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297148", - "name" : "Recommendation PA166297148", + "id" : "PA166297006", + "name" : "Recommendation PA166297006", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -3270,7 +3179,7 @@ "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -3278,27 +3187,27 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059750, + "id" : 1452059608, "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297192", - "name" : "Recommendation PA166297192", - "alternateDrugAvailable" : true, + "id" : "PA166297014", + "name" : "Recommendation PA166297014", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, "parents" : [], @@ -3308,12 +3217,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -3321,42 +3230,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059794, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452059616, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297003", - "name" : "Recommendation PA166297003", - "alternateDrugAvailable" : true, + "id" : "PA166296990", + "name" : "Recommendation PA166296990", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -3364,42 +3273,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059605, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059592, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297082", - "name" : "Recommendation PA166297082", - "alternateDrugAvailable" : true, + "id" : "PA166297013", + "name" : "Recommendation PA166297013", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -3407,42 +3316,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059684, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059615, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297135", - "name" : "Recommendation PA166297135", - "alternateDrugAvailable" : true, + "id" : "PA166296989", + "name" : "Recommendation PA166296989", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -3450,27 +3359,27 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059737, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059591, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297038", - "name" : "Recommendation PA166297038", - "alternateDrugAvailable" : true, + "id" : "PA166297007", + "name" : "Recommendation PA166297007", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, "parents" : [], @@ -3482,10 +3391,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -3493,42 +3402,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059640, - "html" : "

Avoid amitriptyline use. If amitripyline is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452059609, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

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Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452059610, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297025", - "name" : "Recommendation PA166297025", - "alternateDrugAvailable" : true, + "id" : "PA166297010", + "name" : "Recommendation PA166297010", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -3579,42 +3488,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059627, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", + "id" : 1452059612, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297157", - "name" : "Recommendation PA166297157", - "alternateDrugAvailable" : true, + "id" : "PA166296986", + "name" : "Recommendation PA166296986", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -3622,42 +3531,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059759, - "html" : "

Avoid amitriptyline use. If amitripyline is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452059588, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297012", - "name" : "Recommendation PA166297012", + "id" : "PA166297009", + "name" : "Recommendation PA166297009", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Normal metabolism of TCAs" + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -3665,42 +3574,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059614, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452059611, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297117", - "name" : "Recommendation PA166297117", - "alternateDrugAvailable" : true, + "id" : "PA166296985", + "name" : "Recommendation PA166296985", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -3708,42 +3617,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059719, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452059587, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297104", - "name" : "Recommendation PA166297104", + "id" : "PA166296987", + "name" : "Recommendation PA166296987", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -3751,42 +3660,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059706, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452059589, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297051", - "name" : "Recommendation PA166297051", - "alternateDrugAvailable" : true, + "id" : "PA166297011", + "name" : "Recommendation PA166297011", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -3794,42 +3703,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059653, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059613, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297099", - "name" : "Recommendation PA166297099", - "alternateDrugAvailable" : true, + "id" : "PA166296988", + "name" : "Recommendation PA166296988", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -3837,42 +3746,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059701, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452059590, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297007", - "name" : "Recommendation PA166297007", + "id" : "PA166297015", + "name" : "Recommendation PA166297015", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -3880,42 +3789,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059609, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452059617, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297086", - "name" : "Recommendation PA166297086", - "alternateDrugAvailable" : true, + "id" : "PA166296991", + "name" : "Recommendation PA166296991", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -3923,27 +3832,27 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059688, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452059593, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297183", - "name" : "Recommendation PA166297183", - "alternateDrugAvailable" : true, + "id" : "PA166297012", + "name" : "Recommendation PA166297012", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, "parents" : [], @@ -3953,12 +3862,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -3966,42 +3875,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059785, - "html" : "

Avoid tricyclic use due to potential for side effects. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452059614, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297139", - "name" : "Recommendation PA166297139", + "id" : "PA166297017", + "name" : "Recommendation PA166297017", "alternateDrugAvailable" : true, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -4009,27 +3918,27 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059741, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059619, + "html" : "

Avoid amitriptyline use. If a amitripyline is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166296991", - "name" : "Recommendation PA166296991", - "alternateDrugAvailable" : false, + "id" : "PA166297018", + "name" : "Recommendation PA166297018", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, "parents" : [], @@ -4039,12 +3948,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -4052,42 +3961,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059593, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452059620, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297126", - "name" : "Recommendation PA166297126", - "alternateDrugAvailable" : false, + "id" : "PA166297019", + "name" : "Recommendation PA166297019", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -4095,42 +4004,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059728, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059621, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297073", - "name" : "Recommendation PA166297073", + "id" : "PA166297021", + "name" : "Recommendation PA166297021", "alternateDrugAvailable" : true, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Normal metabolism of tertiary amines", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -4138,42 +4047,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059675, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452059623, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297170", - "name" : "Recommendation PA166297170", + "id" : "PA166297022", + "name" : "Recommendation PA166297022", "alternateDrugAvailable" : true, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Normal metabolism of tertiary amines", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -4181,42 +4090,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059772, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059624, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297029", - "name" : "Recommendation PA166297029", + "id" : "PA166297023", + "name" : "Recommendation PA166297023", "alternateDrugAvailable" : true, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -4224,42 +4133,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059631, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059625, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297060", - "name" : "Recommendation PA166297060", + "id" : "PA166297024", + "name" : "Recommendation PA166297024", "alternateDrugAvailable" : true, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -4267,26 +4176,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059662, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452059626, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297113", - "name" : "Recommendation PA166297113", + "id" : "PA166297025", + "name" : "Recommendation PA166297025", "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, @@ -4299,10 +4208,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -4310,42 +4219,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059715, - "html" : "

Avoid tricyclic use due to potential for side effects. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452059627, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297016", - "name" : "Recommendation PA166297016", + "id" : "PA166297029", + "name" : "Recommendation PA166297029", "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -4353,42 +4262,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059618, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", + "id" : 1452059631, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297109", - "name" : "Recommendation PA166297109", - "alternateDrugAvailable" : false, + "id" : "PA166297030", + "name" : "Recommendation PA166297030", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -4396,42 +4305,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059711, - "html" : "

No recommendation

\n", + "id" : 1452059632, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297188", - "name" : "Recommendation PA166297188", + "id" : "PA166297031", + "name" : "Recommendation PA166297031", "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -4439,26 +4348,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059790, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452059633, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297043", - "name" : "Recommendation PA166297043", + "id" : "PA166297032", + "name" : "Recommendation PA166297032", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -4472,9 +4381,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -4482,42 +4391,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059645, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059634, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297140", - "name" : "Recommendation PA166297140", + "id" : "PA166297033", + "name" : "Recommendation PA166297033", "alternateDrugAvailable" : true, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -4525,27 +4434,27 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059742, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059635, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297175", - "name" : "Recommendation PA166297175", - "alternateDrugAvailable" : false, + "id" : "PA166297034", + "name" : "Recommendation PA166297034", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501931, "parents" : [], @@ -4557,10 +4466,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -4568,42 +4477,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059777, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452059636, + "html" : "

Avoid amitriptyline use. If amitripyline is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297030", - "name" : "Recommendation PA166297030", + "id" : "PA166297035", + "name" : "Recommendation PA166297035", "alternateDrugAvailable" : true, "classification" : { - "id" : 981565059, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -4611,42 +4520,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059632, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059637, + "html" : "

Avoid amitriptyline use. If amitripyline is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166296995", - "name" : "Recommendation PA166296995", + "id" : "PA166297036", + "name" : "Recommendation PA166297036", "alternateDrugAvailable" : true, "classification" : { - "id" : 981565059, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -4654,42 +4563,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059597, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059638, + "html" : "

Avoid amitriptyline use. If amitripyline is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297065", - "name" : "Recommendation PA166297065", + "id" : "PA166297037", + "name" : "Recommendation PA166297037", "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -4697,42 +4606,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059667, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452059639, + "html" : "

Avoid amitriptyline use. If amitripyline is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297118", - "name" : "Recommendation PA166297118", + "id" : "PA166297038", + "name" : "Recommendation PA166297038", "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -4740,72 +4649,85 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059720, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452059640, + "html" : "

Avoid amitriptyline use. If amitripyline is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301337", - "name" : "Recommendation Annotation PA166301337", - "alternateDrugAvailable" : false, - "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "No Result"}, + "id" : "PA166297039", + "name" : "Recommendation PA166297039", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981565059, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + ], + "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, + "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452095656, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "id" : 1452059641, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297052", - "name" : "Recommendation PA166297052", + "id" : "PA166297041", + "name" : "Recommendation PA166297041", "alternateDrugAvailable" : true, "classification" : { - "id" : 981501931, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: n/a" + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -4813,42 +4735,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059654, - "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. For tertiary amines, consider a 50% reduction of the recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452059643, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297105", - "name" : "Recommendation PA166297105", - "alternateDrugAvailable" : false, + "id" : "PA166297042", + "name" : "Recommendation PA166297042", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501931, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -4856,27 +4778,27 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059707, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452059644, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166296986", - "name" : "Recommendation PA166296986", - "alternateDrugAvailable" : false, + "id" : "PA166297044", + "name" : "Recommendation PA166297044", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -4888,10 +4810,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -4899,42 +4821,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059588, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059646, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297091", - "name" : "Recommendation PA166297091", - "alternateDrugAvailable" : false, + "id" : "PA166297045", + "name" : "Recommendation PA166297045", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -4942,26 +4864,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059693, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452059647, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297144", - "name" : "Recommendation PA166297144", + "id" : "PA166297046", + "name" : "Recommendation PA166297046", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -4974,10 +4896,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -4985,18 +4907,18 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059746, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059648, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 @@ -5028,14 +4950,14 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { "id" : 1452059649, @@ -5046,8 +4968,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166296999", - "name" : "Recommendation PA166296999", + "id" : "PA166297048", + "name" : "Recommendation PA166297048", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -5060,10 +4982,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -5071,42 +4993,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059601, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059650, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297131", - "name" : "Recommendation PA166297131", - "alternateDrugAvailable" : false, + "id" : "PA166297050", + "name" : "Recommendation PA166297050", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -5114,42 +5036,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059733, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452059652, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297179", - "name" : "Recommendation PA166297179", - "alternateDrugAvailable" : false, + "id" : "PA166297051", + "name" : "Recommendation PA166297051", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -5157,26 +5079,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059781, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452059653, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297034", - "name" : "Recommendation PA166297034", + "id" : "PA166297052", + "name" : "Recommendation PA166297052", "alternateDrugAvailable" : true, "classification" : { "id" : 981501931, @@ -5190,9 +5112,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -5200,42 +5122,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059636, - "html" : "

Avoid amitriptyline use. If amitripyline is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452059654, + "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. For tertiary amines, consider a 50% reduction of the recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297166", - "name" : "Recommendation PA166297166", + "id" : "PA166297053", + "name" : "Recommendation PA166297053", "alternateDrugAvailable" : true, "classification" : { - "id" : 981565059, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -5243,42 +5165,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059768, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059655, + "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. For tertiary amines, consider a 50% reduction of the recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297021", - "name" : "Recommendation PA166297021", + "id" : "PA166297054", + "name" : "Recommendation PA166297054", "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -5286,26 +5208,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059623, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", + "id" : 1452059656, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297069", - "name" : "Recommendation PA166297069", + "id" : "PA166297055", + "name" : "Recommendation PA166297055", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -5319,9 +5241,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -5329,72 +5251,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166105006", - "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 - }, - "text" : { - "id" : 1452059671, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166301333", - "name" : "Recommendation Annotation PA166301333", - "alternateDrugAvailable" : false, - "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Indeterminate"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA448385", - "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452095652, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "id" : 1452059657, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297153", - "name" : "Recommendation PA166297153", + "id" : "PA166297056", + "name" : "Recommendation PA166297056", "alternateDrugAvailable" : true, "classification" : { - "id" : 981501931, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -5402,26 +5294,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059755, - "html" : "

Avoid amitriptyline use. If amitripyline is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452059658, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297056", - "name" : "Recommendation PA166297056", + "id" : "PA166297057", + "name" : "Recommendation PA166297057", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -5437,7 +5329,7 @@ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -5445,17 +5337,17 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059658, + "id" : 1452059659, "html" : "

Consider alternative drug not metabolized by CYP2C19; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, @@ -5463,24 +5355,24 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297136", - "name" : "Recommendation PA166297136", + "id" : "PA166297058", + "name" : "Recommendation PA166297058", "alternateDrugAvailable" : true, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -5488,26 +5380,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059738, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059660, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297083", - "name" : "Recommendation PA166297083", + "id" : "PA166297059", + "name" : "Recommendation PA166297059", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -5521,9 +5413,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -5531,42 +5423,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059685, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059661, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297180", - "name" : "Recommendation PA166297180", - "alternateDrugAvailable" : false, + "id" : "PA166297060", + "name" : "Recommendation PA166297060", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -5574,26 +5466,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059782, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452059662, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297039", - "name" : "Recommendation PA166297039", + "id" : "PA166297061", + "name" : "Recommendation PA166297061", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -5606,10 +5498,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -5617,26 +5509,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059641, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059663, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297070", - "name" : "Recommendation PA166297070", + "id" : "PA166297062", + "name" : "Recommendation PA166297062", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -5650,9 +5542,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -5660,42 +5552,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059672, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452059664, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297123", - "name" : "Recommendation PA166297123", - "alternateDrugAvailable" : false, + "id" : "PA166297063", + "name" : "Recommendation PA166297063", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: n/a" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -5703,42 +5595,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059725, - "html" : "

No recommendation

\n", + "id" : 1452059665, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297026", - "name" : "Recommendation PA166297026", + "id" : "PA166297064", + "name" : "Recommendation PA166297064", "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -5746,42 +5638,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059628, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", + "id" : 1452059666, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297110", - "name" : "Recommendation PA166297110", - "alternateDrugAvailable" : false, + "id" : "PA166297066", + "name" : "Recommendation PA166297066", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -5789,42 +5681,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059712, - "html" : "

No recommendation

\n", + "id" : 1452059668, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297158", - "name" : "Recommendation PA166297158", + "id" : "PA166297067", + "name" : "Recommendation PA166297067", "alternateDrugAvailable" : true, "classification" : { - "id" : 981501931, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -5832,42 +5724,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059760, - "html" : "

Avoid amitriptyline use. If amitripyline is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452059669, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297013", - "name" : "Recommendation PA166297013", - "alternateDrugAvailable" : false, + "id" : "PA166297069", + "name" : "Recommendation PA166297069", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -5875,56 +5767,69 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059615, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452059671, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301341", - "name" : "Recommendation Annotation PA166301341", - "alternateDrugAvailable" : false, - "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Rapid Metabolizer"}, + "id" : "PA166297070", + "name" : "Recommendation PA166297070", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981565059, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + ], + "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, + "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452095660, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "id" : 1452059672, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297092", - "name" : "Recommendation PA166297092", + "id" : "PA166297071", + "name" : "Recommendation PA166297071", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -5940,7 +5845,7 @@ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -5948,17 +5853,17 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059694, + "id" : 1452059673, "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, @@ -5966,8 +5871,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297145", - "name" : "Recommendation PA166297145", + "id" : "PA166297072", + "name" : "Recommendation PA166297072", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -5980,10 +5885,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -5991,26 +5896,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059747, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059674, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297000", - "name" : "Recommendation PA166297000", + "id" : "PA166297073", + "name" : "Recommendation PA166297073", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -6023,10 +5928,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -6034,26 +5939,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059602, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059675, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297048", - "name" : "Recommendation PA166297048", + "id" : "PA166297075", + "name" : "Recommendation PA166297075", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -6066,10 +5971,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -6077,42 +5982,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059650, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059677, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297008", - "name" : "Recommendation PA166297008", - "alternateDrugAvailable" : false, + "id" : "PA166297076", + "name" : "Recommendation PA166297076", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501931, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -6120,26 +6025,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059610, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452059678, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297087", - "name" : "Recommendation PA166297087", + "id" : "PA166297077", + "name" : "Recommendation PA166297077", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -6153,9 +6058,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -6163,26 +6068,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059689, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452059679, + "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. If a tertiary amine is warranted, utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297184", - "name" : "Recommendation PA166297184", + "id" : "PA166297020", + "name" : "Recommendation PA166297020", "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, @@ -6195,10 +6100,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Normal metabolism of tertiary amines", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -6206,27 +6111,27 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059786, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452059622, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166296990", - "name" : "Recommendation PA166296990", - "alternateDrugAvailable" : false, + "id" : "PA166297026", + "name" : "Recommendation PA166297026", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, "parents" : [], @@ -6236,12 +6141,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -6249,26 +6154,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059592, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452059628, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297074", - "name" : "Recommendation PA166297074", + "id" : "PA166297043", + "name" : "Recommendation PA166297043", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -6281,10 +6186,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -6292,42 +6197,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059676, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452059645, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297127", - "name" : "Recommendation PA166297127", - "alternateDrugAvailable" : false, + "id" : "PA166297065", + "name" : "Recommendation PA166297065", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: n/a", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -6335,26 +6240,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059729, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059667, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297171", - "name" : "Recommendation PA166297171", + "id" : "PA166297068", + "name" : "Recommendation PA166297068", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -6367,10 +6272,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -6378,26 +6283,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059773, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059670, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297061", - "name" : "Recommendation PA166297061", + "id" : "PA166297074", + "name" : "Recommendation PA166297074", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -6411,9 +6316,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -6421,42 +6326,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059663, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452059676, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297017", - "name" : "Recommendation PA166297017", - "alternateDrugAvailable" : true, + "id" : "PA166297027", + "name" : "Recommendation PA166297027", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -6464,42 +6369,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059619, - "html" : "

Avoid amitriptyline use. If a amitripyline is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452059629, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297101", - "name" : "Recommendation PA166297101", - "alternateDrugAvailable" : true, + "id" : "PA166297028", + "name" : "Recommendation PA166297028", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -6507,26 +6412,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059703, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452059630, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297096", - "name" : "Recommendation PA166297096", + "id" : "PA166297079", + "name" : "Recommendation PA166297079", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -6540,9 +6445,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -6550,26 +6455,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059698, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452059681, + "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. If a tertiary amine is warranted, utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297149", - "name" : "Recommendation PA166297149", + "id" : "PA166297080", + "name" : "Recommendation PA166297080", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -6582,10 +6487,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -6593,26 +6498,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059751, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059682, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297004", - "name" : "Recommendation PA166297004", + "id" : "PA166297081", + "name" : "Recommendation PA166297081", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -6625,10 +6530,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -6636,42 +6541,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059606, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059683, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297193", - "name" : "Recommendation PA166297193", + "id" : "PA166297082", + "name" : "Recommendation PA166297082", "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -6679,42 +6584,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059795, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452059684, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297176", - "name" : "Recommendation PA166297176", - "alternateDrugAvailable" : false, + "id" : "PA166297083", + "name" : "Recommendation PA166297083", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501931, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -6722,26 +6627,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059778, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452059685, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297031", - "name" : "Recommendation PA166297031", + "id" : "PA166297084", + "name" : "Recommendation PA166297084", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -6754,10 +6659,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -6765,26 +6670,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059633, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059686, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297079", - "name" : "Recommendation PA166297079", + "id" : "PA166297085", + "name" : "Recommendation PA166297085", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -6798,9 +6703,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: n/a" + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -6808,26 +6713,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059681, - "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. If a tertiary amine is warranted, utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452059687, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166296994", - "name" : "Recommendation PA166296994", + "id" : "PA166297086", + "name" : "Recommendation PA166297086", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -6840,10 +6745,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -6851,26 +6756,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059596, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059688, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297066", - "name" : "Recommendation PA166297066", + "id" : "PA166297087", + "name" : "Recommendation PA166297087", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -6884,9 +6789,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -6894,26 +6799,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059668, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452059689, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297163", - "name" : "Recommendation PA166297163", + "id" : "PA166297088", + "name" : "Recommendation PA166297088", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -6926,10 +6831,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -6937,42 +6842,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059765, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059690, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297119", - "name" : "Recommendation PA166297119", + "id" : "PA166297089", + "name" : "Recommendation PA166297089", "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -6980,42 +6885,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059721, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452059691, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297053", - "name" : "Recommendation PA166297053", + "id" : "PA166297090", + "name" : "Recommendation PA166297090", "alternateDrugAvailable" : true, "classification" : { - "id" : 981501931, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: n/a" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -7023,26 +6928,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059655, - "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. For tertiary amines, consider a 50% reduction of the recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452059692, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297150", - "name" : "Recommendation PA166297150", + "id" : "PA166297092", + "name" : "Recommendation PA166297092", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -7055,10 +6960,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -7066,42 +6971,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059752, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059694, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297009", - "name" : "Recommendation PA166297009", - "alternateDrugAvailable" : false, + "id" : "PA166297094", + "name" : "Recommendation PA166297094", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501931, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -7109,27 +7014,27 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059611, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452059696, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166296985", - "name" : "Recommendation PA166296985", - "alternateDrugAvailable" : false, + "id" : "PA166297095", + "name" : "Recommendation PA166297095", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -7141,10 +7046,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -7152,42 +7057,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059587, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059697, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297106", - "name" : "Recommendation PA166297106", - "alternateDrugAvailable" : false, + "id" : "PA166297096", + "name" : "Recommendation PA166297096", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501931, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -7195,26 +7100,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059708, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452059698, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297088", - "name" : "Recommendation PA166297088", + "id" : "PA166297097", + "name" : "Recommendation PA166297097", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -7228,9 +7133,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -7238,42 +7143,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059690, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452059699, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297185", - "name" : "Recommendation PA166297185", + "id" : "PA166297098", + "name" : "Recommendation PA166297098", "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -7281,26 +7186,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059787, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452059700, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166296998", - "name" : "Recommendation PA166296998", + "id" : "PA166297100", + "name" : "Recommendation PA166297100", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -7313,10 +7218,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -7324,72 +7229,85 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059600, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059702, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301336", - "name" : "Recommendation Annotation PA166301336", - "alternateDrugAvailable" : false, - "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Likely Poor Metabolizer"}, + "id" : "PA166297101", + "name" : "Recommendation PA166297101", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981565059, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + ], + "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, + "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452095655, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "id" : 1452059703, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297132", - "name" : "Recommendation PA166297132", - "alternateDrugAvailable" : false, + "id" : "PA166297102", + "name" : "Recommendation PA166297102", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -7397,42 +7315,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059734, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452059704, + "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. If a tertiary amine is warranted, utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297035", - "name" : "Recommendation PA166297035", + "id" : "PA166297103", + "name" : "Recommendation PA166297103", "alternateDrugAvailable" : true, "classification" : { - "id" : 981501931, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -7440,42 +7358,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059637, - "html" : "

Avoid amitriptyline use. If amitripyline is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452059705, + "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. If a tertiary amine is warranted, utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297167", - "name" : "Recommendation PA166297167", + "id" : "PA166297113", + "name" : "Recommendation PA166297113", "alternateDrugAvailable" : true, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: n/a", + "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -7483,26 +7401,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059769, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059715, + "html" : "

Avoid tricyclic use due to potential for side effects. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297022", - "name" : "Recommendation PA166297022", + "id" : "PA166297115", + "name" : "Recommendation PA166297115", "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, @@ -7515,10 +7433,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", + "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -7526,42 +7444,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059624, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", + "id" : 1452059717, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297154", - "name" : "Recommendation PA166297154", + "id" : "PA166297116", + "name" : "Recommendation PA166297116", "alternateDrugAvailable" : true, "classification" : { - "id" : 981501931, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: n/a", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -7569,42 +7487,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059756, - "html" : "

Avoid amitriptyline use. If amitripyline is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452059718, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297057", - "name" : "Recommendation PA166297057", + "id" : "PA166297117", + "name" : "Recommendation PA166297117", "alternateDrugAvailable" : true, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: n/a", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -7612,27 +7530,27 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059659, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059719, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166296989", - "name" : "Recommendation PA166296989", - "alternateDrugAvailable" : false, + "id" : "PA166297118", + "name" : "Recommendation PA166297118", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, "parents" : [], @@ -7642,12 +7560,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: n/a", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -7655,26 +7573,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059591, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452059720, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297189", - "name" : "Recommendation PA166297189", + "id" : "PA166297119", + "name" : "Recommendation PA166297119", "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, @@ -7690,7 +7608,7 @@ "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -7698,17 +7616,17 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059791, + "id" : 1452059721, "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, @@ -7716,24 +7634,24 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297044", - "name" : "Recommendation PA166297044", + "id" : "PA166297121", + "name" : "Recommendation PA166297121", "alternateDrugAvailable" : true, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -7741,42 +7659,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059646, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059723, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297071", - "name" : "Recommendation PA166297071", + "id" : "PA166297122", + "name" : "Recommendation PA166297122", "alternateDrugAvailable" : true, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -7784,42 +7702,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059673, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452059724, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297124", - "name" : "Recommendation PA166297124", - "alternateDrugAvailable" : false, + "id" : "PA166297134", + "name" : "Recommendation PA166297134", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: n/a" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -7827,42 +7745,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059726, - "html" : "

No recommendation

\n", + "id" : 1452059736, + "html" : "

Avoid amitriptyline use. If a amitripyline is warranted, consider a 50% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297027", - "name" : "Recommendation PA166297027", - "alternateDrugAvailable" : false, + "id" : "PA166297135", + "name" : "Recommendation PA166297135", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: n/a" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -7870,42 +7788,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059629, - "html" : "

No recommendation

\n", + "id" : 1452059737, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297111", - "name" : "Recommendation PA166297111", - "alternateDrugAvailable" : false, + "id" : "PA166297136", + "name" : "Recommendation PA166297136", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -7913,26 +7831,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059713, - "html" : "

No recommendation

\n", + "id" : 1452059738, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297159", - "name" : "Recommendation PA166297159", + "id" : "PA166297138", + "name" : "Recommendation PA166297138", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -7945,10 +7863,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -7956,42 +7874,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059761, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059740, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297014", - "name" : "Recommendation PA166297014", - "alternateDrugAvailable" : false, + "id" : "PA166297139", + "name" : "Recommendation PA166297139", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -7999,18 +7917,18 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059616, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452059741, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 @@ -8042,26 +7960,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { "id" : 1452059695, "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297146", - "name" : "Recommendation PA166297146", + "id" : "PA166297099", + "name" : "Recommendation PA166297099", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -8074,10 +7992,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -8085,42 +8003,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059748, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059701, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297001", - "name" : "Recommendation PA166297001", + "id" : "PA166297120", + "name" : "Recommendation PA166297120", "alternateDrugAvailable" : true, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -8128,42 +8046,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059603, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059722, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297190", - "name" : "Recommendation PA166297190", + "id" : "PA166297137", + "name" : "Recommendation PA166297137", "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -8171,42 +8089,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059792, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452059739, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297049", - "name" : "Recommendation PA166297049", - "alternateDrugAvailable" : true, + "id" : "PA166297123", + "name" : "Recommendation PA166297123", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: n/a", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -8214,42 +8132,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059651, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059725, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297080", - "name" : "Recommendation PA166297080", - "alternateDrugAvailable" : true, + "id" : "PA166297124", + "name" : "Recommendation PA166297124", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: n/a", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -8257,42 +8175,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059682, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059726, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297036", - "name" : "Recommendation PA166297036", - "alternateDrugAvailable" : true, + "id" : "PA166297091", + "name" : "Recommendation PA166297091", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -8300,72 +8218,85 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059638, - "html" : "

Avoid amitriptyline use. If amitripyline is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452059693, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301340", - "name" : "Recommendation Annotation PA166301340", + "id" : "PA166297111", + "name" : "Recommendation PA166297111", "alternateDrugAvailable" : false, + "classification" : { + "id" : 1448526251, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", + "valid" : true, + "version" : 0 + }, "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Ultrarapid Metabolizer"}, + "implications" : [ + "CYP2C19: n/a", + "CYP2D6: Normal metabolism of TCAs" + ], + "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, + "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452095659, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "id" : 1452059713, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297075", - "name" : "Recommendation PA166297075", - "alternateDrugAvailable" : true, + "id" : "PA166297132", + "name" : "Recommendation PA166297132", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -8373,27 +8304,27 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059677, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452059734, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297172", - "name" : "Recommendation PA166297172", - "alternateDrugAvailable" : true, + "id" : "PA166297104", + "name" : "Recommendation PA166297104", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, "parents" : [], @@ -8405,10 +8336,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: n/a" + "CYP2C19: n/a", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -8416,26 +8347,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059774, - "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. For tertiary amines, consider a 50% reduction of the recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452059706, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297128", - "name" : "Recommendation PA166297128", + "id" : "PA166297126", + "name" : "Recommendation PA166297126", "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, @@ -8451,7 +8382,7 @@ "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -8459,42 +8390,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059730, + "id" : 1452059728, "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297115", - "name" : "Recommendation PA166297115", - "alternateDrugAvailable" : true, + "id" : "PA166297105", + "name" : "Recommendation PA166297105", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -8502,27 +8433,27 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059717, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452059707, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297062", - "name" : "Recommendation PA166297062", - "alternateDrugAvailable" : true, + "id" : "PA166297129", + "name" : "Recommendation PA166297129", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -8534,10 +8465,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -8545,42 +8476,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059664, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452059731, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297018", - "name" : "Recommendation PA166297018", - "alternateDrugAvailable" : true, + "id" : "PA166297107", + "name" : "Recommendation PA166297107", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: n/a", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -8588,27 +8519,27 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059620, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", + "id" : 1452059709, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297097", - "name" : "Recommendation PA166297097", - "alternateDrugAvailable" : true, + "id" : "PA166297128", + "name" : "Recommendation PA166297128", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -8620,10 +8551,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -8631,42 +8562,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059699, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452059730, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297102", - "name" : "Recommendation PA166297102", - "alternateDrugAvailable" : true, + "id" : "PA166297106", + "name" : "Recommendation PA166297106", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: n/a" + "CYP2C19: n/a", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -8674,26 +8605,69 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059704, - "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. If a tertiary amine is warranted, utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452059708, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297005", - "name" : "Recommendation PA166297005", + "id" : "PA166297130", + "name" : "Recommendation PA166297130", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501930, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : false, + "implications" : [ + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Normal metabolism of TCAs" + ], + "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Likely Intermediate Metabolizer"}, + "otherPrescribingGuidance" : false, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA448385", + "name" : "amitriptyline", + "version" : 36 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166105006", + "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", + "version" : 939 + }, + "text" : { + "id" : 1452059732, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "version" : 0 + }, + "version" : 1 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166297108", + "name" : "Recommendation PA166297108", "alternateDrugAvailable" : false, "classification" : { "id" : 1448526251, @@ -8706,10 +8680,10 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: n/a" + "CYP2C19: n/a", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -8717,42 +8691,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059607, + "id" : 1452059710, "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297194", - "name" : "Recommendation PA166297194", - "alternateDrugAvailable" : true, + "id" : "PA166297109", + "name" : "Recommendation PA166297109", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -8760,42 +8734,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059796, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452059711, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297084", - "name" : "Recommendation PA166297084", - "alternateDrugAvailable" : true, + "id" : "PA166297131", + "name" : "Recommendation PA166297131", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -8803,42 +8777,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059686, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452059733, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297137", - "name" : "Recommendation PA166297137", - "alternateDrugAvailable" : true, + "id" : "PA166297110", + "name" : "Recommendation PA166297110", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: n/a", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -8846,26 +8820,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059739, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059712, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297181", - "name" : "Recommendation PA166297181", + "id" : "PA166297125", + "name" : "Recommendation PA166297125", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -8878,10 +8852,10 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -8889,42 +8863,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059783, + "id" : 1452059727, "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297164", - "name" : "Recommendation PA166297164", - "alternateDrugAvailable" : true, + "id" : "PA166297112", + "name" : "Recommendation PA166297112", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: n/a", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -8932,26 +8906,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059766, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059714, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166296993", - "name" : "Recommendation PA166296993", + "id" : "PA166297140", + "name" : "Recommendation PA166297140", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -8967,7 +8941,7 @@ "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -8975,17 +8949,17 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059595, + "id" : 1452059742, "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, @@ -8993,8 +8967,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297067", - "name" : "Recommendation PA166297067", + "id" : "PA166297142", + "name" : "Recommendation PA166297142", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -9007,10 +8981,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -9018,56 +8992,69 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059669, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452059744, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301339", - "name" : "Recommendation Annotation PA166301339", - "alternateDrugAvailable" : false, - "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Poor Metabolizer"}, + "id" : "PA166297143", + "name" : "Recommendation PA166297143", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981565059, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + ], + "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, + "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452095658, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "id" : 1452059745, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297054", - "name" : "Recommendation PA166297054", + "id" : "PA166297145", + "name" : "Recommendation PA166297145", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -9080,10 +9067,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -9091,26 +9078,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059656, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059747, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297151", - "name" : "Recommendation PA166297151", + "id" : "PA166297146", + "name" : "Recommendation PA166297146", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -9123,10 +9110,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -9134,42 +9121,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059753, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059748, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297107", - "name" : "Recommendation PA166297107", - "alternateDrugAvailable" : false, + "id" : "PA166297149", + "name" : "Recommendation PA166297149", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501931, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -9177,42 +9164,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059709, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452059751, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297186", - "name" : "Recommendation PA166297186", + "id" : "PA166297150", + "name" : "Recommendation PA166297150", "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -9220,26 +9207,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059788, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452059752, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297041", - "name" : "Recommendation PA166297041", + "id" : "PA166297151", + "name" : "Recommendation PA166297151", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -9253,9 +9240,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -9263,26 +9250,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059643, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059753, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297089", - "name" : "Recommendation PA166297089", + "id" : "PA166297152", + "name" : "Recommendation PA166297152", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -9295,10 +9282,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -9306,42 +9293,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059691, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059754, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166296997", - "name" : "Recommendation PA166296997", + "id" : "PA166297153", + "name" : "Recommendation PA166297153", "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -9349,42 +9336,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059599, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", + "id" : 1452059755, + "html" : "

Avoid amitriptyline use. If amitripyline is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166296984", - "name" : "Recommendation PA166296984", - "alternateDrugAvailable" : false, + "id" : "PA166297154", + "name" : "Recommendation PA166297154", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981565059, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -9392,42 +9379,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059586, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059756, + "html" : "

Avoid amitriptyline use. If amitripyline is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297076", - "name" : "Recommendation PA166297076", + "id" : "PA166297156", + "name" : "Recommendation PA166297156", "alternateDrugAvailable" : true, "classification" : { - "id" : 981565059, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -9435,26 +9422,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059678, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452059758, + "html" : "

Avoid amitriptyline use. If amitripyline is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297173", - "name" : "Recommendation PA166297173", + "id" : "PA166297157", + "name" : "Recommendation PA166297157", "alternateDrugAvailable" : true, "classification" : { "id" : 981501931, @@ -9468,9 +9455,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: n/a" + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -9478,42 +9465,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059775, - "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. For tertiary amines, consider a 50% reduction of the recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452059759, + "html" : "

Avoid amitriptyline use. If amitripyline is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297120", - "name" : "Recommendation PA166297120", + "id" : "PA166297158", + "name" : "Recommendation PA166297158", "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -9521,26 +9508,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059722, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452059760, + "html" : "

Avoid amitriptyline use. If amitripyline is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297168", - "name" : "Recommendation PA166297168", + "id" : "PA166297159", + "name" : "Recommendation PA166297159", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -9554,9 +9541,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -9564,17 +9551,17 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059770, + "id" : 1452059761, "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, @@ -9582,24 +9569,24 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297023", - "name" : "Recommendation PA166297023", + "id" : "PA166297160", + "name" : "Recommendation PA166297160", "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -9607,72 +9594,85 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059625, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", + "id" : 1452059762, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301335", - "name" : "Recommendation Annotation PA166301335", - "alternateDrugAvailable" : false, - "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Likely Intermediate Metabolizer"}, + "id" : "PA166297161", + "name" : "Recommendation PA166297161", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981565059, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + ], + "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, + "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452095654, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "id" : 1452059763, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297010", - "name" : "Recommendation PA166297010", - "alternateDrugAvailable" : false, + "id" : "PA166297164", + "name" : "Recommendation PA166297164", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501931, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -9680,42 +9680,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059612, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452059766, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297058", - "name" : "Recommendation PA166297058", + "id" : "PA166297165", + "name" : "Recommendation PA166297165", "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -9723,42 +9723,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059660, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452059767, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166296988", - "name" : "Recommendation PA166296988", - "alternateDrugAvailable" : false, + "id" : "PA166297166", + "name" : "Recommendation PA166297166", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -9766,26 +9766,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059590, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452059768, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297142", - "name" : "Recommendation PA166297142", + "id" : "PA166297167", + "name" : "Recommendation PA166297167", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -9798,10 +9798,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -9809,26 +9809,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059744, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059769, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297045", - "name" : "Recommendation PA166297045", + "id" : "PA166297168", + "name" : "Recommendation PA166297168", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -9844,7 +9844,7 @@ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -9852,17 +9852,17 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059647, + "id" : 1452059770, "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, @@ -9870,24 +9870,24 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297177", - "name" : "Recommendation PA166297177", - "alternateDrugAvailable" : false, + "id" : "PA166297170", + "name" : "Recommendation PA166297170", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501931, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -9895,26 +9895,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059779, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452059772, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297032", - "name" : "Recommendation PA166297032", + "id" : "PA166297171", + "name" : "Recommendation PA166297171", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -9928,9 +9928,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -9938,42 +9938,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059634, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059773, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297112", - "name" : "Recommendation PA166297112", - "alternateDrugAvailable" : false, + "id" : "PA166297172", + "name" : "Recommendation PA166297172", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -9981,42 +9981,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059714, - "html" : "

No recommendation

\n", + "id" : 1452059774, + "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. For tertiary amines, consider a 50% reduction of the recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297015", - "name" : "Recommendation PA166297015", - "alternateDrugAvailable" : false, + "id" : "PA166297173", + "name" : "Recommendation PA166297173", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -10024,42 +10024,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059617, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452059775, + "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. For tertiary amines, consider a 50% reduction of the recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297147", - "name" : "Recommendation PA166297147", - "alternateDrugAvailable" : false, + "id" : "PA166297183", + "name" : "Recommendation PA166297183", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: n/a" + "CYP2C19: n/a", + "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -10067,42 +10067,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059749, - "html" : "

No recommendation

\n", + "id" : 1452059785, + "html" : "

Avoid tricyclic use due to potential for side effects. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297094", - "name" : "Recommendation PA166297094", + "id" : "PA166297184", + "name" : "Recommendation PA166297184", "alternateDrugAvailable" : true, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -10110,26 +10110,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059696, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452059786, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297191", - "name" : "Recommendation PA166297191", + "id" : "PA166297185", + "name" : "Recommendation PA166297185", "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, @@ -10145,7 +10145,7 @@ "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -10153,17 +10153,17 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059793, + "id" : 1452059787, "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, @@ -10171,24 +10171,24 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297002", - "name" : "Recommendation PA166297002", + "id" : "PA166297187", + "name" : "Recommendation PA166297187", "alternateDrugAvailable" : true, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -10196,42 +10196,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059604, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059789, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297081", - "name" : "Recommendation PA166297081", + "id" : "PA166297188", + "name" : "Recommendation PA166297188", "alternateDrugAvailable" : true, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: n/a", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -10239,42 +10239,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059683, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059790, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297134", - "name" : "Recommendation PA166297134", + "id" : "PA166297189", + "name" : "Recommendation PA166297189", "alternateDrugAvailable" : true, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: n/a", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -10282,42 +10282,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059736, - "html" : "

Avoid amitriptyline use. If a amitripyline is warranted, consider a 50% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059791, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297037", - "name" : "Recommendation PA166297037", + "id" : "PA166297190", + "name" : "Recommendation PA166297190", "alternateDrugAvailable" : true, "classification" : { - "id" : 981501931, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: n/a", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -10325,26 +10325,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059639, - "html" : "

Avoid amitriptyline use. If amitripyline is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452059792, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297121", - "name" : "Recommendation PA166297121", + "id" : "PA166297191", + "name" : "Recommendation PA166297191", "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, @@ -10360,7 +10360,7 @@ "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -10368,17 +10368,17 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059723, + "id" : 1452059793, "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, @@ -10386,24 +10386,24 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297169", - "name" : "Recommendation PA166297169", + "id" : "PA166297193", + "name" : "Recommendation PA166297193", "alternateDrugAvailable" : true, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -10411,26 +10411,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059771, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059795, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297024", - "name" : "Recommendation PA166297024", + "id" : "PA166297194", + "name" : "Recommendation PA166297194", "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, @@ -10443,10 +10443,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", + "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -10454,27 +10454,27 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059626, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", + "id" : 1452059796, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297129", - "name" : "Recommendation PA166297129", - "alternateDrugAvailable" : false, + "id" : "PA166297144", + "name" : "Recommendation PA166297144", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -10487,9 +10487,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -10497,26 +10497,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059731, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059746, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297063", - "name" : "Recommendation PA166297063", + "id" : "PA166297163", + "name" : "Recommendation PA166297163", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -10529,10 +10529,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -10540,42 +10540,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059665, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452059765, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297116", - "name" : "Recommendation PA166297116", + "id" : "PA166297169", + "name" : "Recommendation PA166297169", "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -10583,42 +10583,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059718, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452059771, + "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297160", - "name" : "Recommendation PA166297160", + "id" : "PA166297186", + "name" : "Recommendation PA166297186", "alternateDrugAvailable" : true, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -10626,26 +10626,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059762, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059788, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297019", - "name" : "Recommendation PA166297019", + "id" : "PA166297192", + "name" : "Recommendation PA166297192", "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, @@ -10658,10 +10658,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", + "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -10669,42 +10669,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059621, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", + "id" : 1452059794, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297103", - "name" : "Recommendation PA166297103", - "alternateDrugAvailable" : true, + "id" : "PA166297195", + "name" : "Recommendation PA166297195", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: n/a", "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -10712,42 +10712,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059705, - "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. If a tertiary amine is warranted, utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452059797, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297050", - "name" : "Recommendation PA166297050", - "alternateDrugAvailable" : true, + "id" : "PA166297147", + "name" : "Recommendation PA166297147", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -10755,42 +10755,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059652, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059749, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297098", - "name" : "Recommendation PA166297098", - "alternateDrugAvailable" : true, + "id" : "PA166297148", + "name" : "Recommendation PA166297148", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -10798,26 +10798,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059700, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452059750, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297006", - "name" : "Recommendation PA166297006", + "id" : "PA166297181", + "name" : "Recommendation PA166297181", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -10830,10 +10830,10 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: n/a" + "CYP2C19: n/a", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -10841,42 +10841,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059608, + "id" : 1452059783, "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297085", - "name" : "Recommendation PA166297085", - "alternateDrugAvailable" : true, + "id" : "PA166297180", + "name" : "Recommendation PA166297180", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: n/a", "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -10884,42 +10884,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059687, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452059782, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297138", - "name" : "Recommendation PA166297138", - "alternateDrugAvailable" : true, + "id" : "PA166297174", + "name" : "Recommendation PA166297174", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: n/a", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -10927,42 +10927,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059740, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059776, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297182", - "name" : "Recommendation PA166297182", + "id" : "PA166297175", + "name" : "Recommendation PA166297175", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ "CYP2C19: n/a", - "CYP2D6: Normal metabolism of TCAs" + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -10970,42 +10970,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059784, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452059777, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166296992", - "name" : "Recommendation PA166296992", - "alternateDrugAvailable" : true, + "id" : "PA166297177", + "name" : "Recommendation PA166297177", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: n/a", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -11013,42 +11013,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059594, - "html" : "

Avoid amitriptyline use. If a amitripyline is warranted, consider a 50% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059779, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297125", - "name" : "Recommendation PA166297125", + "id" : "PA166297176", + "name" : "Recommendation PA166297176", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: n/a", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -11056,42 +11056,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059727, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452059778, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297072", - "name" : "Recommendation PA166297072", - "alternateDrugAvailable" : true, + "id" : "PA166297178", + "name" : "Recommendation PA166297178", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: n/a", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -11099,26 +11099,26 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059674, - "html" : "

Avoid amitriptyline use; If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452059780, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297028", - "name" : "Recommendation PA166297028", + "id" : "PA166297179", + "name" : "Recommendation PA166297179", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -11131,10 +11131,10 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: n/a" + "CYP2C19: n/a", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -11142,42 +11142,42 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059630, + "id" : 1452059781, "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297195", - "name" : "Recommendation PA166297195", + "id" : "PA166297182", + "name" : "Recommendation PA166297182", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ "CYP2C19: n/a", - "CYP2D6: n/a" + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -11185,18 +11185,18 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105006", "name" : "Annotation of CPIC Guideline for amitriptyline and CYP2C19, CYP2D6", - "version" : 58 + "version" : 939 }, "text" : { - "id" : 1452059797, - "html" : "

No recommendation

\n", + "id" : 1452059784, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 1 @@ -11421,49 +11421,49 @@ "id" : "PA166115841", "symbol" : "UGT1A1*1", "name" : "*1", - "version" : 15 + "version" : 32 }, { "objCls" : "Haplotype", "id" : "PA166115842", "symbol" : "UGT1A1*28", "name" : "*28", - "version" : 16 + "version" : 34 }, { "objCls" : "Haplotype", "id" : "PA166115843", "symbol" : "UGT1A1*36", "name" : "*36", - "version" : 15 + "version" : 32 }, { "objCls" : "Haplotype", "id" : "PA166115844", "symbol" : "UGT1A1*37", "name" : "*37", - "version" : 15 + "version" : 32 }, { "objCls" : "Haplotype", "id" : "PA166115858", "symbol" : "UGT1A1*6", "name" : "*6", - "version" : 13 + "version" : 32 }, { "objCls" : "Haplotype", "id" : "PA166115850", "symbol" : "UGT1A1*80", "name" : "*80", - "version" : 13 + "version" : 31 }, { "objCls" : "Haplotype", "id" : "PA166220483", "symbol" : "UGT1A1*80+*28", "name" : "*80+*28", - "version" : 7 + "version" : 21 } ], "relatedChemicals" : [ @@ -11471,7 +11471,7 @@ "objCls" : "Chemical", "id" : "PA10251", "name" : "atazanavir", - "version" : 7 + "version" : 33 } ], "relatedGenes" : [ @@ -11480,14 +11480,14 @@ "id" : "PA420", "symbol" : "UGT1A1", "name" : "UDP glucuronosyltransferase 1 family, polypeptide A1", - "version" : 6110 + "version" : 6350 } ], "source" : "CPIC", "summaryMarkdown" : { "id" : 1447982423, "html" : "

The CPIC dosing guideline recommends considering advising individuals who carry two decreased function UGT1A1 alleles about a substantial likelihood of developing jaundice, which may cause non-adherence. The dosing guideline recommends that alternative agents be considered if the risk of non-adherence due to jaundice is high. The risk of discontinuation is low and very low for individuals carrying one, or no decreased function UGT1A1 alleles, respectively.

\n", - "version" : 0 + "version" : 1 }, "terms" : [], "textMarkdown" : { @@ -11496,7 +11496,7 @@ "version" : 3 }, "userId" : "whaleyr", - "version" : 51 + "version" : 139 }, "recommendations" : [ { @@ -11525,21 +11525,21 @@ "objCls" : "Chemical", "id" : "PA10251", "name" : "atazanavir", - "version" : 7 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166128738", "name" : "Annotation of CPIC Guideline for atazanavir and UGT1A1", - "version" : 51 + "version" : 139 }, "text" : { "id" : 1452059798, "html" : "

There is no need to avoid prescribing of atazanavir based on UGT1A1 genetic test result. Inform the patient that some patients stop atazanavir because of jaundice (yellow eyes and skin), but that this patient’s genotype makes this unlikely (less than about a 1 in 20 chance of stopping atazanavir because of jaundice).

\n

Other Considerations

\n

All studies correlating UGT1A1 genotypes with atazanavir adverse events have involved ritonavir boosting. However, concentration-time profiles are equivalent when boosted with either cobicistat or ritonavir (PMID 23532097), and bilirubin-related adverse events including discontinuation of atazanavir occur in a similar percentage of patients prescribed atazanavir with cobicistat or ritonavir (PMID 23532097). Associations between UGT1A1 genotype, bilirubin elevations, and atazanavir/r discontinuation therefore almost certainly translate to atazanavir/cobicistat. "reference" function refers to the UGT1A1 allele to which other alleles are compared.

\n", "version" : 0 }, - "version" : 0 + "version" : 4 }, { "objCls" : "Recommendation Annotation", @@ -11567,21 +11567,21 @@ "objCls" : "Chemical", "id" : "PA10251", "name" : "atazanavir", - "version" : 7 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166128738", "name" : "Annotation of CPIC Guideline for atazanavir and UGT1A1", - "version" : 51 + "version" : 139 }, "text" : { "id" : 1452059799, "html" : "

There is no need to avoid prescribing of atazanavir based on UGT1A1 genetic test result. Inform the patient that some patients stop atazanavir because of jaundice (yellow eyes and skin), but that this patient’s genotype makes this unlikely (less than about a 1 in 20 chance of stopping atazanavir because of jaundice).

\n

Other Considerations

\n

All studies correlating UGT1A1 genotypes with atazanavir adverse events have involved ritonavir boosting. However, concentration-time profiles are equivalent when boosted with either cobicistat or ritonavir (PMID 23532097), and bilirubin-related adverse events including discontinuation of atazanavir occur in a similar percentage of patients prescribed atazanavir with cobicistat or ritonavir (PMID 23532097). Associations between UGT1A1 genotype, bilirubin elevations, and atazanavir/r discontinuation therefore almost certainly translate to atazanavir/cobicistat.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", @@ -11609,14 +11609,14 @@ "objCls" : "Chemical", "id" : "PA10251", "name" : "atazanavir", - "version" : 7 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166128738", "name" : "Annotation of CPIC Guideline for atazanavir and UGT1A1", - "version" : 51 + "version" : 139 }, "text" : { "id" : 1452059800, @@ -11651,21 +11651,21 @@ "objCls" : "Chemical", "id" : "PA10251", "name" : "atazanavir", - "version" : 7 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166128738", "name" : "Annotation of CPIC Guideline for atazanavir and UGT1A1", - "version" : 51 + "version" : 139 }, "text" : { "id" : 1452059743, "html" : "

No recommendation

\n

Other Considerations

\n

UGT1A1*80 is in very high linkage disequilibrium with *28 and *37. In the rare event that *80 is detected but *28 and *37 are not, there are not enough clinical data to predict metabolizer status with certainty. However, if only *80 is interrogated and the patient is heterozygous or homozygous for *80, an intermediate or poor metabolizer phenotype may be inferred, respectively.

\n", "version" : 0 }, - "version" : 0 + "version" : 3 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166128738" @@ -11770,7 +11770,7 @@ "id" : 1450369524, "date" : "2019-02-25T00:00:00-08:00", "type" : "Update", - "version" : 0 + "version" : 1 }, { "id" : 1450806460, @@ -11825,7 +11825,7 @@ "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "relatedGenes" : [ @@ -11834,14 +11834,14 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "CPIC", "summaryMarkdown" : { "id" : 1450369184, "html" : "

The CPIC Dosing Guideline for atomoxetine provides therapeutic recommendations for CYP2D6 ultrarapid, normal, intermediate, and poor metabolizer, which includes guidance for plasma drug concentration testing, as a means to estimate atomoxetine exposure, if no clinical response and in the absence of adverse events after 2 weeks of therapy.

\n", - "version" : 0 + "version" : 1 }, "terms" : [], "textMarkdown" : { @@ -11850,13 +11850,43 @@ "version" : 1 }, "userId" : "katrin", - "version" : 13 + "version" : 68 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166297218", - "name" : "Recommendation PA166297218", + "id" : "PA166301301", + "name" : "Recommendation Annotation PA166301301", + "alternateDrugAvailable" : false, + "dosingInformation" : false, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA134688071", + "name" : "atomoxetine", + "version" : 33 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166181885", + "name" : "Annotation of CPIC Guideline for atomoxetine and CYP2D6", + "version" : 68 + }, + "text" : { + "id" : 1452095580, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "version" : 3 + }, + "version" : 3 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166297214", + "name" : "Recommendation PA166297214", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -11869,9 +11899,9 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2D6: Decreased metabolism of atomoxetine and higher atomoxetine concentrations as compared to normal metabolizers. Intermediate metabolizers may be at an increased risk of discontinuation as compared to poor metabolizers." + "CYP2D6: Normal metabolizers of atomoxetine have a lower likelihood of response as compared to poor metabolizers. This is associated with increased discontinuation due to lack of efficacy as compared to poor metabolizers." ], - "lookupKey" : {"CYP2D6": "0.25"}, + "lookupKey" : {"CYP2D6": "1.25"}, "otherPrescribingGuidance" : false, "population" : "pediatrics", "relatedChemicals" : [ @@ -11879,26 +11909,26 @@ "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166181885", "name" : "Annotation of CPIC Guideline for atomoxetine and CYP2D6", - "version" : 13 + "version" : 68 }, "text" : { - "id" : 1452059820, - "html" : "

Initiate with a dose of 0.5 mg/kg/day and if no clinical response and in the absence of adverse events after 2 weeks, consider obtaining a plasma concentration 2 to 4 hours after dosing. If response is inadequate and concentration is < 200 ng/mL, consider a proportional dose increase to achieve a concentration to approach 400 ng/mL. If unacceptable side effects are present at any time, consider a reduction in dose.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL.

\n", + "id" : 1452059816, + "html" : "

Initiate with a dose of 0.5 mg/kg/day and increase to 1.2 mg/kg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If < 200 ng/mL, consider a proportional increase in dose to approach 400 ng/mL.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297205", - "name" : "Recommendation PA166297205", + "id" : "PA166297199", + "name" : "Recommendation PA166297199", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -11913,7 +11943,7 @@ "implications" : [ "CYP2D6: Based on very limited data available for CYP2D6 ultrarapid metabolizers taking atomoxetine, it is unlikely ultrarapid metabolizers would achieve adequate serum concentrations for the intended effect at standard dosing." ], - "lookupKey" : {"CYP2D6": "≥3.0"}, + "lookupKey" : {"CYP2D6": "≥6.0"}, "otherPrescribingGuidance" : false, "population" : "pediatrics", "relatedChemicals" : [ @@ -11921,17 +11951,17 @@ "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166181885", "name" : "Annotation of CPIC Guideline for atomoxetine and CYP2D6", - "version" : 13 + "version" : 68 }, "text" : { - "id" : 1452059807, + "id" : 1452059801, "html" : "

Initiate with a dose of 0.5 mg/kg/day and increase to 1.2 mg/kg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If <200 ng/mL, consider a proportional increase in dose to approach 400 ng/mL.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL.

\n", "version" : 0 }, @@ -11939,8 +11969,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297227", - "name" : "Recommendation PA166297227", + "id" : "PA166297200", + "name" : "Recommendation PA166297200", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -11955,34 +11985,76 @@ "implications" : [ "CYP2D6: Based on very limited data available for CYP2D6 ultrarapid metabolizers taking atomoxetine, it is unlikely ultrarapid metabolizers would achieve adequate serum concentrations for the intended effect at standard dosing." ], - "lookupKey" : {"CYP2D6": "≥3.25"}, + "lookupKey" : {"CYP2D6": "≥5.0"}, "otherPrescribingGuidance" : false, - "population" : "adults", + "population" : "pediatrics", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166181885", "name" : "Annotation of CPIC Guideline for atomoxetine and CYP2D6", - "version" : 13 + "version" : 68 }, "text" : { - "id" : 1452059829, - "html" : "

Initiate with a dose of 40 mg/day and increase to 80 mg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider increasing dose to 100 mg/day. If no clinical response observed after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If <200 ng/mL, consider a proportional increase in dose to approach 400 ng/mL. Dosages greater than 100 mg/day may be needed to achieve target concentrations.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL. Doses above 120 mg/day have not been evaluated.

\n", + "id" : 1452059802, + "html" : "

Initiate with a dose of 0.5 mg/kg/day and increase to 1.2 mg/kg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If <200 ng/mL, consider a proportional increase in dose to approach 400 ng/mL.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297214", - "name" : "Recommendation PA166297214", + "id" : "PA166297202", + "name" : "Recommendation PA166297202", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501931, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "CYP2D6: Based on very limited data available for CYP2D6 ultrarapid metabolizers taking atomoxetine, it is unlikely ultrarapid metabolizers would achieve adequate serum concentrations for the intended effect at standard dosing." + ], + "lookupKey" : {"CYP2D6": "≥4.0"}, + "otherPrescribingGuidance" : false, + "population" : "pediatrics", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA134688071", + "name" : "atomoxetine", + "version" : 33 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166181885", + "name" : "Annotation of CPIC Guideline for atomoxetine and CYP2D6", + "version" : 68 + }, + "text" : { + "id" : 1452059804, + "html" : "

Initiate with a dose of 0.5 mg/kg/day and increase to 1.2 mg/kg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If <200 ng/mL, consider a proportional increase in dose to approach 400 ng/mL.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL.

\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166297203", + "name" : "Recommendation PA166297203", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -11997,7 +12069,7 @@ "implications" : [ "CYP2D6: Normal metabolizers of atomoxetine have a lower likelihood of response as compared to poor metabolizers. This is associated with increased discontinuation due to lack of efficacy as compared to poor metabolizers." ], - "lookupKey" : {"CYP2D6": "1.25"}, + "lookupKey" : {"CYP2D6": "≥3.5"}, "otherPrescribingGuidance" : false, "population" : "pediatrics", "relatedChemicals" : [ @@ -12005,26 +12077,26 @@ "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166181885", "name" : "Annotation of CPIC Guideline for atomoxetine and CYP2D6", - "version" : 13 + "version" : 68 }, "text" : { - "id" : 1452059816, - "html" : "

Initiate with a dose of 0.5 mg/kg/day and increase to 1.2 mg/kg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If < 200 ng/mL, consider a proportional increase in dose to approach 400 ng/mL.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL.

\n", + "id" : 1452059805, + "html" : "

Initiate with a dose of 0.5 mg/kg and increase to 1.2 mg/kg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If < 200 ng/mL, consider a proportional increase in dose to approach 400 ng/mL.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297240", - "name" : "Recommendation PA166297240", + "id" : "PA166297201", + "name" : "Recommendation PA166297201", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -12037,36 +12109,78 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2D6: Decreased metabolism of atomoxetine and higher atomoxetine concentrations as compared to normal metabolizers. Individuals with activity score of 1.0 with CYP2D6*10 may be at an increased risk of discontinuation as compared to poor metabolizers." + "CYP2D6: Based on very limited data available for CYP2D6 ultrarapid metabolizers taking atomoxetine, it is unlikely ultrarapid metabolizers would achieve adequate serum concentrations for the intended effect at standard dosing." ], - "lookupKey" : {"CYP2D6": "0.75"}, + "lookupKey" : {"CYP2D6": "≥3.75"}, "otherPrescribingGuidance" : false, - "population" : "adults", + "population" : "pediatrics", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166181885", "name" : "Annotation of CPIC Guideline for atomoxetine and CYP2D6", - "version" : 13 + "version" : 68 }, "text" : { - "id" : 1452059842, - "html" : "

Initiate with a dose of 40 mg/day and if no clinical response and in the absence of adverse events after 2 weeks increase dose to 80 mg/day. If response is inadequate after 2 weeks consider obtaining a plasma concentration 2-4 h after dosing. If concentration is <200 ng/mL, consider a proportional dose increase to achieve a concentration to approach 400 ng/mL. If unacceptable side effects are present at any time, consider a reduction in dose.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL.

\n", + "id" : 1452059803, + "html" : "

Initiate with a dose of 0.5 mg/kg/day and increase to 1.2 mg/kg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If <200 ng/mL, consider a proportional increase in dose to approach 400 ng/mL.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL.

\n", + "version" : 0 + }, + "version" : 1 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166297204", + "name" : "Recommendation PA166297204", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501931, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "CYP2D6: Based on very limited data available for CYP2D6 ultrarapid metabolizers taking atomoxetine, it is unlikely ultrarapid metabolizers would achieve adequate serum concentrations for the intended effect at standard dosing." + ], + "lookupKey" : {"CYP2D6": "≥3.25"}, + "otherPrescribingGuidance" : false, + "population" : "pediatrics", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA134688071", + "name" : "atomoxetine", + "version" : 33 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166181885", + "name" : "Annotation of CPIC Guideline for atomoxetine and CYP2D6", + "version" : 68 + }, + "text" : { + "id" : 1452059806, + "html" : "

Initiate with a dose of 0.5 mg/kg/day and increase to 1.2 mg/kg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If <200 ng/mL, consider a proportional increase in dose to approach 400 ng/mL.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297209", - "name" : "Recommendation PA166297209", + "id" : "PA166297205", + "name" : "Recommendation PA166297205", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -12081,7 +12195,7 @@ "implications" : [ "CYP2D6: Based on very limited data available for CYP2D6 ultrarapid metabolizers taking atomoxetine, it is unlikely ultrarapid metabolizers would achieve adequate serum concentrations for the intended effect at standard dosing." ], - "lookupKey" : {"CYP2D6": "2.5"}, + "lookupKey" : {"CYP2D6": "≥3.0"}, "otherPrescribingGuidance" : false, "population" : "pediatrics", "relatedChemicals" : [ @@ -12089,17 +12203,17 @@ "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166181885", "name" : "Annotation of CPIC Guideline for atomoxetine and CYP2D6", - "version" : 13 + "version" : 68 }, "text" : { - "id" : 1452059811, + "id" : 1452059807, "html" : "

Initiate with a dose of 0.5 mg/kg/day and increase to 1.2 mg/kg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If <200 ng/mL, consider a proportional increase in dose to approach 400 ng/mL.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL.

\n", "version" : 0 }, @@ -12107,8 +12221,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297232", - "name" : "Recommendation PA166297232", + "id" : "PA166297206", + "name" : "Recommendation PA166297206", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -12123,34 +12237,34 @@ "implications" : [ "CYP2D6: Based on very limited data available for CYP2D6 ultrarapid metabolizers taking atomoxetine, it is unlikely ultrarapid metabolizers would achieve adequate serum concentrations for the intended effect at standard dosing." ], - "lookupKey" : {"CYP2D6": "2.5"}, + "lookupKey" : {"CYP2D6": "4.0"}, "otherPrescribingGuidance" : false, - "population" : "adults", + "population" : "pediatrics", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166181885", "name" : "Annotation of CPIC Guideline for atomoxetine and CYP2D6", - "version" : 13 + "version" : 68 }, "text" : { - "id" : 1452059834, - "html" : "

Initiate with a dose of 40 mg/day and increase to 80 mg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider increasing dose to 100 mg/day. If no clinical response observed after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If <200 ng/mL, consider a proportional increase in dose to approach 400 ng/mL. Dosages greater than 100 mg/day may be needed to achieve target concentrations.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL. Doses above 120 mg/day have not been evaluated.

\n", + "id" : 1452059808, + "html" : "

Initiate with a dose of 0.5 mg/kg/day and increase to 1.2 mg/kg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If <200 ng/mL, consider a proportional increase in dose to approach 400 ng/mL.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297201", - "name" : "Recommendation PA166297201", + "id" : "PA166297208", + "name" : "Recommendation PA166297208", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -12165,7 +12279,7 @@ "implications" : [ "CYP2D6: Based on very limited data available for CYP2D6 ultrarapid metabolizers taking atomoxetine, it is unlikely ultrarapid metabolizers would achieve adequate serum concentrations for the intended effect at standard dosing." ], - "lookupKey" : {"CYP2D6": "≥3.75"}, + "lookupKey" : {"CYP2D6": "3.0"}, "otherPrescribingGuidance" : false, "population" : "pediatrics", "relatedChemicals" : [ @@ -12173,17 +12287,17 @@ "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166181885", "name" : "Annotation of CPIC Guideline for atomoxetine and CYP2D6", - "version" : 13 + "version" : 68 }, "text" : { - "id" : 1452059803, + "id" : 1452059810, "html" : "

Initiate with a dose of 0.5 mg/kg/day and increase to 1.2 mg/kg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If <200 ng/mL, consider a proportional increase in dose to approach 400 ng/mL.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL.

\n", "version" : 0 }, @@ -12191,8 +12305,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297236", - "name" : "Recommendation PA166297236", + "id" : "PA166297209", + "name" : "Recommendation PA166297209", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -12205,28 +12319,28 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2D6: Normal metabolizers of atomoxetine have a lower likelihood of response as compared to poor metabolizers. This is associated with increased discontinuation due to lack of efficacy as compared to poor metabolizers." + "CYP2D6: Based on very limited data available for CYP2D6 ultrarapid metabolizers taking atomoxetine, it is unlikely ultrarapid metabolizers would achieve adequate serum concentrations for the intended effect at standard dosing." ], - "lookupKey" : {"CYP2D6": "1.5"}, + "lookupKey" : {"CYP2D6": "2.5"}, "otherPrescribingGuidance" : false, - "population" : "adults", + "population" : "pediatrics", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166181885", "name" : "Annotation of CPIC Guideline for atomoxetine and CYP2D6", - "version" : 13 + "version" : 68 }, "text" : { - "id" : 1452059838, - "html" : "

Initiate with a dose of 40 mg/day and increase to 80 mg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider increasing dose to 100 mg/day. If no clinical response observed after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If <200 ng/mL, consider a proportional increase in dose to approach 400 ng/mL. Dosages greater than 100 mg/day may be needed to achieve target concentrations.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL. Doses above 120 mg/day have not been evaluated.

\n", + "id" : 1452059811, + "html" : "

Initiate with a dose of 0.5 mg/kg/day and increase to 1.2 mg/kg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If <200 ng/mL, consider a proportional increase in dose to approach 400 ng/mL.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL.

\n", "version" : 0 }, "version" : 0 @@ -12257,14 +12371,14 @@ "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166181885", "name" : "Annotation of CPIC Guideline for atomoxetine and CYP2D6", - "version" : 13 + "version" : 68 }, "text" : { "id" : 1452059812, @@ -12275,8 +12389,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297206", - "name" : "Recommendation PA166297206", + "id" : "PA166297211", + "name" : "Recommendation PA166297211", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -12289,9 +12403,9 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2D6: Based on very limited data available for CYP2D6 ultrarapid metabolizers taking atomoxetine, it is unlikely ultrarapid metabolizers would achieve adequate serum concentrations for the intended effect at standard dosing." + "CYP2D6: Normal metabolizers of atomoxetine have a lower likelihood of response as compared to poor metabolizers. This is associated with increased discontinuation due to lack of efficacy as compared to poor metabolizers." ], - "lookupKey" : {"CYP2D6": "4.0"}, + "lookupKey" : {"CYP2D6": "2.0"}, "otherPrescribingGuidance" : false, "population" : "pediatrics", "relatedChemicals" : [ @@ -12299,26 +12413,26 @@ "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166181885", "name" : "Annotation of CPIC Guideline for atomoxetine and CYP2D6", - "version" : 13 + "version" : 68 }, "text" : { - "id" : 1452059808, - "html" : "

Initiate with a dose of 0.5 mg/kg/day and increase to 1.2 mg/kg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If <200 ng/mL, consider a proportional increase in dose to approach 400 ng/mL.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL.

\n", + "id" : 1452059813, + "html" : "

Initiate with a dose of 0.5 mg/kg/day and increase to 1.2 mg/kg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If < 200 ng/mL, consider a proportional increase in dose to approach 400 ng/mL.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297228", - "name" : "Recommendation PA166297228", + "id" : "PA166297212", + "name" : "Recommendation PA166297212", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -12331,28 +12445,70 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2D6: Based on very limited data available for CYP2D6 ultrarapid metabolizers taking atomoxetine, it is unlikely ultrarapid metabolizers would achieve adequate serum concentrations for the intended effect at standard dosing." + "CYP2D6: Normal metabolizers of atomoxetine have a lower likelihood of response as compared to poor metabolizers. This is associated with increased discontinuation due to lack of efficacy as compared to poor metabolizers." ], - "lookupKey" : {"CYP2D6": "≥3.0"}, + "lookupKey" : {"CYP2D6": "1.75"}, "otherPrescribingGuidance" : false, - "population" : "adults", + "population" : "pediatrics", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166181885", "name" : "Annotation of CPIC Guideline for atomoxetine and CYP2D6", - "version" : 13 + "version" : 68 }, "text" : { - "id" : 1452059830, - "html" : "

Initiate with a dose of 40 mg/day and increase to 80 mg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider increasing dose to 100 mg/day. If no clinical response observed after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If <200 ng/mL, consider a proportional increase in dose to approach 400 ng/mL. Dosages greater than 100 mg/day may be needed to achieve target concentrations.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL. Doses above 120 mg/day have not been evaluated.

\n", + "id" : 1452059814, + "html" : "

Initiate with a dose of 0.5 mg/kg/day and increase to 1.2 mg/kg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If < 200 ng/mL, consider a proportional increase in dose to approach 400 ng/mL.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL.

\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166297213", + "name" : "Recommendation PA166297213", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501931, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "CYP2D6: Normal metabolizers of atomoxetine have a lower likelihood of response as compared to poor metabolizers. This is associated with increased discontinuation due to lack of efficacy as compared to poor metabolizers." + ], + "lookupKey" : {"CYP2D6": "1.5"}, + "otherPrescribingGuidance" : false, + "population" : "pediatrics", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA134688071", + "name" : "atomoxetine", + "version" : 33 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166181885", + "name" : "Annotation of CPIC Guideline for atomoxetine and CYP2D6", + "version" : 68 + }, + "text" : { + "id" : 1452059815, + "html" : "

Initiate with a dose of 0.5 mg/kg/day and increase to 1.2 mg/kg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If < 200 ng/mL, consider a proportional increase in dose to approach 400 ng/mL.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL.

\n", "version" : 0 }, "version" : 0 @@ -12383,14 +12539,14 @@ "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166181885", "name" : "Annotation of CPIC Guideline for atomoxetine and CYP2D6", - "version" : 13 + "version" : 68 }, "text" : { "id" : 1452059817, @@ -12401,8 +12557,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297202", - "name" : "Recommendation PA166297202", + "id" : "PA166297216", + "name" : "Recommendation PA166297216", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -12415,9 +12571,9 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2D6: Based on very limited data available for CYP2D6 ultrarapid metabolizers taking atomoxetine, it is unlikely ultrarapid metabolizers would achieve adequate serum concentrations for the intended effect at standard dosing." + "CYP2D6: Decreased metabolism of atomoxetine and higher atomoxetine concentrations as compared to normal metabolizers. Individuals with activity score of 1.0 with CYP2D6*10 may be at an increased risk of discontinuation as compared to poor metabolizers." ], - "lookupKey" : {"CYP2D6": "≥4.0"}, + "lookupKey" : {"CYP2D6": "0.75"}, "otherPrescribingGuidance" : false, "population" : "pediatrics", "relatedChemicals" : [ @@ -12425,26 +12581,26 @@ "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166181885", "name" : "Annotation of CPIC Guideline for atomoxetine and CYP2D6", - "version" : 13 + "version" : 68 }, "text" : { - "id" : 1452059804, - "html" : "

Initiate with a dose of 0.5 mg/kg/day and increase to 1.2 mg/kg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If <200 ng/mL, consider a proportional increase in dose to approach 400 ng/mL.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL.

\n", + "id" : 1452059818, + "html" : "

Initiate with a dose of 0.5 mg/kg/day and if no clinical response and in the absence of adverse events after 2 weeks, consider obtaining a plasma concentration 2 to 4 hours after dosing. If response is inadequate and concentration is < 200 ng/mL, consider a proportional dose increase to achieve a concentration to approach 400 ng/mL. If unacceptable side effects are present at any time, consider a reduction in dose.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297241", - "name" : "Recommendation PA166297241", + "id" : "PA166297217", + "name" : "Recommendation PA166297217", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -12461,24 +12617,66 @@ ], "lookupKey" : {"CYP2D6": "0.5"}, "otherPrescribingGuidance" : false, - "population" : "adults", + "population" : "pediatrics", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166181885", "name" : "Annotation of CPIC Guideline for atomoxetine and CYP2D6", - "version" : 13 + "version" : 68 }, "text" : { - "id" : 1452059843, - "html" : "

Initiate with a dose of 40 mg/day and if no clinical response and in the absence of adverse events after 2 weeks increase dose to 80 mg/day. If response is inadequate after 2 weeks consider obtaining a plasma concentration 2-4 h after dosing. If concentration is <200 ng/mL, consider a proportional dose increase to achieve a concentration to approach 400 ng/mL. If unacceptable side effects are present at any time, consider a reduction in dose.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL.

\n", + "id" : 1452059819, + "html" : "

Initiate with a dose of 0.5 mg/kg/day and if no clinical response and in the absence of adverse events after 2 weeks, consider obtaining a plasma concentration 2 to 4 hours after dosing. If response is inadequate and concentration is < 200 ng/mL, consider a proportional dose increase to achieve a concentration to approach 400 ng/mL. If unacceptable side effects are present at any time, consider a reduction in dose.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL.

\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166297218", + "name" : "Recommendation PA166297218", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501931, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "CYP2D6: Decreased metabolism of atomoxetine and higher atomoxetine concentrations as compared to normal metabolizers. Intermediate metabolizers may be at an increased risk of discontinuation as compared to poor metabolizers." + ], + "lookupKey" : {"CYP2D6": "0.25"}, + "otherPrescribingGuidance" : false, + "population" : "pediatrics", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA134688071", + "name" : "atomoxetine", + "version" : 33 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166181885", + "name" : "Annotation of CPIC Guideline for atomoxetine and CYP2D6", + "version" : 68 + }, + "text" : { + "id" : 1452059820, + "html" : "

Initiate with a dose of 0.5 mg/kg/day and if no clinical response and in the absence of adverse events after 2 weeks, consider obtaining a plasma concentration 2 to 4 hours after dosing. If response is inadequate and concentration is < 200 ng/mL, consider a proportional dose increase to achieve a concentration to approach 400 ng/mL. If unacceptable side effects are present at any time, consider a reduction in dose.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL.

\n", "version" : 0 }, "version" : 0 @@ -12509,14 +12707,14 @@ "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166181885", "name" : "Annotation of CPIC Guideline for atomoxetine and CYP2D6", - "version" : 13 + "version" : 68 }, "text" : { "id" : 1452059821, @@ -12527,8 +12725,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297233", - "name" : "Recommendation PA166297233", + "id" : "PA166297221", + "name" : "Recommendation PA166297221", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -12541,9 +12739,9 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2D6: Normal metabolizers of atomoxetine have a lower likelihood of response as compared to poor metabolizers. This is associated with increased discontinuation due to lack of efficacy as compared to poor metabolizers." + "CYP2D6: Based on very limited data available for CYP2D6 ultrarapid metabolizers taking atomoxetine, it is unlikely ultrarapid metabolizers would achieve adequate serum concentrations for the intended effect at standard dosing." ], - "lookupKey" : {"CYP2D6": "2.25"}, + "lookupKey" : {"CYP2D6": "≥6.0"}, "otherPrescribingGuidance" : false, "population" : "adults", "relatedChemicals" : [ @@ -12551,17 +12749,17 @@ "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166181885", "name" : "Annotation of CPIC Guideline for atomoxetine and CYP2D6", - "version" : 13 + "version" : 68 }, "text" : { - "id" : 1452059835, + "id" : 1452059823, "html" : "

Initiate with a dose of 40 mg/day and increase to 80 mg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider increasing dose to 100 mg/day. If no clinical response observed after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If <200 ng/mL, consider a proportional increase in dose to approach 400 ng/mL. Dosages greater than 100 mg/day may be needed to achieve target concentrations.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL. Doses above 120 mg/day have not been evaluated.

\n", "version" : 0 }, @@ -12569,50 +12767,50 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297220", - "name" : "Recommendation PA166297220", + "id" : "PA166297222", + "name" : "Recommendation PA166297222", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2D6: n/a" + "CYP2D6: Based on very limited data available for CYP2D6 ultrarapid metabolizers taking atomoxetine, it is unlikely ultrarapid metabolizers would achieve adequate serum concentrations for the intended effect at standard dosing." ], - "lookupKey" : {"CYP2D6": "n/a"}, + "lookupKey" : {"CYP2D6": "≥5.0"}, "otherPrescribingGuidance" : false, - "population" : "pediatrics", + "population" : "adults", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166181885", "name" : "Annotation of CPIC Guideline for atomoxetine and CYP2D6", - "version" : 13 + "version" : 68 }, "text" : { - "id" : 1452059822, - "html" : "

No recommendation

\n", + "id" : 1452059824, + "html" : "

Initiate with a dose of 40 mg/day and increase to 80 mg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider increasing dose to 100 mg/day. If no clinical response observed after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If <200 ng/mL, consider a proportional increase in dose to approach 400 ng/mL. Dosages greater than 100 mg/day may be needed to achieve target concentrations.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL. Doses above 120 mg/day have not been evaluated.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297242", - "name" : "Recommendation PA166297242", + "id" : "PA166297225", + "name" : "Recommendation PA166297225", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -12625,9 +12823,9 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2D6: Decreased metabolism of atomoxetine and higher atomoxetine concentrations as compared to normal metabolizers. Intermediate metabolizers may be at an increased risk of discontinuation as compared to poor metabolizers." + "CYP2D6: Based on very limited data available for CYP2D6 ultrarapid metabolizers taking atomoxetine, it is unlikely ultrarapid metabolizers would achieve adequate serum concentrations for the intended effect at standard dosing." ], - "lookupKey" : {"CYP2D6": "0.25"}, + "lookupKey" : {"CYP2D6": "≥4.0"}, "otherPrescribingGuidance" : false, "population" : "adults", "relatedChemicals" : [ @@ -12635,26 +12833,26 @@ "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166181885", "name" : "Annotation of CPIC Guideline for atomoxetine and CYP2D6", - "version" : 13 + "version" : 68 }, "text" : { - "id" : 1452059844, - "html" : "

Initiate with a dose of 40 mg/day and if no clinical response and in the absence of adverse events after 2 weeks increase dose to 80 mg/day. If response is inadequate after 2 weeks consider obtaining a plasma concentration 2-4 h after dosing. If concentration is <200 ng/mL, consider a proportional dose increase to achieve a concentration to approach 400 ng/mL. If unacceptable side effects are present at any time, consider a reduction in dose.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL.

\n", + "id" : 1452059827, + "html" : "

Initiate with a dose of 40 mg/day and increase to 80 mg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider increasing dose to 100 mg/day. If no clinical response observed after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If <200 ng/mL, consider a proportional increase in dose to approach 400 ng/mL. Dosages greater than 100 mg/day may be needed to achieve target concentrations.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL. Doses above 120 mg/day have not been evaluated.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297237", - "name" : "Recommendation PA166297237", + "id" : "PA166297226", + "name" : "Recommendation PA166297226", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -12667,9 +12865,9 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2D6: Normal metabolizers of atomoxetine have a lower likelihood of response as compared to poor metabolizers. This is associated with increased discontinuation due to lack of efficacy as compared to poor metabolizers." + "CYP2D6: Based on very limited data available for CYP2D6 ultrarapid metabolizers taking atomoxetine, it is unlikely ultrarapid metabolizers would achieve adequate serum concentrations for the intended effect at standard dosing." ], - "lookupKey" : {"CYP2D6": "1.25"}, + "lookupKey" : {"CYP2D6": "≥3.5"}, "otherPrescribingGuidance" : false, "population" : "adults", "relatedChemicals" : [ @@ -12677,17 +12875,17 @@ "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166181885", "name" : "Annotation of CPIC Guideline for atomoxetine and CYP2D6", - "version" : 13 + "version" : 68 }, "text" : { - "id" : 1452059839, + "id" : 1452059828, "html" : "

Initiate with a dose of 40 mg/day and increase to 80 mg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider increasing dose to 100 mg/day. If no clinical response observed after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If <200 ng/mL, consider a proportional increase in dose to approach 400 ng/mL. Dosages greater than 100 mg/day may be needed to achieve target concentrations.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL. Doses above 120 mg/day have not been evaluated.

\n", "version" : 0 }, @@ -12695,8 +12893,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297224", - "name" : "Recommendation PA166297224", + "id" : "PA166297227", + "name" : "Recommendation PA166297227", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -12711,7 +12909,7 @@ "implications" : [ "CYP2D6: Based on very limited data available for CYP2D6 ultrarapid metabolizers taking atomoxetine, it is unlikely ultrarapid metabolizers would achieve adequate serum concentrations for the intended effect at standard dosing." ], - "lookupKey" : {"CYP2D6": "≥3.75"}, + "lookupKey" : {"CYP2D6": "≥3.25"}, "otherPrescribingGuidance" : false, "population" : "adults", "relatedChemicals" : [ @@ -12719,17 +12917,17 @@ "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166181885", "name" : "Annotation of CPIC Guideline for atomoxetine and CYP2D6", - "version" : 13 + "version" : 68 }, "text" : { - "id" : 1452059826, + "id" : 1452059829, "html" : "

Initiate with a dose of 40 mg/day and increase to 80 mg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider increasing dose to 100 mg/day. If no clinical response observed after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If <200 ng/mL, consider a proportional increase in dose to approach 400 ng/mL. Dosages greater than 100 mg/day may be needed to achieve target concentrations.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL. Doses above 120 mg/day have not been evaluated.

\n", "version" : 0 }, @@ -12737,8 +12935,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297211", - "name" : "Recommendation PA166297211", + "id" : "PA166297228", + "name" : "Recommendation PA166297228", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -12751,28 +12949,28 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2D6: Normal metabolizers of atomoxetine have a lower likelihood of response as compared to poor metabolizers. This is associated with increased discontinuation due to lack of efficacy as compared to poor metabolizers." + "CYP2D6: Based on very limited data available for CYP2D6 ultrarapid metabolizers taking atomoxetine, it is unlikely ultrarapid metabolizers would achieve adequate serum concentrations for the intended effect at standard dosing." ], - "lookupKey" : {"CYP2D6": "2.0"}, + "lookupKey" : {"CYP2D6": "≥3.0"}, "otherPrescribingGuidance" : false, - "population" : "pediatrics", + "population" : "adults", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166181885", "name" : "Annotation of CPIC Guideline for atomoxetine and CYP2D6", - "version" : 13 + "version" : 68 }, "text" : { - "id" : 1452059813, - "html" : "

Initiate with a dose of 0.5 mg/kg/day and increase to 1.2 mg/kg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If < 200 ng/mL, consider a proportional increase in dose to approach 400 ng/mL.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL.

\n", + "id" : 1452059830, + "html" : "

Initiate with a dose of 40 mg/day and increase to 80 mg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider increasing dose to 100 mg/day. If no clinical response observed after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If <200 ng/mL, consider a proportional increase in dose to approach 400 ng/mL. Dosages greater than 100 mg/day may be needed to achieve target concentrations.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL. Doses above 120 mg/day have not been evaluated.

\n", "version" : 0 }, "version" : 0 @@ -12803,14 +13001,14 @@ "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166181885", "name" : "Annotation of CPIC Guideline for atomoxetine and CYP2D6", - "version" : 13 + "version" : 68 }, "text" : { "id" : 1452059831, @@ -12821,8 +13019,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297216", - "name" : "Recommendation PA166297216", + "id" : "PA166297231", + "name" : "Recommendation PA166297231", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -12835,36 +13033,36 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2D6: Decreased metabolism of atomoxetine and higher atomoxetine concentrations as compared to normal metabolizers. Individuals with activity score of 1.0 with CYP2D6*10 may be at an increased risk of discontinuation as compared to poor metabolizers." + "CYP2D6: Based on very limited data available for CYP2D6 ultrarapid metabolizers taking atomoxetine, it is unlikely ultrarapid metabolizers would achieve adequate serum concentrations for the intended effect at standard dosing." ], - "lookupKey" : {"CYP2D6": "0.75"}, + "lookupKey" : {"CYP2D6": "3.0"}, "otherPrescribingGuidance" : false, - "population" : "pediatrics", + "population" : "adults", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166181885", "name" : "Annotation of CPIC Guideline for atomoxetine and CYP2D6", - "version" : 13 + "version" : 68 }, "text" : { - "id" : 1452059818, - "html" : "

Initiate with a dose of 0.5 mg/kg/day and if no clinical response and in the absence of adverse events after 2 weeks, consider obtaining a plasma concentration 2 to 4 hours after dosing. If response is inadequate and concentration is < 200 ng/mL, consider a proportional dose increase to achieve a concentration to approach 400 ng/mL. If unacceptable side effects are present at any time, consider a reduction in dose.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL.

\n", + "id" : 1452059833, + "html" : "

Initiate with a dose of 40 mg/day and increase to 80 mg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider increasing dose to 100 mg/day. If no clinical response observed after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If <200 ng/mL, consider a proportional increase in dose to approach 400 ng/mL. Dosages greater than 100 mg/day may be needed to achieve target concentrations.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL. Doses above 120 mg/day have not been evaluated.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297203", - "name" : "Recommendation PA166297203", + "id" : "PA166297232", + "name" : "Recommendation PA166297232", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -12877,66 +13075,78 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2D6: Normal metabolizers of atomoxetine have a lower likelihood of response as compared to poor metabolizers. This is associated with increased discontinuation due to lack of efficacy as compared to poor metabolizers." + "CYP2D6: Based on very limited data available for CYP2D6 ultrarapid metabolizers taking atomoxetine, it is unlikely ultrarapid metabolizers would achieve adequate serum concentrations for the intended effect at standard dosing." ], - "lookupKey" : {"CYP2D6": "≥3.5"}, + "lookupKey" : {"CYP2D6": "2.5"}, "otherPrescribingGuidance" : false, - "population" : "pediatrics", + "population" : "adults", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166181885", "name" : "Annotation of CPIC Guideline for atomoxetine and CYP2D6", - "version" : 13 + "version" : 68 }, "text" : { - "id" : 1452059805, - "html" : "

Initiate with a dose of 0.5 mg/kg and increase to 1.2 mg/kg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If < 200 ng/mL, consider a proportional increase in dose to approach 400 ng/mL.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL.

\n", + "id" : 1452059834, + "html" : "

Initiate with a dose of 40 mg/day and increase to 80 mg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider increasing dose to 100 mg/day. If no clinical response observed after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If <200 ng/mL, consider a proportional increase in dose to approach 400 ng/mL. Dosages greater than 100 mg/day may be needed to achieve target concentrations.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL. Doses above 120 mg/day have not been evaluated.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301301", - "name" : "Recommendation Annotation PA166301301", + "id" : "PA166297233", + "name" : "Recommendation PA166297233", "alternateDrugAvailable" : false, - "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations"}, + "classification" : { + "id" : 981501931, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "CYP2D6: Normal metabolizers of atomoxetine have a lower likelihood of response as compared to poor metabolizers. This is associated with increased discontinuation due to lack of efficacy as compared to poor metabolizers." + ], + "lookupKey" : {"CYP2D6": "2.25"}, "otherPrescribingGuidance" : false, + "population" : "adults", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166181885", "name" : "Annotation of CPIC Guideline for atomoxetine and CYP2D6", - "version" : 13 + "version" : 68 }, "text" : { - "id" : 1452095580, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "id" : 1452059835, + "html" : "

Initiate with a dose of 40 mg/day and increase to 80 mg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider increasing dose to 100 mg/day. If no clinical response observed after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If <200 ng/mL, consider a proportional increase in dose to approach 400 ng/mL. Dosages greater than 100 mg/day may be needed to achieve target concentrations.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL. Doses above 120 mg/day have not been evaluated.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297207", - "name" : "Recommendation PA166297207", + "id" : "PA166297234", + "name" : "Recommendation PA166297234", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -12949,36 +13159,36 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2D6: Based on very limited data available for CYP2D6 ultrarapid metabolizers taking atomoxetine, it is unlikely ultrarapid metabolizers would achieve adequate serum concentrations for the intended effect at standard dosing." + "CYP2D6: Normal metabolizers of atomoxetine have a lower likelihood of response as compared to poor metabolizers. This is associated with increased discontinuation due to lack of efficacy as compared to poor metabolizers." ], - "lookupKey" : {"CYP2D6": "2.75"}, + "lookupKey" : {"CYP2D6": "2.0"}, "otherPrescribingGuidance" : false, - "population" : "pediatrics", + "population" : "adults", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166181885", "name" : "Annotation of CPIC Guideline for atomoxetine and CYP2D6", - "version" : 13 + "version" : 68 }, "text" : { - "id" : 1452059809, - "html" : "

Initiate with a dose of 0.5 mg/kg/day and increase to 1.2 mg/kg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If <200 ng/mL, consider a proportional increase in dose to approach 400 ng/mL.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL.

\n", + "id" : 1452059836, + "html" : "

Initiate with a dose of 40 mg/day and increase to 80 mg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider increasing dose to 100 mg/day. If no clinical response observed after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If <200 ng/mL, consider a proportional increase in dose to approach 400 ng/mL. Dosages greater than 100 mg/day may be needed to achieve target concentrations.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL. Doses above 120 mg/day have not been evaluated.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297221", - "name" : "Recommendation PA166297221", + "id" : "PA166297235", + "name" : "Recommendation PA166297235", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -12991,9 +13201,9 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2D6: Based on very limited data available for CYP2D6 ultrarapid metabolizers taking atomoxetine, it is unlikely ultrarapid metabolizers would achieve adequate serum concentrations for the intended effect at standard dosing." + "CYP2D6: Normal metabolizers of atomoxetine have a lower likelihood of response as compared to poor metabolizers. This is associated with increased discontinuation due to lack of efficacy as compared to poor metabolizers." ], - "lookupKey" : {"CYP2D6": "≥6.0"}, + "lookupKey" : {"CYP2D6": "1.75"}, "otherPrescribingGuidance" : false, "population" : "adults", "relatedChemicals" : [ @@ -13001,17 +13211,17 @@ "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166181885", "name" : "Annotation of CPIC Guideline for atomoxetine and CYP2D6", - "version" : 13 + "version" : 68 }, "text" : { - "id" : 1452059823, + "id" : 1452059837, "html" : "

Initiate with a dose of 40 mg/day and increase to 80 mg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider increasing dose to 100 mg/day. If no clinical response observed after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If <200 ng/mL, consider a proportional increase in dose to approach 400 ng/mL. Dosages greater than 100 mg/day may be needed to achieve target concentrations.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL. Doses above 120 mg/day have not been evaluated.

\n", "version" : 0 }, @@ -13019,8 +13229,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297243", - "name" : "Recommendation PA166297243", + "id" : "PA166297236", + "name" : "Recommendation PA166297236", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -13033,9 +13243,9 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2D6: Significantly decreased metabolism of atomoxetine may result in higher concentrations as compared to non-poor metabolizers. This may increase the occurrence of treatment-emergent side effects, but also a greater improvement of ADHD symptoms as compared to non-poor metabolizers in those who tolerate treatment. Poor metabolizer status is associated with lower final dose requirements as compared to non-poor metabolizers." + "CYP2D6: Normal metabolizers of atomoxetine have a lower likelihood of response as compared to poor metabolizers. This is associated with increased discontinuation due to lack of efficacy as compared to poor metabolizers." ], - "lookupKey" : {"CYP2D6": "0.0"}, + "lookupKey" : {"CYP2D6": "1.5"}, "otherPrescribingGuidance" : false, "population" : "adults", "relatedChemicals" : [ @@ -13043,26 +13253,26 @@ "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166181885", "name" : "Annotation of CPIC Guideline for atomoxetine and CYP2D6", - "version" : 13 + "version" : 68 }, "text" : { - "id" : 1452059845, - "html" : "

Initiate with a dose of 40 mg/day and if no clinical response and in the absence of adverse events after 2 weeks increase dose to 80 mg/day. If response is inadequate after 2 weeks, consider obtaining a plasma concentration 2 to 4 hours after dosing. If concentration is <200 ng/mL, consider a proportional dose increase to achieve a concentration to approach 400 ng/mL. If unacceptable side effects are present at any time, consider a reduction in dose.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL.

\n", + "id" : 1452059838, + "html" : "

Initiate with a dose of 40 mg/day and increase to 80 mg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider increasing dose to 100 mg/day. If no clinical response observed after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If <200 ng/mL, consider a proportional increase in dose to approach 400 ng/mL. Dosages greater than 100 mg/day may be needed to achieve target concentrations.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL. Doses above 120 mg/day have not been evaluated.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297230", - "name" : "Recommendation PA166297230", + "id" : "PA166297237", + "name" : "Recommendation PA166297237", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -13075,9 +13285,9 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2D6: Based on very limited data available for CYP2D6 ultrarapid metabolizers taking atomoxetine, it is unlikely ultrarapid metabolizers would achieve adequate serum concentrations for the intended effect at standard dosing." + "CYP2D6: Normal metabolizers of atomoxetine have a lower likelihood of response as compared to poor metabolizers. This is associated with increased discontinuation due to lack of efficacy as compared to poor metabolizers." ], - "lookupKey" : {"CYP2D6": "2.75"}, + "lookupKey" : {"CYP2D6": "1.25"}, "otherPrescribingGuidance" : false, "population" : "adults", "relatedChemicals" : [ @@ -13085,17 +13295,17 @@ "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166181885", "name" : "Annotation of CPIC Guideline for atomoxetine and CYP2D6", - "version" : 13 + "version" : 68 }, "text" : { - "id" : 1452059832, + "id" : 1452059839, "html" : "

Initiate with a dose of 40 mg/day and increase to 80 mg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider increasing dose to 100 mg/day. If no clinical response observed after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If <200 ng/mL, consider a proportional increase in dose to approach 400 ng/mL. Dosages greater than 100 mg/day may be needed to achieve target concentrations.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL. Doses above 120 mg/day have not been evaluated.

\n", "version" : 0 }, @@ -13127,14 +13337,14 @@ "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166181885", "name" : "Annotation of CPIC Guideline for atomoxetine and CYP2D6", - "version" : 13 + "version" : 68 }, "text" : { "id" : 1452059840, @@ -13145,92 +13355,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297225", - "name" : "Recommendation PA166297225", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 981501931, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : true, - "implications" : [ - "CYP2D6: Based on very limited data available for CYP2D6 ultrarapid metabolizers taking atomoxetine, it is unlikely ultrarapid metabolizers would achieve adequate serum concentrations for the intended effect at standard dosing." - ], - "lookupKey" : {"CYP2D6": "≥4.0"}, - "otherPrescribingGuidance" : false, - "population" : "adults", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA134688071", - "name" : "atomoxetine", - "version" : 6 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166181885", - "name" : "Annotation of CPIC Guideline for atomoxetine and CYP2D6", - "version" : 13 - }, - "text" : { - "id" : 1452059827, - "html" : "

Initiate with a dose of 40 mg/day and increase to 80 mg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider increasing dose to 100 mg/day. If no clinical response observed after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If <200 ng/mL, consider a proportional increase in dose to approach 400 ng/mL. Dosages greater than 100 mg/day may be needed to achieve target concentrations.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL. Doses above 120 mg/day have not been evaluated.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166297212", - "name" : "Recommendation PA166297212", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 981501931, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : true, - "implications" : [ - "CYP2D6: Normal metabolizers of atomoxetine have a lower likelihood of response as compared to poor metabolizers. This is associated with increased discontinuation due to lack of efficacy as compared to poor metabolizers." - ], - "lookupKey" : {"CYP2D6": "1.75"}, - "otherPrescribingGuidance" : false, - "population" : "pediatrics", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA134688071", - "name" : "atomoxetine", - "version" : 6 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166181885", - "name" : "Annotation of CPIC Guideline for atomoxetine and CYP2D6", - "version" : 13 - }, - "text" : { - "id" : 1452059814, - "html" : "

Initiate with a dose of 0.5 mg/kg/day and increase to 1.2 mg/kg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If < 200 ng/mL, consider a proportional increase in dose to approach 400 ng/mL.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166297234", - "name" : "Recommendation PA166297234", + "id" : "PA166297240", + "name" : "Recommendation PA166297240", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -13243,9 +13369,9 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2D6: Normal metabolizers of atomoxetine have a lower likelihood of response as compared to poor metabolizers. This is associated with increased discontinuation due to lack of efficacy as compared to poor metabolizers." + "CYP2D6: Decreased metabolism of atomoxetine and higher atomoxetine concentrations as compared to normal metabolizers. Individuals with activity score of 1.0 with CYP2D6*10 may be at an increased risk of discontinuation as compared to poor metabolizers." ], - "lookupKey" : {"CYP2D6": "2.0"}, + "lookupKey" : {"CYP2D6": "0.75"}, "otherPrescribingGuidance" : false, "population" : "adults", "relatedChemicals" : [ @@ -13253,26 +13379,26 @@ "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166181885", "name" : "Annotation of CPIC Guideline for atomoxetine and CYP2D6", - "version" : 13 + "version" : 68 }, "text" : { - "id" : 1452059836, - "html" : "

Initiate with a dose of 40 mg/day and increase to 80 mg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider increasing dose to 100 mg/day. If no clinical response observed after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If <200 ng/mL, consider a proportional increase in dose to approach 400 ng/mL. Dosages greater than 100 mg/day may be needed to achieve target concentrations.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL. Doses above 120 mg/day have not been evaluated.

\n", + "id" : 1452059842, + "html" : "

Initiate with a dose of 40 mg/day and if no clinical response and in the absence of adverse events after 2 weeks increase dose to 80 mg/day. If response is inadequate after 2 weeks consider obtaining a plasma concentration 2-4 h after dosing. If concentration is <200 ng/mL, consider a proportional dose increase to achieve a concentration to approach 400 ng/mL. If unacceptable side effects are present at any time, consider a reduction in dose.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297217", - "name" : "Recommendation PA166297217", + "id" : "PA166297241", + "name" : "Recommendation PA166297241", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -13289,116 +13415,32 @@ ], "lookupKey" : {"CYP2D6": "0.5"}, "otherPrescribingGuidance" : false, - "population" : "pediatrics", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA134688071", - "name" : "atomoxetine", - "version" : 6 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166181885", - "name" : "Annotation of CPIC Guideline for atomoxetine and CYP2D6", - "version" : 13 - }, - "text" : { - "id" : 1452059819, - "html" : "

Initiate with a dose of 0.5 mg/kg/day and if no clinical response and in the absence of adverse events after 2 weeks, consider obtaining a plasma concentration 2 to 4 hours after dosing. If response is inadequate and concentration is < 200 ng/mL, consider a proportional dose increase to achieve a concentration to approach 400 ng/mL. If unacceptable side effects are present at any time, consider a reduction in dose.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166297199", - "name" : "Recommendation PA166297199", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 981501931, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : true, - "implications" : [ - "CYP2D6: Based on very limited data available for CYP2D6 ultrarapid metabolizers taking atomoxetine, it is unlikely ultrarapid metabolizers would achieve adequate serum concentrations for the intended effect at standard dosing." - ], - "lookupKey" : {"CYP2D6": "≥6.0"}, - "otherPrescribingGuidance" : false, - "population" : "pediatrics", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA134688071", - "name" : "atomoxetine", - "version" : 6 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166181885", - "name" : "Annotation of CPIC Guideline for atomoxetine and CYP2D6", - "version" : 13 - }, - "text" : { - "id" : 1452059801, - "html" : "

Initiate with a dose of 0.5 mg/kg/day and increase to 1.2 mg/kg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If <200 ng/mL, consider a proportional increase in dose to approach 400 ng/mL.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166297204", - "name" : "Recommendation PA166297204", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 981501931, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : true, - "implications" : [ - "CYP2D6: Based on very limited data available for CYP2D6 ultrarapid metabolizers taking atomoxetine, it is unlikely ultrarapid metabolizers would achieve adequate serum concentrations for the intended effect at standard dosing." - ], - "lookupKey" : {"CYP2D6": "≥3.25"}, - "otherPrescribingGuidance" : false, - "population" : "pediatrics", + "population" : "adults", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166181885", "name" : "Annotation of CPIC Guideline for atomoxetine and CYP2D6", - "version" : 13 + "version" : 68 }, "text" : { - "id" : 1452059806, - "html" : "

Initiate with a dose of 0.5 mg/kg/day and increase to 1.2 mg/kg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If <200 ng/mL, consider a proportional increase in dose to approach 400 ng/mL.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL.

\n", + "id" : 1452059843, + "html" : "

Initiate with a dose of 40 mg/day and if no clinical response and in the absence of adverse events after 2 weeks increase dose to 80 mg/day. If response is inadequate after 2 weeks consider obtaining a plasma concentration 2-4 h after dosing. If concentration is <200 ng/mL, consider a proportional dose increase to achieve a concentration to approach 400 ng/mL. If unacceptable side effects are present at any time, consider a reduction in dose.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297231", - "name" : "Recommendation PA166297231", + "id" : "PA166297242", + "name" : "Recommendation PA166297242", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -13411,9 +13453,9 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2D6: Based on very limited data available for CYP2D6 ultrarapid metabolizers taking atomoxetine, it is unlikely ultrarapid metabolizers would achieve adequate serum concentrations for the intended effect at standard dosing." + "CYP2D6: Decreased metabolism of atomoxetine and higher atomoxetine concentrations as compared to normal metabolizers. Intermediate metabolizers may be at an increased risk of discontinuation as compared to poor metabolizers." ], - "lookupKey" : {"CYP2D6": "3.0"}, + "lookupKey" : {"CYP2D6": "0.25"}, "otherPrescribingGuidance" : false, "population" : "adults", "relatedChemicals" : [ @@ -13421,26 +13463,26 @@ "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166181885", "name" : "Annotation of CPIC Guideline for atomoxetine and CYP2D6", - "version" : 13 + "version" : 68 }, "text" : { - "id" : 1452059833, - "html" : "

Initiate with a dose of 40 mg/day and increase to 80 mg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider increasing dose to 100 mg/day. If no clinical response observed after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If <200 ng/mL, consider a proportional increase in dose to approach 400 ng/mL. Dosages greater than 100 mg/day may be needed to achieve target concentrations.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL. Doses above 120 mg/day have not been evaluated.

\n", + "id" : 1452059844, + "html" : "

Initiate with a dose of 40 mg/day and if no clinical response and in the absence of adverse events after 2 weeks increase dose to 80 mg/day. If response is inadequate after 2 weeks consider obtaining a plasma concentration 2-4 h after dosing. If concentration is <200 ng/mL, consider a proportional dose increase to achieve a concentration to approach 400 ng/mL. If unacceptable side effects are present at any time, consider a reduction in dose.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297226", - "name" : "Recommendation PA166297226", + "id" : "PA166297243", + "name" : "Recommendation PA166297243", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -13453,9 +13495,9 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2D6: Based on very limited data available for CYP2D6 ultrarapid metabolizers taking atomoxetine, it is unlikely ultrarapid metabolizers would achieve adequate serum concentrations for the intended effect at standard dosing." + "CYP2D6: Significantly decreased metabolism of atomoxetine may result in higher concentrations as compared to non-poor metabolizers. This may increase the occurrence of treatment-emergent side effects, but also a greater improvement of ADHD symptoms as compared to non-poor metabolizers in those who tolerate treatment. Poor metabolizer status is associated with lower final dose requirements as compared to non-poor metabolizers." ], - "lookupKey" : {"CYP2D6": "≥3.5"}, + "lookupKey" : {"CYP2D6": "0.0"}, "otherPrescribingGuidance" : false, "population" : "adults", "relatedChemicals" : [ @@ -13463,41 +13505,41 @@ "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166181885", "name" : "Annotation of CPIC Guideline for atomoxetine and CYP2D6", - "version" : 13 + "version" : 68 }, "text" : { - "id" : 1452059828, - "html" : "

Initiate with a dose of 40 mg/day and increase to 80 mg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider increasing dose to 100 mg/day. If no clinical response observed after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If <200 ng/mL, consider a proportional increase in dose to approach 400 ng/mL. Dosages greater than 100 mg/day may be needed to achieve target concentrations.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL. Doses above 120 mg/day have not been evaluated.

\n", + "id" : 1452059845, + "html" : "

Initiate with a dose of 40 mg/day and if no clinical response and in the absence of adverse events after 2 weeks increase dose to 80 mg/day. If response is inadequate after 2 weeks, consider obtaining a plasma concentration 2 to 4 hours after dosing. If concentration is <200 ng/mL, consider a proportional dose increase to achieve a concentration to approach 400 ng/mL. If unacceptable side effects are present at any time, consider a reduction in dose.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297208", - "name" : "Recommendation PA166297208", + "id" : "PA166297220", + "name" : "Recommendation PA166297220", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2D6: Based on very limited data available for CYP2D6 ultrarapid metabolizers taking atomoxetine, it is unlikely ultrarapid metabolizers would achieve adequate serum concentrations for the intended effect at standard dosing." + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "3.0"}, + "lookupKey" : {"CYP2D6": "n/a"}, "otherPrescribingGuidance" : false, "population" : "pediatrics", "relatedChemicals" : [ @@ -13505,21 +13547,21 @@ "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166181885", "name" : "Annotation of CPIC Guideline for atomoxetine and CYP2D6", - "version" : 13 + "version" : 68 }, "text" : { - "id" : 1452059810, - "html" : "

Initiate with a dose of 0.5 mg/kg/day and increase to 1.2 mg/kg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If <200 ng/mL, consider a proportional increase in dose to approach 400 ng/mL.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL.

\n", + "id" : 1452059822, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -13547,68 +13589,26 @@ "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166181885", "name" : "Annotation of CPIC Guideline for atomoxetine and CYP2D6", - "version" : 13 + "version" : 68 }, "text" : { "id" : 1452059846, "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166297213", - "name" : "Recommendation PA166297213", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 981501931, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : true, - "implications" : [ - "CYP2D6: Normal metabolizers of atomoxetine have a lower likelihood of response as compared to poor metabolizers. This is associated with increased discontinuation due to lack of efficacy as compared to poor metabolizers." - ], - "lookupKey" : {"CYP2D6": "1.5"}, - "otherPrescribingGuidance" : false, - "population" : "pediatrics", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA134688071", - "name" : "atomoxetine", - "version" : 6 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166181885", - "name" : "Annotation of CPIC Guideline for atomoxetine and CYP2D6", - "version" : 13 - }, - "text" : { - "id" : 1452059815, - "html" : "

Initiate with a dose of 0.5 mg/kg/day and increase to 1.2 mg/kg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If < 200 ng/mL, consider a proportional increase in dose to approach 400 ng/mL.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL.

\n", - "version" : 0 - }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297200", - "name" : "Recommendation PA166297200", + "id" : "PA166297207", + "name" : "Recommendation PA166297207", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -13623,7 +13623,7 @@ "implications" : [ "CYP2D6: Based on very limited data available for CYP2D6 ultrarapid metabolizers taking atomoxetine, it is unlikely ultrarapid metabolizers would achieve adequate serum concentrations for the intended effect at standard dosing." ], - "lookupKey" : {"CYP2D6": "≥5.0"}, + "lookupKey" : {"CYP2D6": "2.75"}, "otherPrescribingGuidance" : false, "population" : "pediatrics", "relatedChemicals" : [ @@ -13631,26 +13631,26 @@ "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166181885", "name" : "Annotation of CPIC Guideline for atomoxetine and CYP2D6", - "version" : 13 + "version" : 68 }, "text" : { - "id" : 1452059802, + "id" : 1452059809, "html" : "

Initiate with a dose of 0.5 mg/kg/day and increase to 1.2 mg/kg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If <200 ng/mL, consider a proportional increase in dose to approach 400 ng/mL.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297235", - "name" : "Recommendation PA166297235", + "id" : "PA166297224", + "name" : "Recommendation PA166297224", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -13663,9 +13663,9 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2D6: Normal metabolizers of atomoxetine have a lower likelihood of response as compared to poor metabolizers. This is associated with increased discontinuation due to lack of efficacy as compared to poor metabolizers." + "CYP2D6: Based on very limited data available for CYP2D6 ultrarapid metabolizers taking atomoxetine, it is unlikely ultrarapid metabolizers would achieve adequate serum concentrations for the intended effect at standard dosing." ], - "lookupKey" : {"CYP2D6": "1.75"}, + "lookupKey" : {"CYP2D6": "≥3.75"}, "otherPrescribingGuidance" : false, "population" : "adults", "relatedChemicals" : [ @@ -13673,26 +13673,26 @@ "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166181885", "name" : "Annotation of CPIC Guideline for atomoxetine and CYP2D6", - "version" : 13 + "version" : 68 }, "text" : { - "id" : 1452059837, + "id" : 1452059826, "html" : "

Initiate with a dose of 40 mg/day and increase to 80 mg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider increasing dose to 100 mg/day. If no clinical response observed after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If <200 ng/mL, consider a proportional increase in dose to approach 400 ng/mL. Dosages greater than 100 mg/day may be needed to achieve target concentrations.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL. Doses above 120 mg/day have not been evaluated.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297222", - "name" : "Recommendation PA166297222", + "id" : "PA166297230", + "name" : "Recommendation PA166297230", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -13707,7 +13707,7 @@ "implications" : [ "CYP2D6: Based on very limited data available for CYP2D6 ultrarapid metabolizers taking atomoxetine, it is unlikely ultrarapid metabolizers would achieve adequate serum concentrations for the intended effect at standard dosing." ], - "lookupKey" : {"CYP2D6": "≥5.0"}, + "lookupKey" : {"CYP2D6": "2.75"}, "otherPrescribingGuidance" : false, "population" : "adults", "relatedChemicals" : [ @@ -13715,21 +13715,21 @@ "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166181885", "name" : "Annotation of CPIC Guideline for atomoxetine and CYP2D6", - "version" : 13 + "version" : 68 }, "text" : { - "id" : 1452059824, + "id" : 1452059832, "html" : "

Initiate with a dose of 40 mg/day and increase to 80 mg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider increasing dose to 100 mg/day. If no clinical response observed after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If <200 ng/mL, consider a proportional increase in dose to approach 400 ng/mL. Dosages greater than 100 mg/day may be needed to achieve target concentrations.

\n

Other Considerations

\n

Therapeutic range of 200 to 1000 ng/mL has been proposed (PMID 29493375). Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in poor metabolizers (PMs) compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-rating scale, is observed at peak concentrations greater than 400 ng/mL. Doses above 120 mg/day have not been evaluated.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166181885" @@ -13898,14 +13898,14 @@ "id" : "PA165819265", "symbol" : "SLCO1B1*15", "name" : "*15", - "version" : 23 + "version" : 39 }, { "objCls" : "Haplotype", "id" : "PA165819255", "symbol" : "SLCO1B1*5", "name" : "*5", - "version" : 23 + "version" : 39 } ], "relatedChemicals" : [ @@ -13913,7 +13913,7 @@ "objCls" : "Chemical", "id" : "PA448500", "name" : "atorvastatin", - "version" : 22 + "version" : 67 } ], "relatedGenes" : [ @@ -13922,7 +13922,7 @@ "id" : "PA134865839", "symbol" : "SLCO1B1", "name" : "solute carrier organic anion transporter family member 1B1", - "version" : 49 + "version" : 109 } ], "source" : "CPIC", @@ -13935,31 +13935,31 @@ "textMarkdown" : { "id" : 1451668701, "html" : "

This annotation is based on the CPIC® guideline for SLCO1B1, ABCG2, and CYP2C9 and statin-associated musculoskeletal symptoms.

\n

February 2022

\n\n\n

Adapted from Table 1 and 2 of the 2022 guideline update manuscript.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
PhenotypeGenotypeExamples of diplotypes aImplications for atorvastatinDosing recommendations for atorvastatin b,cClassification of recommendations d
Normal functionAn individual carrying two normal function alleles or one normal plus one increased function allele*1/*1, *1/*14Typical myopathy risk and statin exposurePrescribe desired starting dose and adjust doses based on disease-specific guidelines.Strong
Increased functionAn individual carrying two increased function alleles*14/*14Typical myopathy risk and statin exposurePrescribe desired starting dose and adjust doses based on disease-specific guidelines.Strong
Decreased functionAn individual carrying one normal or increased function allele plus one no function allele*1/*5, *1/*15Increased atorvastatin exposure as compared to normal function which may translate to increased myopathy riskPrescribe ≤40mg as a starting dose and adjust doses of atorvastatin based on disease-specific guidelines. Prescriber should be aware of possible increased risk for myopathy especially for 40mg dose. If dose >40mg needed for desired efficacy, consider combination therapy (i.e., atorvastatin plus non-statin guideline directed medical therapy).Moderate
Possible decreased functionAn individual carrying one no function allele plus one uncertain/unknown function allele*5/*6, *15/*10, *5/*43Increased atorvastatin exposure as compared to normal function which may translate to increased myopathy riskPrescribe ≤40mg as a starting dose and adjust doses of atorvastatin based on disease-specific guidelines. Prescriber should be aware of possible increased risk for myopathy especially for 40mg dose. If dose >40mg needed for desired efficacy, consider combination therapy (i.e., atorvastatin plus non-statin guideline directed medical therapy).Moderate
Poor functionAn individual carrying two no function alleles*5/*5, *5/*15, *15/*15Increased atorvastatin exposure as compared to normal and decreased function which may translate to increased myopathy risk.Prescribe ≤20mg as a starting dose and adjust doses of atorvastatin based on disease-specific guidelines. If dose >20mg is needed for desired efficacy, consider rosuvastatin or combination therapy (i.e., atorvastatin plus non-statin guideline directed medical therapy).Moderate
IndeterminateAn individual carrying one normal function allele plus one uncertain or unknown function allele OR allele combinations with uncertain and/or unknown function alleles*1/*7, *1/*10, *7/*10n/aNo recommendation.No recommendation.
\n

Figure 1 : SLCO1B1 recommendations with intensity and statin dose stratified by SLCO1B1 phenotype; all doses assume adult dosing.

\n

Adapted from Figure 1 of the 2022 guideline manuscript

\n

\"Fig1\"

\n\n", - "version" : 3 + "version" : 9 }, "userId" : "lgong", - "version" : 5 + "version" : 21 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166297245", - "name" : "Recommendation PA166297245", + "id" : "PA166297247", + "name" : "Recommendation PA166297247", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "SLCO1B1: Typical myopathy risk and statin exposure" + "SLCO1B1: Increased atorvastatin exposure as compared to normal function which may translate to increased myopathy risk" ], - "lookupKey" : {"SLCO1B1": "Increased Function"}, + "lookupKey" : {"SLCO1B1": "Possible Decreased Function"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -13967,27 +13967,27 @@ "objCls" : "Chemical", "id" : "PA448500", "name" : "atorvastatin", - "version" : 22 + "version" : 67 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262221", "name" : "Annotation of CPIC Guideline for atorvastatin and SLCO1B1", - "version" : 5 + "version" : 21 }, "text" : { - "id" : 1452059847, - "html" : "

Prescribe desired starting dose and adjust doses based on disease-specific guidelines.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and ancestry should be evaluated prior to initiating a statin.

\n", + "id" : 1452059849, + "html" : "

Prescribe ≤40mg as a starting dose and adjust doses of atorvastatin based on disease-specific guidelines. Prescriber should be aware of possible increased risk for myopathy especially for 40mg dose. If dose >40mg needed for desired efficacy, consider combination therapy (i.e., atorvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297249", - "name" : "Recommendation PA166297249", - "alternateDrugAvailable" : true, + "id" : "PA166297248", + "name" : "Recommendation PA166297248", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, "parents" : [], @@ -13999,9 +13999,9 @@ }, "dosingInformation" : true, "implications" : [ - "SLCO1B1: Increased atorvastatin exposure as compared to normal and decreased function which may translate to increased myopathy risk." + "SLCO1B1: Increased atorvastatin exposure as compared to normal function which may translate to increased myopathy risk" ], - "lookupKey" : {"SLCO1B1": "Poor Function"}, + "lookupKey" : {"SLCO1B1": "Decreased Function"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -14009,18 +14009,18 @@ "objCls" : "Chemical", "id" : "PA448500", "name" : "atorvastatin", - "version" : 22 + "version" : 67 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262221", "name" : "Annotation of CPIC Guideline for atorvastatin and SLCO1B1", - "version" : 5 + "version" : 21 }, "text" : { - "id" : 1452059851, - "html" : "

Prescribe ≤20mg as a starting dose and adjust doses of atorvastatin based on disease-specific guidelines. If dose >20mg is needed for desired efficacy, consider rosuvastatin or combination therapy (i.e., atorvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452059850, + "html" : "

Prescribe ≤40mg as a starting dose and adjust doses of atorvastatin based on disease-specific guidelines. Prescriber should be aware of possible increased risk for myopathy especially for 40mg dose. If dose >40mg needed for desired efficacy, consider combination therapy (i.e., atorvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, "version" : 0 @@ -14051,26 +14051,26 @@ "objCls" : "Chemical", "id" : "PA448500", "name" : "atorvastatin", - "version" : 22 + "version" : 67 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262221", "name" : "Annotation of CPIC Guideline for atorvastatin and SLCO1B1", - "version" : 5 + "version" : 21 }, "text" : { "id" : 1452059852, "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297246", - "name" : "Recommendation PA166297246", + "id" : "PA166297245", + "name" : "Recommendation PA166297245", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -14085,7 +14085,7 @@ "implications" : [ "SLCO1B1: Typical myopathy risk and statin exposure" ], - "lookupKey" : {"SLCO1B1": "Normal Function"}, + "lookupKey" : {"SLCO1B1": "Increased Function"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -14093,41 +14093,41 @@ "objCls" : "Chemical", "id" : "PA448500", "name" : "atorvastatin", - "version" : 22 + "version" : 67 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262221", "name" : "Annotation of CPIC Guideline for atorvastatin and SLCO1B1", - "version" : 5 + "version" : 21 }, "text" : { - "id" : 1452059848, + "id" : 1452059847, "html" : "

Prescribe desired starting dose and adjust doses based on disease-specific guidelines.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and ancestry should be evaluated prior to initiating a statin.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297247", - "name" : "Recommendation PA166297247", + "id" : "PA166297246", + "name" : "Recommendation PA166297246", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "SLCO1B1: Increased atorvastatin exposure as compared to normal function which may translate to increased myopathy risk" + "SLCO1B1: Typical myopathy risk and statin exposure" ], - "lookupKey" : {"SLCO1B1": "Possible Decreased Function"}, + "lookupKey" : {"SLCO1B1": "Normal Function"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -14135,27 +14135,27 @@ "objCls" : "Chemical", "id" : "PA448500", "name" : "atorvastatin", - "version" : 22 + "version" : 67 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262221", "name" : "Annotation of CPIC Guideline for atorvastatin and SLCO1B1", - "version" : 5 + "version" : 21 }, "text" : { - "id" : 1452059849, - "html" : "

Prescribe ≤40mg as a starting dose and adjust doses of atorvastatin based on disease-specific guidelines. Prescriber should be aware of possible increased risk for myopathy especially for 40mg dose. If dose >40mg needed for desired efficacy, consider combination therapy (i.e., atorvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452059848, + "html" : "

Prescribe desired starting dose and adjust doses based on disease-specific guidelines.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and ancestry should be evaluated prior to initiating a statin.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297248", - "name" : "Recommendation PA166297248", - "alternateDrugAvailable" : false, + "id" : "PA166297249", + "name" : "Recommendation PA166297249", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501931, "parents" : [], @@ -14167,9 +14167,9 @@ }, "dosingInformation" : true, "implications" : [ - "SLCO1B1: Increased atorvastatin exposure as compared to normal function which may translate to increased myopathy risk" + "SLCO1B1: Increased atorvastatin exposure as compared to normal and decreased function which may translate to increased myopathy risk." ], - "lookupKey" : {"SLCO1B1": "Decreased Function"}, + "lookupKey" : {"SLCO1B1": "Poor Function"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -14177,21 +14177,21 @@ "objCls" : "Chemical", "id" : "PA448500", "name" : "atorvastatin", - "version" : 22 + "version" : 67 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262221", "name" : "Annotation of CPIC Guideline for atorvastatin and SLCO1B1", - "version" : 5 + "version" : 21 }, "text" : { - "id" : 1452059850, - "html" : "

Prescribe ≤40mg as a starting dose and adjust doses of atorvastatin based on disease-specific guidelines. Prescriber should be aware of possible increased risk for myopathy especially for 40mg dose. If dose >40mg needed for desired efficacy, consider combination therapy (i.e., atorvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452059851, + "html" : "

Prescribe ≤20mg as a starting dose and adjust doses of atorvastatin based on disease-specific guidelines. If dose >20mg is needed for desired efficacy, consider rosuvastatin or combination therapy (i.e., atorvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166262221" @@ -14499,7 +14499,7 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "relatedGenes" : [ @@ -14508,14 +14508,14 @@ "id" : "PA134963132", "symbol" : "NUDT15", "name" : "nudix hydrolase 15", - "version" : 11 + "version" : 39 }, { "objCls" : "Gene", "id" : "PA356", "symbol" : "TPMT", "name" : "thiopurine S-methyltransferase", - "version" : 7545 + "version" : 7628 } ], "source" : "CPIC", @@ -14531,14 +14531,14 @@ "version" : 3 }, "userId" : "rachel", - "version" : 53 + "version" : 353 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166297284", - "name" : "Recommendation PA166297284", - "alternateDrugAvailable" : true, + "id" : "PA166297040", + "name" : "Recommendation PA166297040", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, "parents" : [], @@ -14548,39 +14548,82 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "NUDT15: Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression", - "TPMT: Extremely high concentrations of TGN metabolites; fatal toxicity possible without dose decrease; no MeTIMP metabolites. Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." + "NUDT15: n/a", + "TPMT: n/a" ], - "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Normal Metabolizer"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"TPMT": "No Result", "NUDT15": "Indeterminate"}, + "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104933", "name" : "Annotation of CPIC Guideline for azathioprine and NUDT15, TPMT", - "version" : 53 + "version" : 353 }, "text" : { - "id" : 1452059886, - "html" : "

For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy. For malignancy, start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily) and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment (PMID 16530578, 11302950, 15606506, 16530532, 12477776).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "id" : 1452059642, + "html" : "

NUDT15 phenotype could not be assigned based on genotyping performed and no TPMT genotype is available. Consider evaluating TPMT erythrocyte activity to assess TPMT phenotype. If thiopurines are required and either TPMT or NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297271", - "name" : "Recommendation PA166297271", + "id" : "PA166297251", + "name" : "Recommendation PA166297251", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501930, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : false, + "implications" : [ + "NUDT15: n/a", + "TPMT: n/a" + ], + "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "Indeterminate"}, + "otherPrescribingGuidance" : true, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA448515", + "name" : "azathioprine", + "version" : 57 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104933", + "name" : "Annotation of CPIC Guideline for azathioprine and NUDT15, TPMT", + "version" : 353 + }, + "text" : { + "id" : 1452059853, + "html" : "

Neither TPMT or NUDT15 phenotype could be assigned based on genotyping performed. Consider evaluating TPMT erythrocyte activity to assess TPMT phenotype. If thiopurines are required and either TPMT or NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", + "version" : 0 + }, + "version" : 1 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166297252", + "name" : "Recommendation PA166297252", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -14593,10 +14636,10 @@ }, "dosingInformation" : true, "implications" : [ - "NUDT15: Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression", - "TPMT: Moderate to high concentrations of TGN metabolites; low concentrations of MeTIMP. Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." + "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "TPMT: n/a" ], - "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Normal Metabolizer"}, + "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -14604,26 +14647,26 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104933", "name" : "Annotation of CPIC Guideline for azathioprine and NUDT15, TPMT", - "version" : 53 + "version" : 353 }, "text" : { - "id" : 1452059873, - "html" : "

Start with reduced starting doses (30%-80% of normal dose) if normal starting dose is 2-3 mg/kg/day (e.g., 0.6 – 2.4 mg/kg/day), and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment (PMID 20354201, 11302950, 15606506, 16530532).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "id" : 1452059854, + "html" : "

Based on NUDT15 status, start with reduced starting doses (30%-80% of normal dose) if normal starting dose is 2-3 mg/kg/day (e.g., 0.6 – 2.4 mg/kg/day), and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment (PMID 20354201, 11302950, 15606506, 16530532). TPMT phenotype could not be assigned based on genotyping performed. Consider evaluating erythrocyte TPMT activity to assess TPMT phenotype. If thiopurines are required and TPMT status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers. Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297253", - "name" : "Recommendation PA166297253", + "id" : "PA166297155", + "name" : "Recommendation PA166297155", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -14636,10 +14679,10 @@ }, "dosingInformation" : false, "implications" : [ - "NUDT15: Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "NUDT15: n/a", "TPMT: n/a" ], - "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "Normal Metabolizer"}, + "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "No Result"}, "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ @@ -14647,26 +14690,26 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104933", "name" : "Annotation of CPIC Guideline for azathioprine and NUDT15, TPMT", - "version" : 53 + "version" : 353 }, "text" : { - "id" : 1452059855, - "html" : "

Based on NUDT15, start with normal starting dose (e.g., 2-3 mg/kg/day) and adjust doses of azathioprine based on disease-specific guidelines. Allow 2 weeks to reach steady-state after each dose adjustment (PMID 20354201, 11302950, 15606506). TPMT phenotype could not be assigned based on genotyping performed. Consider evaluating erythrocyte TPMT activity to assess TPMT phenotype. If thiopurines are required and TPMT status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers. Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", + "id" : 1452059757, + "html" : "

TPMT phenotype could not be assigned based on genotyping performed and NUDT15 genotype is not available. Consider evaluating TPMT erythrocyte activity to assess TPMT phenotype. If thiopurines are required and either TPMT or NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297288", - "name" : "Recommendation PA166297288", + "id" : "PA166297254", + "name" : "Recommendation PA166297254", "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, @@ -14679,10 +14722,10 @@ }, "dosingInformation" : true, "implications" : [ - "NUDT15: n/a", - "TPMT: Extremely high concentrations of TGN metabolites; fatal toxicity possible without dose decrease; no MeTIMP metabolites. Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." + "NUDT15: Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "TPMT: n/a" ], - "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "No Result"}, + "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -14690,27 +14733,27 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104933", "name" : "Annotation of CPIC Guideline for azathioprine and NUDT15, TPMT", - "version" : 53 + "version" : 353 }, "text" : { - "id" : 1452059890, - "html" : "

Based on TPMT status, for non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy. For malignancy, start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily) and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment (PMID 16530578, 11302950, 15606506, 16530532, 12477776). NUDT15 genotype is not available. If thiopurines are required and NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "id" : 1452059856, + "html" : "

Based on NUDT15 status, for non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy. For malignant conditions, start with drastically reduced normal daily doses (reduce daily dose by 10-fold) and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment (PMID 16530578, 11302950, 15606506, 16530532, 12477776). TPMT phenotype could not be assigned based on genotyping performed. Consider evaluating erythrocyte TPMT activity to assess TPMT phenotype. If thiopurines are required and TPMT status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers. Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297275", - "name" : "Recommendation PA166297275", - "alternateDrugAvailable" : false, + "id" : "PA166297259", + "name" : "Recommendation PA166297259", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, "parents" : [], @@ -14720,12 +14763,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "NUDT15: n/a", - "TPMT: Lower concentrations of TGN metabolites, higher MeTIMP, this is the ‘normal’ pattern. Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression." + "NUDT15: Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "TPMT: n/a" ], - "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "Indeterminate"}, + "lookupKey" : {"TPMT": "No Result", "NUDT15": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -14733,27 +14776,27 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104933", "name" : "Annotation of CPIC Guideline for azathioprine and NUDT15, TPMT", - "version" : 53 + "version" : 353 }, "text" : { - "id" : 1452059877, - "html" : "

Based on TPMT status, start with normal starting dose (e.g., 2-3 mg/kg/day) and adjust doses of azathioprine based on disease-specific guidelines. Allow 2 weeks to reach steady-state after each dose adjustment (PMID 20354201, 11302950, 15606506). NUDT15 status could not be determined based on genotyping. If thiopurines are required and NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "id" : 1452059861, + "html" : "

Based on NUDT15 status, for non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy. For malignant conditions, start with drastically reduced normal daily doses (reduce daily dose by 10-fold) and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment (PMID 16530578, 11302950, 15606506, 16530532, 12477776). TPMT genotype is not available. Consider evaluating erythrocyte TPMT activity to assess TPMT phenotype. If thiopurines are required and TPMT status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers. Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297262", - "name" : "Recommendation PA166297262", - "alternateDrugAvailable" : false, + "id" : "PA166297265", + "name" : "Recommendation PA166297265", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, "parents" : [], @@ -14765,10 +14808,10 @@ }, "dosingInformation" : true, "implications" : [ - "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "NUDT15: Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", "TPMT: Moderate to high concentrations of TGN metabolites; low concentrations of MeTIMP. Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." ], - "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -14776,26 +14819,26 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104933", "name" : "Annotation of CPIC Guideline for azathioprine and NUDT15, TPMT", - "version" : 53 + "version" : 353 }, "text" : { - "id" : 1452059864, - "html" : "

Start with reduced starting doses (20%-50% of normal dose) if normal starting dose is 2-3 mg/kg/day (e.g., 0.4 – 1.5 mg/kg/day), and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines. At least 2-4 weeks will be required to reach steady-state after each dose adjustment (PMID 20354201, 11302950, 15606506, 16530532).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", - "version" : 1 + "id" : 1452059867, + "html" : "

For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy. For malignant conditions, start with drastically reduced normal daily doses (reduce daily dose by 10-fold) and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment (PMID 16530578, 11302950, 15606506, 16530532, 12477776).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "version" : 0 }, - "version" : 1 + "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297267", - "name" : "Recommendation PA166297267", + "id" : "PA166297253", + "name" : "Recommendation PA166297253", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -14806,40 +14849,40 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "NUDT15: n/a", - "TPMT: Moderate to high concentrations of TGN metabolites; low concentrations of MeTIMP. Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." + "NUDT15: Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "TPMT: n/a" ], - "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "No Result"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "Normal Metabolizer"}, + "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104933", "name" : "Annotation of CPIC Guideline for azathioprine and NUDT15, TPMT", - "version" : 53 + "version" : 353 }, "text" : { - "id" : 1452059869, - "html" : "

Based on TPMT status, start with reduced starting doses (30%-80% of normal dose) if normal starting dose is 2-3 mg/kg/day (e.g., 0.6 – 2.4 mg/kg/day), and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment (PMID 20354201, 11302950, 15606506, 16530532). NUDT15 genotype is not available. If thiopurines are required and either TPMT or NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "id" : 1452059855, + "html" : "

Based on NUDT15, start with normal starting dose (e.g., 2-3 mg/kg/day) and adjust doses of azathioprine based on disease-specific guidelines. Allow 2 weeks to reach steady-state after each dose adjustment (PMID 20354201, 11302950, 15606506). TPMT phenotype could not be assigned based on genotyping performed. Consider evaluating erythrocyte TPMT activity to assess TPMT phenotype. If thiopurines are required and TPMT status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers. Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297254", - "name" : "Recommendation PA166297254", - "alternateDrugAvailable" : true, + "id" : "PA166297255", + "name" : "Recommendation PA166297255", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, "parents" : [], @@ -14851,10 +14894,10 @@ }, "dosingInformation" : true, "implications" : [ - "NUDT15: Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", "TPMT: n/a" ], - "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "Poor Metabolizer"}, + "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "Possible Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -14862,26 +14905,26 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104933", "name" : "Annotation of CPIC Guideline for azathioprine and NUDT15, TPMT", - "version" : 53 + "version" : 353 }, "text" : { - "id" : 1452059856, - "html" : "

Based on NUDT15 status, for non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy. For malignant conditions, start with drastically reduced normal daily doses (reduce daily dose by 10-fold) and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment (PMID 16530578, 11302950, 15606506, 16530532, 12477776). TPMT phenotype could not be assigned based on genotyping performed. Consider evaluating erythrocyte TPMT activity to assess TPMT phenotype. If thiopurines are required and TPMT status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers. Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", + "id" : 1452059857, + "html" : "

Based on NUDT15 status, start with reduced starting doses (30%-80% of normal dose) if normal starting dose is 2-3 mg/kg/day (e.g., 0.6 – 2.4 mg/kg/day), and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment (PMID 20354201, 11302950, 15606506, 16530532). TPMT phenotype could not be assigned based on genotyping performed. Consider evaluating erythrocyte TPMT activity to assess TPMT phenotype. If thiopurines are required and TPMT status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers. Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297280", - "name" : "Recommendation PA166297280", + "id" : "PA166297257", + "name" : "Recommendation PA166297257", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -14895,9 +14938,9 @@ "dosingInformation" : true, "implications" : [ "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", - "TPMT: Lower concentrations of TGN metabolites, higher MeTIMP, this is the ‘normal’ pattern. Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression." + "TPMT: n/a" ], - "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "Possible Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "No Result", "NUDT15": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -14905,21 +14948,21 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104933", "name" : "Annotation of CPIC Guideline for azathioprine and NUDT15, TPMT", - "version" : 53 + "version" : 353 }, "text" : { - "id" : 1452059882, - "html" : "

Start with reduced starting doses (30%-80% of normal dose) if normal starting dose is 2-3 mg/kg/day (e.g., 0.6 – 2.4 mg/kg/day), and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment (PMID 20354201, 11302950, 15606506, 16530532).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "id" : 1452059859, + "html" : "

Based on NUDT15 status, start with reduced starting doses (30%-80% of normal dose) if normal starting dose is 2-3 mg/kg/day (e.g., 0.6 – 2.4 mg/kg/day), and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment (PMID 20354201, 11302950, 15606506, 16530532). TPMT genotype is not available. Consider evaluating erythrocyte TPMT activity to assess TPMT phenotype. If thiopurines are required and TPMT status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers. Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -14948,27 +14991,27 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104933", "name" : "Annotation of CPIC Guideline for azathioprine and NUDT15, TPMT", - "version" : 53 + "version" : 353 }, "text" : { "id" : 1452059860, "html" : "

Based on NUDT15, start with normal starting dose (e.g., 2-3 mg/kg/day) and adjust doses of azathioprine based on disease-specific guidelines. Allow 2 weeks to reach steady-state after each dose adjustment (PMID 20354201, 11302950, 15606506). TPMT genotype is not available. Consider evaluating erythrocyte TPMT activity to assess TPMT phenotype. If thiopurines are required and TPMT status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers. Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297272", - "name" : "Recommendation PA166297272", - "alternateDrugAvailable" : true, + "id" : "PA166297260", + "name" : "Recommendation PA166297260", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, "parents" : [], @@ -14980,10 +15023,10 @@ }, "dosingInformation" : true, "implications" : [ - "NUDT15: Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", - "TPMT: Moderate to high concentrations of TGN metabolites; low concentrations of MeTIMP. Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." + "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "TPMT: n/a" ], - "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Poor Metabolizer"}, + "lookupKey" : {"TPMT": "No Result", "NUDT15": "Possible Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -14991,26 +15034,26 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104933", "name" : "Annotation of CPIC Guideline for azathioprine and NUDT15, TPMT", - "version" : 53 + "version" : 353 }, "text" : { - "id" : 1452059874, - "html" : "

For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy. For malignant conditions, start with drastically reduced normal daily doses (reduce daily dose by 10-fold) and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment (PMID 16530578, 11302950, 15606506, 16530532, 12477776).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "id" : 1452059862, + "html" : "

Based on NUDT15 status, start with reduced starting doses (30%-80% of normal dose) if normal starting dose is 2-3 mg/kg/day (e.g., 0.6 – 2.4 mg/kg/day), and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment (PMID 20354201, 11302950, 15606506, 16530532). TPMT genotype is not available. Consider evaluating erythrocyte TPMT activity to assess TPMT phenotype. If thiopurines are required and TPMT status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers. Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297276", - "name" : "Recommendation PA166297276", + "id" : "PA166297261", + "name" : "Recommendation PA166297261", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -15023,10 +15066,10 @@ }, "dosingInformation" : true, "implications" : [ - "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", - "TPMT: Lower concentrations of TGN metabolites, higher MeTIMP, this is the ‘normal’ pattern. Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression." + "NUDT15: n/a", + "TPMT: Moderate to high concentrations of TGN metabolites; low concentrations of MeTIMP. Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." ], - "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -15034,26 +15077,26 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104933", "name" : "Annotation of CPIC Guideline for azathioprine and NUDT15, TPMT", - "version" : 53 + "version" : 353 }, "text" : { - "id" : 1452059878, - "html" : "

Start with reduced starting doses (30%-80% of normal dose) if normal starting dose is 2-3 mg/kg/day (e.g., 0.6 – 2.4 mg/kg/day), and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment (PMID 20354201, 11302950, 15606506, 16530532).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "id" : 1452059863, + "html" : "

Based on TPMT status, start with reduced starting doses (30%-80% of normal dose) if normal starting dose is 2-3 mg/kg/day (e.g., 0.6 – 2.4 mg/kg/day), and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment (PMID 20354201, 11302950, 15606506, 16530532). NUDT15 phenotype could not be assigned based on genotyping. If thiopurines are required and either TPMT or NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297268", - "name" : "Recommendation PA166297268", + "id" : "PA166297264", + "name" : "Recommendation PA166297264", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -15066,10 +15109,10 @@ }, "dosingInformation" : true, "implications" : [ - "NUDT15: n/a", + "NUDT15: Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression", "TPMT: Moderate to high concentrations of TGN metabolites; low concentrations of MeTIMP. Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." ], - "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Indeterminate"}, + "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -15077,26 +15120,26 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104933", "name" : "Annotation of CPIC Guideline for azathioprine and NUDT15, TPMT", - "version" : 53 + "version" : 353 }, "text" : { - "id" : 1452059870, - "html" : "

Based on TPMT status, start with reduced starting doses (30%-80% of normal dose) if normal starting dose is 2-3 mg/kg/day (e.g., 0.6 – 2.4 mg/kg/day), and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment (PMID 20354201, 11302950, 15606506, 16530532). NUDT15 phenotype could not be assigned based on genotyping. If thiopurines are required and NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "id" : 1452059866, + "html" : "

Start with reduced starting doses (30%-80% of normal dose) if normal starting dose is 2-3 mg/kg/day (e.g., 0.6 – 2.4 mg/kg/day), and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment (PMID 20354201, 11302950, 15606506, 16530532).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297255", - "name" : "Recommendation PA166297255", + "id" : "PA166297267", + "name" : "Recommendation PA166297267", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -15109,10 +15152,10 @@ }, "dosingInformation" : true, "implications" : [ - "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", - "TPMT: n/a" + "NUDT15: n/a", + "TPMT: Moderate to high concentrations of TGN metabolites; low concentrations of MeTIMP. Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." ], - "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "Possible Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -15120,26 +15163,26 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104933", "name" : "Annotation of CPIC Guideline for azathioprine and NUDT15, TPMT", - "version" : 53 + "version" : 353 }, "text" : { - "id" : 1452059857, - "html" : "

Based on NUDT15 status, start with reduced starting doses (30%-80% of normal dose) if normal starting dose is 2-3 mg/kg/day (e.g., 0.6 – 2.4 mg/kg/day), and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment (PMID 20354201, 11302950, 15606506, 16530532). TPMT phenotype could not be assigned based on genotyping performed. Consider evaluating erythrocyte TPMT activity to assess TPMT phenotype. If thiopurines are required and TPMT status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers. Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", + "id" : 1452059869, + "html" : "

Based on TPMT status, start with reduced starting doses (30%-80% of normal dose) if normal starting dose is 2-3 mg/kg/day (e.g., 0.6 – 2.4 mg/kg/day), and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment (PMID 20354201, 11302950, 15606506, 16530532). NUDT15 genotype is not available. If thiopurines are required and either TPMT or NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297281", - "name" : "Recommendation PA166297281", + "id" : "PA166297268", + "name" : "Recommendation PA166297268", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -15150,12 +15193,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ "NUDT15: n/a", - "TPMT: Lower concentrations of TGN metabolites, higher MeTIMP, this is the ‘normal’ pattern. Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression." + "TPMT: Moderate to high concentrations of TGN metabolites; low concentrations of MeTIMP. Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." ], - "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "No Result"}, + "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -15163,27 +15206,27 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104933", "name" : "Annotation of CPIC Guideline for azathioprine and NUDT15, TPMT", - "version" : 53 + "version" : 353 }, "text" : { - "id" : 1452059883, - "html" : "

Based on TPMT status, start with normal starting dose (e.g., 2-3 mg/kg/day) and adjust doses of azathioprine based on disease-specific guidelines. Allow 2 weeks to reach steady-state after each dose adjustment (PMID 20354201, 11302950, 15606506). NUDT15 genotype is not available. If thiopurines are required and NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "id" : 1452059870, + "html" : "

Based on TPMT status, start with reduced starting doses (30%-80% of normal dose) if normal starting dose is 2-3 mg/kg/day (e.g., 0.6 – 2.4 mg/kg/day), and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment (PMID 20354201, 11302950, 15606506, 16530532). NUDT15 phenotype could not be assigned based on genotyping. If thiopurines are required and NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297259", - "name" : "Recommendation PA166297259", - "alternateDrugAvailable" : true, + "id" : "PA166297271", + "name" : "Recommendation PA166297271", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, "parents" : [], @@ -15195,10 +15238,10 @@ }, "dosingInformation" : true, "implications" : [ - "NUDT15: Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", - "TPMT: n/a" + "NUDT15: Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "TPMT: Moderate to high concentrations of TGN metabolites; low concentrations of MeTIMP. Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." ], - "lookupKey" : {"TPMT": "No Result", "NUDT15": "Poor Metabolizer"}, + "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -15206,27 +15249,27 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104933", "name" : "Annotation of CPIC Guideline for azathioprine and NUDT15, TPMT", - "version" : 53 + "version" : 353 }, "text" : { - "id" : 1452059861, - "html" : "

Based on NUDT15 status, for non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy. For malignant conditions, start with drastically reduced normal daily doses (reduce daily dose by 10-fold) and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment (PMID 16530578, 11302950, 15606506, 16530532, 12477776). TPMT genotype is not available. Consider evaluating erythrocyte TPMT activity to assess TPMT phenotype. If thiopurines are required and TPMT status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers. Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", + "id" : 1452059873, + "html" : "

Start with reduced starting doses (30%-80% of normal dose) if normal starting dose is 2-3 mg/kg/day (e.g., 0.6 – 2.4 mg/kg/day), and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment (PMID 20354201, 11302950, 15606506, 16530532).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297273", - "name" : "Recommendation PA166297273", - "alternateDrugAvailable" : false, + "id" : "PA166297272", + "name" : "Recommendation PA166297272", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, "parents" : [], @@ -15238,10 +15281,10 @@ }, "dosingInformation" : true, "implications" : [ - "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "NUDT15: Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", "TPMT: Moderate to high concentrations of TGN metabolites; low concentrations of MeTIMP. Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." ], - "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Possible Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -15249,27 +15292,27 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104933", "name" : "Annotation of CPIC Guideline for azathioprine and NUDT15, TPMT", - "version" : 53 + "version" : 353 }, "text" : { - "id" : 1452059875, - "html" : "

Start with reduced starting doses (20%-50% of normal dose) if normal starting dose is 2-3 mg/kg/day (e.g., 0.4 – 1.5 mg/kg/day), and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines. At least 2-4 weeks will be required to reach steady-state after each dose adjustment (PMID 20354201, 11302950, 15606506, 16530532).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", - "version" : 1 + "id" : 1452059874, + "html" : "

For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy. For malignant conditions, start with drastically reduced normal daily doses (reduce daily dose by 10-fold) and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment (PMID 16530578, 11302950, 15606506, 16530532, 12477776).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "version" : 0 }, - "version" : 1 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297260", - "name" : "Recommendation PA166297260", - "alternateDrugAvailable" : false, + "id" : "PA166297279", + "name" : "Recommendation PA166297279", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, "parents" : [], @@ -15281,10 +15324,10 @@ }, "dosingInformation" : true, "implications" : [ - "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", - "TPMT: n/a" + "NUDT15: Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "TPMT: Lower concentrations of TGN metabolites, higher MeTIMP, this is the ‘normal’ pattern. Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression." ], - "lookupKey" : {"TPMT": "No Result", "NUDT15": "Possible Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -15292,18 +15335,18 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104933", "name" : "Annotation of CPIC Guideline for azathioprine and NUDT15, TPMT", - "version" : 53 + "version" : 353 }, "text" : { - "id" : 1452059862, - "html" : "

Based on NUDT15 status, start with reduced starting doses (30%-80% of normal dose) if normal starting dose is 2-3 mg/kg/day (e.g., 0.6 – 2.4 mg/kg/day), and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment (PMID 20354201, 11302950, 15606506, 16530532). TPMT genotype is not available. Consider evaluating erythrocyte TPMT activity to assess TPMT phenotype. If thiopurines are required and TPMT status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers. Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", + "id" : 1452059881, + "html" : "

For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy. For malignant conditions, start with drastically reduced normal daily doses (reduce daily dose by 10-fold) and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment (PMID 16530578, 11302950, 15606506, 16530532, 12477776).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", "version" : 0 }, "version" : 0 @@ -15335,14 +15378,14 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104933", "name" : "Annotation of CPIC Guideline for azathioprine and NUDT15, TPMT", - "version" : 53 + "version" : 353 }, "text" : { "id" : 1452059884, @@ -15353,52 +15396,9 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297040", - "name" : "Recommendation PA166297040", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 981501930, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "NUDT15: n/a", - "TPMT: n/a" - ], - "lookupKey" : {"TPMT": "No Result", "NUDT15": "Indeterminate"}, - "otherPrescribingGuidance" : true, - "population" : "general", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA448515", - "name" : "azathioprine", - "version" : 26 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166104933", - "name" : "Annotation of CPIC Guideline for azathioprine and NUDT15, TPMT", - "version" : 53 - }, - "text" : { - "id" : 1452059642, - "html" : "

NUDT15 phenotype could not be assigned based on genotyping performed and no TPMT genotype is available. Consider evaluating TPMT erythrocyte activity to assess TPMT phenotype. If thiopurines are required and either TPMT or NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166297277", - "name" : "Recommendation PA166297277", - "alternateDrugAvailable" : false, + "id" : "PA166297283", + "name" : "Recommendation PA166297283", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, "parents" : [], @@ -15408,12 +15408,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "NUDT15: Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression", - "TPMT: Lower concentrations of TGN metabolites, higher MeTIMP, this is the ‘normal’ pattern. Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression." + "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "TPMT: Extremely high concentrations of TGN metabolites; fatal toxicity possible without dose decrease; no MeTIMP metabolites. Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." ], - "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "Normal Metabolizer"}, + "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -15421,27 +15421,27 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104933", "name" : "Annotation of CPIC Guideline for azathioprine and NUDT15, TPMT", - "version" : 53 + "version" : 353 }, "text" : { - "id" : 1452059879, - "html" : "

Start with normal starting dose (e.g., 2-3 mg/kg/day) and adjust doses of azathioprine based on disease-specific guidelines. Allow 2 weeks to reach steady-state after each dose adjustment (PMID 20354201, 11302950, 15606506).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "id" : 1452059885, + "html" : "

For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy. For malignancy, start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily) and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment (PMID 16530578, 11302950, 15606506, 16530532, 12477776).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297264", - "name" : "Recommendation PA166297264", - "alternateDrugAvailable" : false, + "id" : "PA166297284", + "name" : "Recommendation PA166297284", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, "parents" : [], @@ -15454,9 +15454,9 @@ "dosingInformation" : true, "implications" : [ "NUDT15: Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression", - "TPMT: Moderate to high concentrations of TGN metabolites; low concentrations of MeTIMP. Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." + "TPMT: Extremely high concentrations of TGN metabolites; fatal toxicity possible without dose decrease; no MeTIMP metabolites. Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." ], - "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Normal Metabolizer"}, + "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -15464,27 +15464,27 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104933", "name" : "Annotation of CPIC Guideline for azathioprine and NUDT15, TPMT", - "version" : 53 + "version" : 353 }, "text" : { - "id" : 1452059866, - "html" : "

Start with reduced starting doses (30%-80% of normal dose) if normal starting dose is 2-3 mg/kg/day (e.g., 0.6 – 2.4 mg/kg/day), and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment (PMID 20354201, 11302950, 15606506, 16530532).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "id" : 1452059886, + "html" : "

For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy. For malignancy, start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily) and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment (PMID 16530578, 11302950, 15606506, 16530532, 12477776).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297251", - "name" : "Recommendation PA166297251", - "alternateDrugAvailable" : false, + "id" : "PA166297286", + "name" : "Recommendation PA166297286", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, "parents" : [], @@ -15494,39 +15494,39 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "NUDT15: n/a", - "TPMT: n/a" + "NUDT15: Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "TPMT: Extremely high concentrations of TGN metabolites; fatal toxicity possible without dose decrease; no MeTIMP metabolites. Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." ], - "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "Indeterminate"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Poor Metabolizer"}, + "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104933", "name" : "Annotation of CPIC Guideline for azathioprine and NUDT15, TPMT", - "version" : 53 + "version" : 353 }, "text" : { - "id" : 1452059853, - "html" : "

Neither TPMT or NUDT15 phenotype could be assigned based on genotyping performed. Consider evaluating TPMT erythrocyte activity to assess TPMT phenotype. If thiopurines are required and either TPMT or NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", + "id" : 1452059888, + "html" : "

For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy. For malignancy, start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily) and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment (PMID 16530578, 11302950, 15606506, 16530532, 12477776).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297286", - "name" : "Recommendation PA166297286", + "id" : "PA166297287", + "name" : "Recommendation PA166297287", "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, @@ -15539,10 +15539,10 @@ }, "dosingInformation" : true, "implications" : [ - "NUDT15: Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", "TPMT: Extremely high concentrations of TGN metabolites; fatal toxicity possible without dose decrease; no MeTIMP metabolites. Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." ], - "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Poor Metabolizer"}, + "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Possible Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -15550,17 +15550,17 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104933", "name" : "Annotation of CPIC Guideline for azathioprine and NUDT15, TPMT", - "version" : 53 + "version" : 353 }, "text" : { - "id" : 1452059888, + "id" : 1452059889, "html" : "

For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy. For malignancy, start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily) and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment (PMID 16530578, 11302950, 15606506, 16530532, 12477776).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", "version" : 0 }, @@ -15568,9 +15568,9 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297269", - "name" : "Recommendation PA166297269", - "alternateDrugAvailable" : false, + "id" : "PA166297288", + "name" : "Recommendation PA166297288", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, "parents" : [], @@ -15582,10 +15582,10 @@ }, "dosingInformation" : true, "implications" : [ - "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", - "TPMT: Moderate to high concentrations of TGN metabolites; low concentrations of MeTIMP. Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." + "NUDT15: n/a", + "TPMT: Extremely high concentrations of TGN metabolites; fatal toxicity possible without dose decrease; no MeTIMP metabolites. Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." ], - "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -15593,26 +15593,26 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104933", "name" : "Annotation of CPIC Guideline for azathioprine and NUDT15, TPMT", - "version" : 53 + "version" : 353 }, "text" : { - "id" : 1452059871, - "html" : "

Start with reduced starting doses (20%-50% of normal dose) if normal starting dose is 2-3 mg/kg/day (e.g., 0.4 – 1.5 mg/kg/day), and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment (PMID 20354201, 11302950, 15606506, 16530532).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", - "version" : 1 + "id" : 1452059890, + "html" : "

Based on TPMT status, for non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy. For malignancy, start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily) and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment (PMID 16530578, 11302950, 15606506, 16530532, 12477776). NUDT15 genotype is not available. If thiopurines are required and NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "version" : 0 }, - "version" : 1 + "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297261", - "name" : "Recommendation PA166297261", + "id" : "PA166297274", + "name" : "Recommendation PA166297274", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -15628,7 +15628,7 @@ "NUDT15: n/a", "TPMT: Moderate to high concentrations of TGN metabolites; low concentrations of MeTIMP. Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." ], - "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Indeterminate"}, + "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -15636,27 +15636,27 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104933", "name" : "Annotation of CPIC Guideline for azathioprine and NUDT15, TPMT", - "version" : 53 + "version" : 353 }, "text" : { - "id" : 1452059863, - "html" : "

Based on TPMT status, start with reduced starting doses (30%-80% of normal dose) if normal starting dose is 2-3 mg/kg/day (e.g., 0.6 – 2.4 mg/kg/day), and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment (PMID 20354201, 11302950, 15606506, 16530532). NUDT15 phenotype could not be assigned based on genotyping. If thiopurines are required and either TPMT or NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "id" : 1452059876, + "html" : "

Based on TPMT status, start with reduced starting doses (30%-80% of normal dose) if normal starting dose is 2-3 mg/kg/day (e.g., 0.6 – 2.4 mg/kg/day), and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment (PMID 20354201, 11302950, 15606506, 16530532). NUDT15 genotype is not available. If thiopurines are required and NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297283", - "name" : "Recommendation PA166297283", - "alternateDrugAvailable" : true, + "id" : "PA166297276", + "name" : "Recommendation PA166297276", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, "parents" : [], @@ -15669,9 +15669,9 @@ "dosingInformation" : true, "implications" : [ "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", - "TPMT: Extremely high concentrations of TGN metabolites; fatal toxicity possible without dose decrease; no MeTIMP metabolites. Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." + "TPMT: Lower concentrations of TGN metabolites, higher MeTIMP, this is the ‘normal’ pattern. Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression." ], - "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -15679,27 +15679,27 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104933", "name" : "Annotation of CPIC Guideline for azathioprine and NUDT15, TPMT", - "version" : 53 + "version" : 353 }, "text" : { - "id" : 1452059885, - "html" : "

For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy. For malignancy, start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily) and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment (PMID 16530578, 11302950, 15606506, 16530532, 12477776).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "id" : 1452059878, + "html" : "

Start with reduced starting doses (30%-80% of normal dose) if normal starting dose is 2-3 mg/kg/day (e.g., 0.6 – 2.4 mg/kg/day), and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment (PMID 20354201, 11302950, 15606506, 16530532).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297265", - "name" : "Recommendation PA166297265", - "alternateDrugAvailable" : true, + "id" : "PA166297277", + "name" : "Recommendation PA166297277", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, "parents" : [], @@ -15709,12 +15709,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "NUDT15: Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", - "TPMT: Moderate to high concentrations of TGN metabolites; low concentrations of MeTIMP. Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." + "NUDT15: Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "TPMT: Lower concentrations of TGN metabolites, higher MeTIMP, this is the ‘normal’ pattern. Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression." ], - "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Poor Metabolizer"}, + "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -15722,26 +15722,26 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104933", "name" : "Annotation of CPIC Guideline for azathioprine and NUDT15, TPMT", - "version" : 53 + "version" : 353 }, "text" : { - "id" : 1452059867, - "html" : "

For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy. For malignant conditions, start with drastically reduced normal daily doses (reduce daily dose by 10-fold) and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment (PMID 16530578, 11302950, 15606506, 16530532, 12477776).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "id" : 1452059879, + "html" : "

Start with normal starting dose (e.g., 2-3 mg/kg/day) and adjust doses of azathioprine based on disease-specific guidelines. Allow 2 weeks to reach steady-state after each dose adjustment (PMID 20354201, 11302950, 15606506).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297252", - "name" : "Recommendation PA166297252", + "id" : "PA166297280", + "name" : "Recommendation PA166297280", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -15755,9 +15755,9 @@ "dosingInformation" : true, "implications" : [ "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", - "TPMT: n/a" + "TPMT: Lower concentrations of TGN metabolites, higher MeTIMP, this is the ‘normal’ pattern. Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression." ], - "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "Possible Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -15765,26 +15765,26 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104933", "name" : "Annotation of CPIC Guideline for azathioprine and NUDT15, TPMT", - "version" : 53 + "version" : 353 }, "text" : { - "id" : 1452059854, - "html" : "

Based on NUDT15 status, start with reduced starting doses (30%-80% of normal dose) if normal starting dose is 2-3 mg/kg/day (e.g., 0.6 – 2.4 mg/kg/day), and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment (PMID 20354201, 11302950, 15606506, 16530532). TPMT phenotype could not be assigned based on genotyping performed. Consider evaluating erythrocyte TPMT activity to assess TPMT phenotype. If thiopurines are required and TPMT status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers. Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", + "id" : 1452059882, + "html" : "

Start with reduced starting doses (30%-80% of normal dose) if normal starting dose is 2-3 mg/kg/day (e.g., 0.6 – 2.4 mg/kg/day), and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment (PMID 20354201, 11302950, 15606506, 16530532).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297155", - "name" : "Recommendation PA166297155", + "id" : "PA166297275", + "name" : "Recommendation PA166297275", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -15798,37 +15798,37 @@ "dosingInformation" : false, "implications" : [ "NUDT15: n/a", - "TPMT: n/a" + "TPMT: Lower concentrations of TGN metabolites, higher MeTIMP, this is the ‘normal’ pattern. Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression." ], - "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "No Result"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "Indeterminate"}, + "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104933", "name" : "Annotation of CPIC Guideline for azathioprine and NUDT15, TPMT", - "version" : 53 + "version" : 353 }, "text" : { - "id" : 1452059757, - "html" : "

TPMT phenotype could not be assigned based on genotyping performed and NUDT15 genotype is not available. Consider evaluating TPMT erythrocyte activity to assess TPMT phenotype. If thiopurines are required and either TPMT or NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", + "id" : 1452059877, + "html" : "

Based on TPMT status, start with normal starting dose (e.g., 2-3 mg/kg/day) and adjust doses of azathioprine based on disease-specific guidelines. Allow 2 weeks to reach steady-state after each dose adjustment (PMID 20354201, 11302950, 15606506). NUDT15 status could not be determined based on genotyping. If thiopurines are required and NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297287", - "name" : "Recommendation PA166297287", - "alternateDrugAvailable" : true, + "id" : "PA166297269", + "name" : "Recommendation PA166297269", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, "parents" : [], @@ -15841,9 +15841,9 @@ "dosingInformation" : true, "implications" : [ "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", - "TPMT: Extremely high concentrations of TGN metabolites; fatal toxicity possible without dose decrease; no MeTIMP metabolites. Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." + "TPMT: Moderate to high concentrations of TGN metabolites; low concentrations of MeTIMP. Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." ], - "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Possible Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -15851,26 +15851,26 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104933", "name" : "Annotation of CPIC Guideline for azathioprine and NUDT15, TPMT", - "version" : 53 + "version" : 353 }, "text" : { - "id" : 1452059889, - "html" : "

For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy. For malignancy, start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily) and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment (PMID 16530578, 11302950, 15606506, 16530532, 12477776).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", - "version" : 0 + "id" : 1452059871, + "html" : "

Start with reduced starting doses (20%-50% of normal dose) if normal starting dose is 2-3 mg/kg/day (e.g., 0.4 – 1.5 mg/kg/day), and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment (PMID 20354201, 11302950, 15606506, 16530532).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297274", - "name" : "Recommendation PA166297274", + "id" : "PA166297273", + "name" : "Recommendation PA166297273", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -15883,10 +15883,10 @@ }, "dosingInformation" : true, "implications" : [ - "NUDT15: n/a", + "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", "TPMT: Moderate to high concentrations of TGN metabolites; low concentrations of MeTIMP. Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." ], - "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "No Result"}, + "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Possible Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -15894,26 +15894,26 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104933", "name" : "Annotation of CPIC Guideline for azathioprine and NUDT15, TPMT", - "version" : 53 + "version" : 353 }, "text" : { - "id" : 1452059876, - "html" : "

Based on TPMT status, start with reduced starting doses (30%-80% of normal dose) if normal starting dose is 2-3 mg/kg/day (e.g., 0.6 – 2.4 mg/kg/day), and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment (PMID 20354201, 11302950, 15606506, 16530532). NUDT15 genotype is not available. If thiopurines are required and NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", - "version" : 0 + "id" : 1452059875, + "html" : "

Start with reduced starting doses (20%-50% of normal dose) if normal starting dose is 2-3 mg/kg/day (e.g., 0.4 – 1.5 mg/kg/day), and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines. At least 2-4 weeks will be required to reach steady-state after each dose adjustment (PMID 20354201, 11302950, 15606506, 16530532).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297257", - "name" : "Recommendation PA166297257", + "id" : "PA166297281", + "name" : "Recommendation PA166297281", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -15924,12 +15924,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", - "TPMT: n/a" + "NUDT15: n/a", + "TPMT: Lower concentrations of TGN metabolites, higher MeTIMP, this is the ‘normal’ pattern. Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression." ], - "lookupKey" : {"TPMT": "No Result", "NUDT15": "Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -15937,27 +15937,27 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104933", "name" : "Annotation of CPIC Guideline for azathioprine and NUDT15, TPMT", - "version" : 53 + "version" : 353 }, "text" : { - "id" : 1452059859, - "html" : "

Based on NUDT15 status, start with reduced starting doses (30%-80% of normal dose) if normal starting dose is 2-3 mg/kg/day (e.g., 0.6 – 2.4 mg/kg/day), and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment (PMID 20354201, 11302950, 15606506, 16530532). TPMT genotype is not available. Consider evaluating erythrocyte TPMT activity to assess TPMT phenotype. If thiopurines are required and TPMT status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers. Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", + "id" : 1452059883, + "html" : "

Based on TPMT status, start with normal starting dose (e.g., 2-3 mg/kg/day) and adjust doses of azathioprine based on disease-specific guidelines. Allow 2 weeks to reach steady-state after each dose adjustment (PMID 20354201, 11302950, 15606506). NUDT15 genotype is not available. If thiopurines are required and NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297279", - "name" : "Recommendation PA166297279", - "alternateDrugAvailable" : true, + "id" : "PA166297262", + "name" : "Recommendation PA166297262", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, "parents" : [], @@ -15969,10 +15969,10 @@ }, "dosingInformation" : true, "implications" : [ - "NUDT15: Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", - "TPMT: Lower concentrations of TGN metabolites, higher MeTIMP, this is the ‘normal’ pattern. Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression." + "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "TPMT: Moderate to high concentrations of TGN metabolites; low concentrations of MeTIMP. Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." ], - "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "Poor Metabolizer"}, + "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -15980,21 +15980,21 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104933", "name" : "Annotation of CPIC Guideline for azathioprine and NUDT15, TPMT", - "version" : 53 + "version" : 353 }, "text" : { - "id" : 1452059881, - "html" : "

For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy. For malignant conditions, start with drastically reduced normal daily doses (reduce daily dose by 10-fold) and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment (PMID 16530578, 11302950, 15606506, 16530532, 12477776).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", - "version" : 0 + "id" : 1452059864, + "html" : "

Start with reduced starting doses (20%-50% of normal dose) if normal starting dose is 2-3 mg/kg/day (e.g., 0.4 – 1.5 mg/kg/day), and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines. At least 2-4 weeks will be required to reach steady-state after each dose adjustment (PMID 20354201, 11302950, 15606506, 16530532).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", @@ -16023,21 +16023,21 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104933", "name" : "Annotation of CPIC Guideline for azathioprine and NUDT15, TPMT", - "version" : 53 + "version" : 353 }, "text" : { "id" : 1452059868, "html" : "

Start with reduced starting doses (20%-50% of normal dose) if normal starting dose is 2-3 mg/kg/day (e.g., 0.4 – 1.5 mg/kg/day), and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines. At least 2-4 weeks will be required to reach steady-state after each dose adjustment (PMID 20354201, 11302950, 15606506, 16530532).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", "version" : 1 }, - "version" : 1 + "version" : 2 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166104933" @@ -16300,378 +16300,378 @@ "id" : "PA166171120", "symbol" : "DPYD c.1129-5923C>G, c.1236G>A (HapB3)", "name" : "c.1129-5923C>G, c.1236G>A (HapB3)", - "version" : 15 + "version" : 34 }, { "objCls" : "Variant", "id" : "PA166153916", "symbol" : "rs111858276", "name" : "rs111858276", - "version" : 3 + "version" : 2 }, { "objCls" : "Variant", "id" : "PA166153917", "symbol" : "rs112766203", "name" : "rs112766203", - "version" : 4 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166153918", "symbol" : "rs114096998", "name" : "rs114096998", - "version" : 4 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166153919", "symbol" : "rs115232898", "name" : "rs115232898", - "version" : 5 + "version" : 4 }, { "objCls" : "Variant", "id" : "PA166153921", "symbol" : "rs137999090", "name" : "rs137999090", - "version" : 4 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166159783", "symbol" : "rs138391898", "name" : "rs138391898", - "version" : 4 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166159790", "symbol" : "rs138545885", "name" : "rs138545885", - "version" : 4 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166153922", "symbol" : "rs138616379", "name" : "rs138616379", - "version" : 4 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166159799", "symbol" : "rs139459586", "name" : "rs139459586", - "version" : 4 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166159771", "symbol" : "rs139834141", "name" : "rs139834141", - "version" : 3 + "version" : 2 }, { "objCls" : "Variant", "id" : "PA166159801", "symbol" : "rs140114515", "name" : "rs140114515", - "version" : 4 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166159777", "symbol" : "rs140602333", "name" : "rs140602333", - "version" : 4 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166153923", "symbol" : "rs141044036", "name" : "rs141044036", - "version" : 4 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166159769", "symbol" : "rs141462178", "name" : "rs141462178", - "version" : 4 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166159779", "symbol" : "rs142512579", "name" : "rs142512579", - "version" : 4 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166159786", "symbol" : "rs142619737", "name" : "rs142619737", - "version" : 4 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166153925", "symbol" : "rs143154602", "name" : "rs143154602", - "version" : 4 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166159776", "symbol" : "rs143815742", "name" : "rs143815742", - "version" : 4 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166159781", "symbol" : "rs144395748", "name" : "rs144395748", - "version" : 4 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166159773", "symbol" : "rs145112791", "name" : "rs145112791", - "version" : 4 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166159797", "symbol" : "rs145529148", "name" : "rs145529148", - "version" : 4 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166159791", "symbol" : "rs145548112", "name" : "rs145548112", - "version" : 4 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166153927", "symbol" : "rs145773863", "name" : "rs145773863", - "version" : 4 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166153928", "symbol" : "rs146356975", "name" : "rs146356975", - "version" : 4 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166159792", "symbol" : "rs146529561", "name" : "rs146529561", - "version" : 4 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166153929", "symbol" : "rs147545709", "name" : "rs147545709", - "version" : 4 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166153930", "symbol" : "rs147601618", "name" : "rs147601618", - "version" : 4 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166159802", "symbol" : "rs148799944", "name" : "rs148799944", - "version" : 4 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166159784", "symbol" : "rs148994843", "name" : "rs148994843", - "version" : 4 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166159767", "symbol" : "rs150036960", "name" : "rs150036960", - "version" : 4 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166159768", "symbol" : "rs150385342", "name" : "rs150385342", - "version" : 4 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166159772", "symbol" : "rs150437414", "name" : "rs150437414", - "version" : 4 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166153874", "symbol" : "rs17376848", "name" : "rs17376848", - "version" : 4 + "version" : 5 }, { "objCls" : "Variant", "id" : "PA166153645", "symbol" : "rs1801158", "name" : "rs1801158", - "version" : 6 + "version" : 7 }, { "objCls" : "Variant", "id" : "PA166153646", "symbol" : "rs1801159", "name" : "rs1801159", - "version" : 6 + "version" : 9 }, { "objCls" : "Variant", "id" : "PA166153647", "symbol" : "rs1801160", "name" : "rs1801160", - "version" : 6 + "version" : 7 }, { "objCls" : "Variant", "id" : "PA166153648", "symbol" : "rs1801265", "name" : "rs1801265", - "version" : 8 + "version" : 10 }, { "objCls" : "Variant", "id" : "PA166153649", "symbol" : "rs1801266", "name" : "rs1801266", - "version" : 8 + "version" : 7 }, { "objCls" : "Variant", "id" : "PA166153650", "symbol" : "rs1801267", "name" : "rs1801267", - "version" : 6 + "version" : 5 }, { "objCls" : "Variant", "id" : "PA166153651", "symbol" : "rs1801268", "name" : "rs1801268", - "version" : 7 + "version" : 6 }, { "objCls" : "Variant", "id" : "PA166153932", "symbol" : "rs183385770", "name" : "rs183385770", - "version" : 4 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166153933", "symbol" : "rs186169810", "name" : "rs186169810", - "version" : 4 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166159785", "symbol" : "rs190951787", "name" : "rs190951787", - "version" : 5 + "version" : 4 }, { "objCls" : "Variant", "id" : "PA166159782", "symbol" : "rs199549923", "name" : "rs199549923", - "version" : 5 + "version" : 4 }, { "objCls" : "Variant", "id" : "PA166159794", "symbol" : "rs199634007", "name" : "rs199634007", - "version" : 4 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166159778", "symbol" : "rs200064537", "name" : "rs200064537", - "version" : 4 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166159770", "symbol" : "rs200562975", "name" : "rs200562975", - "version" : 4 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166153936", "symbol" : "rs200687447", "name" : "rs200687447", - "version" : 4 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166159774", "symbol" : "rs201018345", "name" : "rs201018345", - "version" : 4 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166159796", "symbol" : "rs201035051", "name" : "rs201035051", - "version" : 5 + "version" : 4 }, { "objCls" : "Variant", "id" : "PA166159787", "symbol" : "rs201615754", "name" : "rs201615754", - "version" : 4 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166159800", "symbol" : "rs202144771", "name" : "rs202144771", - "version" : 4 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166153696", "symbol" : "rs2297595", "name" : "rs2297595", - "version" : 4 + "version" : 7 }, { "objCls" : "Variant", @@ -16685,21 +16685,21 @@ "id" : "PA166153760", "symbol" : "rs3918290", "name" : "rs3918290", - "version" : 6 + "version" : 7 }, { "objCls" : "Variant", "id" : "PA166153885", "symbol" : "rs45589337", "name" : "rs45589337", - "version" : 4 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166153886", "symbol" : "rs55674432", "name" : "rs55674432", - "version" : 4 + "version" : 3 }, { "objCls" : "Variant", @@ -16713,42 +16713,42 @@ "id" : "PA166159789", "symbol" : "rs55971861", "name" : "rs55971861", - "version" : 4 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166179517", "symbol" : "rs56005131", "name" : "rs56005131", - "version" : 4 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166192823", "symbol" : "rs57918000", "name" : "rs57918000", - "version" : 4 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166153891", "symbol" : "rs59086055", "name" : "rs59086055", - "version" : 4 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166153892", "symbol" : "rs60139309", "name" : "rs60139309", - "version" : 5 + "version" : 4 }, { "objCls" : "Variant", "id" : "PA166159793", "symbol" : "rs60511679", "name" : "rs60511679", - "version" : 4 + "version" : 3 }, { "objCls" : "Variant", @@ -16762,112 +16762,112 @@ "id" : "PA166192821", "symbol" : "rs6670886", "name" : "rs6670886", - "version" : 4 + "version" : 2 }, { "objCls" : "Variant", "id" : "PA166153895", "symbol" : "rs67376798", "name" : "rs67376798", - "version" : 5 + "version" : 7 }, { "objCls" : "Variant", "id" : "PA166153896", "symbol" : "rs72547601", "name" : "rs72547601", - "version" : 6 + "version" : 5 }, { "objCls" : "Variant", "id" : "PA166159798", "symbol" : "rs72547602", "name" : "rs72547602", - "version" : 6 + "version" : 5 }, { "objCls" : "Variant", "id" : "PA166153897", "symbol" : "rs72549303", "name" : "rs72549303", - "version" : 8 + "version" : 6 }, { "objCls" : "Variant", "id" : "PA166153898", "symbol" : "rs72549304", "name" : "rs72549304", - "version" : 6 + "version" : 5 }, { "objCls" : "Variant", "id" : "PA166159775", "symbol" : "rs72549305", "name" : "rs72549305", - "version" : 7 + "version" : 6 }, { "objCls" : "Variant", "id" : "PA166153899", "symbol" : "rs72549306", "name" : "rs72549306", - "version" : 7 + "version" : 6 }, { "objCls" : "Variant", "id" : "PA166153900", "symbol" : "rs72549307", "name" : "rs72549307", - "version" : 6 + "version" : 5 }, { "objCls" : "Variant", "id" : "PA166153901", "symbol" : "rs72549308", "name" : "rs72549308", - "version" : 6 + "version" : 5 }, { "objCls" : "Variant", "id" : "PA166153902", "symbol" : "rs72549309", "name" : "rs72549309", - "version" : 9 + "version" : 8 }, { "objCls" : "Variant", "id" : "PA166159712", "symbol" : "rs72549310", "name" : "rs72549310", - "version" : 7 + "version" : 6 }, { "objCls" : "Variant", "id" : "PA166159780", "symbol" : "rs72975710", "name" : "rs72975710", - "version" : 4 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166192822", "symbol" : "rs764666241", "name" : "rs764666241", - "version" : 4 + "version" : 2 }, { "objCls" : "Variant", "id" : "PA166153913", "symbol" : "rs78060119", "name" : "rs78060119", - "version" : 5 + "version" : 4 }, { "objCls" : "Variant", "id" : "PA166153914", "symbol" : "rs80081766", "name" : "rs80081766", - "version" : 5 + "version" : 4 } ], "relatedChemicals" : [ @@ -16875,7 +16875,7 @@ "objCls" : "Chemical", "id" : "PA448771", "name" : "capecitabine", - "version" : 21 + "version" : 60 } ], "relatedGenes" : [ @@ -16884,7 +16884,7 @@ "id" : "PA145", "symbol" : "DPYD", "name" : "dihydropyrimidine dehydrogenase", - "version" : 6907 + "version" : 6956 } ], "source" : "CPIC", @@ -16897,12 +16897,96 @@ "textMarkdown" : { "id" : 1451433709, "html" : "

This annotation is based on the CPIC® guideline for fluoropyrimidines and DPYD.

\n

January 2024 Update

\n\n

November 2018 Update

\n\n

November 2017 Update

\n

Advance online publication November 2017

\n\n\n

Adapted from Tables 1 and 2 of the 2017 guideline manuscript (November 2018 Update on PharmGKB).

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Likely PhenotypeActivity ScoreaGenotypesbExamples of genotypescImplicationsDosing recommendationsClassification of recommendationsd
DPYD Normal Metabolizer2An individual carrying two normal allelesc.[=];[=], c.[85T>Ce];[=], c.[1627A>Gf];[=]Normal DPD activity and “normal” risk for fluoropyrimidine toxicityBased on genotype, there is no indication to change dose or therapy. Use label-recommended dosage and administrationStrong
DPYD Intermediate Metabolizer1 or 1.5An individual carrying one normal function allele plus one no function allele or one decreased function allele, or an individual carrying two decreased function allelesc.[1905+1G>Ag];[=], c.[1679T>Gh];[=], c.[2846A>Ti];[=]; c.[1129–5923C>Gj];[=]; c.[1129–5923C>G];[1129–5923C>G]; c.[2846A>T];[2846A>T]Decreased DPD activity (leukocyte DPD activity at 30% to 70% that of the normal population) and increased risk for severe or even fatal drug toxicity when treated with fluoropyrimidine drugsReduce starting dose by 50% followed by titration of dose based on toxicity or therapeutic drug monitoring (if available). Patients with the c.[2846A>T];[2846A>T] genotype may require >50% reduction in starting dose.Activity score 1: Strong
Activity score 1.5: Moderate
DPYD Poor Metabolizer0 or 0.5An individual carrying two no function alleles or an individual carrying one no function plus one decreased function allelec.[1905+1G>A];[1905+1G>A], c.[1679T>G];[1679T>G], c.[1905+1G>A];[2846A>T] c.[1905+1G>A];[1129-5923C>G]Complete DPD deficiency and increased risk for severe or even fatal drug toxicity when treated with fluoropyrimidine drugsActivity score 0.5: Avoid use of 5- fluorouracil or 5-fluorouracil prodrug-based regimens. In the event, based on clinical advice, alternative agents are not considered a suitable therapeutic option, 5-fluorouracil should be administered at a strongly reduced dosek with early therapeutic drug monitoring.l
Activity score 0: Avoid use of 5-fluorouracil or 5-fluorouracil prodrug-based regimens.		Strong
\n

a Calculated as the sum of the two lowest individual variant activity scores. See main guideline for further information.
\nb Allele definitions, assignment of allele function and references can be found using the DPYD Allele Functionality Table.
\nc HGVS nomenclature using the reference sequence NM_000110.3.
\nd Rating scheme described in the Supplement.
\ne Also known as rs1801265 or DPYD*9A
\nf Also known as rs1801159 or DPYD*5
\ng Also known as rs3918290 or DPYD*2A
\nh Also known as rs55886062 or DPYD*13
\ni Also known as rs67376798
\nj Also known as rs75017182. Likely HapB3 causal variant. See DPYD Allele Functionality Table for other HapB3 proxy SNPs.
\nk If available, a phenotyping test (see main text for further details) should be considered to estimate the starting dose. In absence of phenotyping data, a dose of <25% of the normal starting dose is estimated assuming additive effects of alleles on 5-FU clearance.
\nl Therapeutic drug monitoring should be done at the earliest time point possible (e.g., minimum time point in steady state) in order to immediately discontinue the infusion if the drug level is too high.

\n

May 2014 Update on PharmGKB

\n\n

December 2013 Publication

\n

Advance online publication October 2013.

\n\n", - "version" : 3 + "version" : 4 }, "userId" : "carrillo", - "version" : 58 + "version" : 176 }, "recommendations" : [ + { + "objCls" : "Recommendation Annotation", + "id" : "PA166297902", + "name" : "Recommendation PA166297902", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981501930, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "DPYD: Complete DPD deficiency and increased risk for severe or even fatal drug toxicity when treated with fluoropyrimidine drugs." + ], + "lookupKey" : {"DPYD": "0.5"}, + "otherPrescribingGuidance" : false, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA448771", + "name" : "capecitabine", + "version" : 60 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166109594", + "name" : "Annotation of CPIC Guideline for capecitabine and DPYD", + "version" : 176 + }, + "text" : { + "id" : 1452060504, + "html" : "

Avoid use of 5-fluorouracil or 5-fluorouracil prodrug-based regimens. In the event, based on clinical advice, alternative agents are not considered a suitable therapeutic option, 5-fluorouracil should be administered at a strongly reduced dose with early therapeutic drug monitoring.

\n

Other Considerations

\n

If available, a phenotyping test (see main text for further details) should be considered to estimate the starting dose. In absence of phenotyping data, a dose of <25% of the normal starting dose is estimated assuming additive effects of alleles on 5-FU clearance. Therapeutic drug monitoring should be done at the earliest time point possible (e.g., minimum time point in steady state) in order to immediately discontinue therapy if the drug level is too high.

\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166297852", + "name" : "Recommendation PA166297852", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501931, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "DPYD: Decreased DPD activity (leukocyte DPD activity at 30% to 70% that of the normal population) and increased risk for severe or even fatal drug toxicity when treated with fluoropyrimidine drugs" + ], + "lookupKey" : {"DPYD": "1.5"}, + "otherPrescribingGuidance" : false, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA448771", + "name" : "capecitabine", + "version" : 60 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166109594", + "name" : "Annotation of CPIC Guideline for capecitabine and DPYD", + "version" : 176 + }, + "text" : { + "id" : 1452060454, + "html" : "

Reduce starting dose by 50% followed by titration of dose based on toxicity or therapeutic drug monitoring (if available).

\n

Other Considerations

\n

Increase the dose in patients experiencing no or clinically tolerable toxicity in the first two cycles to maintain efficacy; decrease the dose in patients who do not tolerate the starting dose to minimize toxicities.

\n", + "version" : 0 + }, + "version" : 1 + }, { "objCls" : "Recommendation Annotation", "id" : "PA166297901", @@ -16929,26 +17013,26 @@ "objCls" : "Chemical", "id" : "PA448771", "name" : "capecitabine", - "version" : 21 + "version" : 60 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166109594", "name" : "Annotation of CPIC Guideline for capecitabine and DPYD", - "version" : 58 + "version" : 176 }, "text" : { "id" : 1452060503, "html" : "

Reduce starting dose by 50% followed by titration of dose based on toxicity or therapeutic drug monitoring (if available). Patients with the c.2846A>T/c.2846A>T genotype may require >50% reduction in starting dose.

\n

Other Considerations

\n

Increase the dose in patients experiencing no or clinically tolerable toxicity in the first two cycles to maintain efficacy; decrease the dose in patients who do not tolerate the starting dose to minimize toxicities.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297902", - "name" : "Recommendation PA166297902", + "id" : "PA166297903", + "name" : "Recommendation PA166297903", "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, @@ -16959,11 +17043,11 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ "DPYD: Complete DPD deficiency and increased risk for severe or even fatal drug toxicity when treated with fluoropyrimidine drugs." ], - "lookupKey" : {"DPYD": "0.5"}, + "lookupKey" : {"DPYD": "0.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -16971,21 +17055,21 @@ "objCls" : "Chemical", "id" : "PA448771", "name" : "capecitabine", - "version" : 21 + "version" : 60 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166109594", "name" : "Annotation of CPIC Guideline for capecitabine and DPYD", - "version" : 58 + "version" : 176 }, "text" : { - "id" : 1452060504, - "html" : "

Avoid use of 5-fluorouracil or 5-fluorouracil prodrug-based regimens. In the event, based on clinical advice, alternative agents are not considered a suitable therapeutic option, 5-fluorouracil should be administered at a strongly reduced dose with early therapeutic drug monitoring.

\n

Other Considerations

\n

If available, a phenotyping test (see main text for further details) should be considered to estimate the starting dose. In absence of phenotyping data, a dose of <25% of the normal starting dose is estimated assuming additive effects of alleles on 5-FU clearance. Therapeutic drug monitoring should be done at the earliest time point possible (e.g., minimum time point in steady state) in order to immediately discontinue therapy if the drug level is too high.

\n", + "id" : 1452060505, + "html" : "

Avoid use of 5-fluorouracil or 5-fluorouracil prodrug-based regimens.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -17013,105 +17097,21 @@ "objCls" : "Chemical", "id" : "PA448771", "name" : "capecitabine", - "version" : 21 + "version" : 60 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166109594", "name" : "Annotation of CPIC Guideline for capecitabine and DPYD", - "version" : 58 + "version" : 176 }, "text" : { "id" : 1452060372, "html" : "

Based on genotype, there is no indication to change dose or therapy. Use label-recommended dosage and administration.

\n", "version" : 0 }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166297903", - "name" : "Recommendation PA166297903", - "alternateDrugAvailable" : true, - "classification" : { - "id" : 981501930, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "DPYD: Complete DPD deficiency and increased risk for severe or even fatal drug toxicity when treated with fluoropyrimidine drugs." - ], - "lookupKey" : {"DPYD": "0.0"}, - "otherPrescribingGuidance" : false, - "population" : "general", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA448771", - "name" : "capecitabine", - "version" : 21 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166109594", - "name" : "Annotation of CPIC Guideline for capecitabine and DPYD", - "version" : 58 - }, - "text" : { - "id" : 1452060505, - "html" : "

Avoid use of 5-fluorouracil or 5-fluorouracil prodrug-based regimens.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166297852", - "name" : "Recommendation PA166297852", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 981501931, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : true, - "implications" : [ - "DPYD: Decreased DPD activity (leukocyte DPD activity at 30% to 70% that of the normal population) and increased risk for severe or even fatal drug toxicity when treated with fluoropyrimidine drugs" - ], - "lookupKey" : {"DPYD": "1.5"}, - "otherPrescribingGuidance" : false, - "population" : "general", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA448771", - "name" : "capecitabine", - "version" : 21 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166109594", - "name" : "Annotation of CPIC Guideline for capecitabine and DPYD", - "version" : 58 - }, - "text" : { - "id" : 1452060454, - "html" : "

Reduce starting dose by 50% followed by titration of dose based on toxicity or therapeutic drug monitoring (if available).

\n

Other Considerations

\n

Increase the dose in patients experiencing no or clinically tolerable toxicity in the first two cycles to maintain efficacy; decrease the dose in patients who do not tolerate the starting dose to minimize toxicities.

\n", - "version" : 0 - }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166109594" @@ -17330,14 +17330,14 @@ "id" : "PA165954030", "symbol" : "HLA-A*31:01", "name" : "*31:01", - "version" : 5 + "version" : 9 }, { "objCls" : "Haplotype", "id" : "PA165954769", "symbol" : "HLA-B*15:02", "name" : "*15:02", - "version" : 5 + "version" : 21 } ], "relatedChemicals" : [ @@ -17345,7 +17345,7 @@ "objCls" : "Chemical", "id" : "PA448785", "name" : "carbamazepine", - "version" : 14 + "version" : 47 } ], "relatedGenes" : [ @@ -17354,37 +17354,37 @@ "id" : "PA35055", "symbol" : "HLA-A", "name" : "major histocompatibility complex, class I, A", - "version" : 42 + "version" : 1500 }, { "objCls" : "Gene", "id" : "PA35056", "symbol" : "HLA-B", "name" : "major histocompatibility complex, class I, B", - "version" : 40 + "version" : 2920 } ], "source" : "CPIC", "summaryMarkdown" : { "id" : 1447981980, "html" : "

The CPIC Dosing Guideline update for carbamazepine recommends an alternative drug for carbamazepine-naive patients carrying at least one copy of either HLA-B*15:02 or HLA-A*31:01 due to the association of those alleles with an increased risk of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). In addition, HLA-A*31:01 is associated with an increased risk of drug reaction with eosinophilia and systemic symptoms (DRESS) and maculopapular exanthema (MPE).

\n", - "version" : 1 + "version" : 3 }, "terms" : [], "textMarkdown" : { "id" : 1451433644, "html" : "

This annotation is based on the CPIC® guideline for carbamazepine, HLA-B and HLA-A.

\n

December 2017

\n

Accepted article preview online January 2018; Advance online publication February 2018.

\n\n

Table 1: Carbamazepine therapy recommendations based on HLA-B and HLA-A genotype

\n

Adapted from Tables 1 and 2 of the 2017 guideline update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Likely phenotypeGenotypesExamples of DiplotypesPhenotypic ImplicationsTherapeutic RecommendationsClassification of Recommendation aConsiderations for other aromatic anticonvulsants
Homozygous for alleles other than HLA-B*15:02 and HLA-A*31:01Non-carrier of HLA-B*15:02 or HLA-A*31:01. No HLA-B*15:02 or HLA-A*31:01 alleles reported, often reported as "negative" on genotyping tests.*X/*X b
*Y/*Y c		Normal or reduced risk of carbamazepine-induced SJS/TEN, DRESS and MPE.Use carbamazepine per standard dosing guidelines. dStrong
Heterozygote or homozygous for HLA-A*31:01 and homozygous for HLA-B alleles other than *15:02Carrier of HLA-A*31:01. One or two *31:01 alleles, often reported as "positive" on a genotyping test.
Non-carrier of HLA-B*15:02. No HLA-B*15:02 alleles reported, often reported as "negative" on genotyping tests.		*X/*X b
*31:01/*Y c
*31:01/*31:01		Increased risk of carbamazepine-induced SJS/TEN, DRESS and MPEA. If patient is carbamazepine-naive and alternative agents are available, do not use carbamazepine.
B. If patient is carbamazepine-naive and alternative agents are not available, consider the use of carbamazepine with increased frequency of clinical monitoring. Discontinue therapy at first evidence of a cutaneous adverse reaction.
C. The latency period for cutaneous adverse drug reactions is variable depending on phenotype; however, all usually occur within 3 months of regular dosing. Therefore, if patient has previously used carbamazepine for longer than 3 months without incidence of cutaneous adverse reactions, cautiously consider use of carbamazepine.		A. Strong
B. Optional
C. Optional		A. Other aromatic anticonvulsants (e.g. eslicarbazepine, lamotrigine, phenytoin, fosphenytoin and phenoarbital) have very limited evidence, if any, linking SJS/TEN, DRESS and/or MPE with the _HLA-A*31:01 allele, and thus no recommendation can be made with respect to choosing another aromatic anticonvulsant as an alternative agent.
C. Previous tolerance of carbamazepine is not indicative of tolerance to other aromatic anticonvulsants.
Heterozygote or homozygous for HLA-B*15:02 and any HLA-A*31:01 genotype (or HLA-A*31:01 genotype unknown)Carrier of HLA-B*15:02. One or two *15:02 alleles, often reported as "positive" on a genotyping test.*15:02/*X b
*15:02/*15:02		Increased risk of carbamazepine-induced SJS/TENA. If patient is carbamazepine-naive, do not use carbamazepine.
B. The latency period for drug-induced SJS/TEN is short with continuous dosing and adherence to therapy (~4-28 days), and cases usually occur within 3 months of dosing; therefore, if the patient has previously used carbamazepine consistently for longer than 3 months without incidence of cutaneous adverse reactions, cautiously consider use of carbamazepine in the future.		A. Strong
B. Optional		A. Other aromatic anticonvulsants (e.g. eslicarbazepine, lamotrigine, phenytoin, fosphenytoin and phenoarbital) have weaker evidence linking SJS/TEN with the HLA-B*15:02 allele; however, caution should still be used in choosing an alternative agent.
B. Previous tolerance of carbamazepine is not indicative of tolerance to other aromatic anticonvulsants.
\n

a Rating scheme described in the 2017 update supplement (see above)

\n

b *X = any HLA-B genotype other than *15:02

\n

c *Y = any HLA-A genotype other than *31:01

\n

HLA-B = human leukocyte antigen B

\n

HLA-A = human leukocyte antigen A

\n

d HLA-B*15:02 has a 100% negative predictive value for carbamazepine-induced SJS/TEN, and its use is currently recommended to guide use of carbamazepine and oxcarbazepine only. Because there is a much weaker association and less than 100% negative predictive value of HLA-B*15:02 for SJS/TEN associated with other aromatic anticonvulsants, using these drugs instead of carbamazepine or oxcarbazepine in the setting of a negative HLA-B*15:02 test in Southeast Asians will not result in prevention of anticonvulsant-associated SJS/TEN.

\n

September 2013

\n

Accepted article preview online May 2013; Advance online publication June 2013.

\n\n
\n

Human leukocyte antigen B (HLA-B) is a gene that encodes a cell surface protein involved in presenting antigens to the immune system. The variant allele HLA-B*15:02 is associated with an increased risk of Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) in response to carbamazepine treatment. We summarize evidence from the published literature supporting this association and provide recommendations for the use of carbamazepine based on HLA-B genotype.

\n
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Use carbamazepine per standard dosing guidelines.

\n

Other Considerations

\n

HLA-B*15:02 has a 100% negative predictive value for carbamazepine-induced SJS/TEN, and its use is currently recommended to guide use of carbamazepine and oxcarbazepine only. Because there is a much weaker association and less than 100% negative predictive value of HLA-B*15:02 for SJS/TEN associated with other aromatic anticonvulsants, using these drugs instead of carbamazepine or oxcarbazepine in the setting of a negative HLA-B*15:02 test in Southeast Asians will not result in prevention of anticonvulsant-associated SJS/TEN (PMID 25355835).

\n", + "id" : 1452059891, + "html" : "

If patient is carbamazepine-naïve and alternative agents are available, do not use carbamazepine.

\n

Other Considerations

\n

Other aromatic anticonvulsants have very limited evidence, if any, linking SJS/TEN, DRESS, and/or MPE with the HLA-A*31:01 allele, and thus no recommendation can be made with respect to choosing another aromatic anticonvulsant as an alternative agent. Aromatic anticonvulsants include carbamazepine, oxcarbazepine, eslicarbazepine, lamotrigine, phenytoin, fosphenytoin, and phenobarbital. Previous tolerance of carbamazepine is not indicative of tolerance to other aromatic anticonvulsants.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297302", - "name" : "Recommendation PA166297302", + "id" : "PA166297291", + "name" : "Recommendation PA166297291", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981501930, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : false, + "implications" : [ + "HLA-A: Normal risk of carbamazepine-induced SJS/TEN, DRESS, and MPE", + "HLA-B: Greater risk of carbamazepine-induced SJS/TEN" + ], + "lookupKey" : {"HLA-A": "*31:01 negative", "HLA-B": "*15:02 positive"}, + "otherPrescribingGuidance" : false, + "population" : "CBZ naive", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA448785", + "name" : "carbamazepine", + "version" : 47 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166105008", + "name" : "Annotation of CPIC Guideline for carbamazepine and HLA-A, HLA-B", + "version" : 115 + }, + "text" : { + "id" : 1452059893, + "html" : "

If patient is carbamazepine-naïve, do not use carbamazepine.

\n

Other Considerations

\n

Other aromatic anticonvulsants have weaker evidence linking SJS/TEN with the HLA-B*15:02 allele; however, caution should still be used in choosing an alternative agent. Previous tolerance of carbamazepine is not indicative of tolerance to other aromatic anticonvulsants. Aromatic anticonvulsants include carbamazepine, oxcarbazepine, eslicarbazepine, lamotrigine, phenytoin, fosphenytoin, and phenobarbital. In addition to HLA-B*15:02, risk for carbamazepine-induced SJS/TEN has been reported in association with the most common B75 serotype alleles in Southeast Asia, HLA-B*15:08, HLA-B*15:11, and HLA-B*15:21. Although not described, the possibility of carbamazepine-induced SJS/TEN in association with less frequently carried B75 serotype alleles, such as HLA-B*15:30 and HLA-B*15:31, should also be considered.

\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166297292", + "name" : "Recommendation PA166297292", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981501930, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : false, + "implications" : [ + "HLA-A: Greater risk of carbamazepine-induced SJS/TEN, DRESS, and MPE", + "HLA-B: Greater risk of carbamazepine-induced SJS/TEN" + ], + "lookupKey" : {"HLA-A": "*31:01 positive", "HLA-B": "*15:02 positive"}, + "otherPrescribingGuidance" : false, + "population" : "CBZ naive", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA448785", + "name" : "carbamazepine", + "version" : 47 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166105008", + "name" : "Annotation of CPIC Guideline for carbamazepine and HLA-A, HLA-B", + "version" : 115 + }, + "text" : { + "id" : 1452059894, + "html" : "

If patient is carbamazepine-naïve, do not use carbamazepine.

\n

Other Considerations

\n

Other aromatic anticonvulsants have weaker evidence linking SJS/TEN with the HLA-B*15:02 allele; however, caution should still be used in choosing an alternative agent. Previous tolerance of carbamazepine is not indicative of tolerance to other aromatic anticonvulsants. Aromatic anticonvulsants include carbamazepine, oxcarbazepine, eslicarbazepine, lamotrigine, phenytoin, fosphenytoin, and phenobarbital. In addition to HLA-B*15:02, risk for carbamazepine-induced SJS/TEN has been reported in association with the most common B75 serotype alleles in Southeast Asia, HLA-B*15:08, HLA-B*15:11, and HLA-B*15:21. Although not described, the possibility of carbamazepine-induced SJS/TEN in association with less frequently carried B75 serotype alleles, such as HLA-B*15:30 and HLA-B*15:31, should also be considered.

\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166297293", + "name" : "Recommendation PA166297293", "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, @@ -17444,23 +17530,23 @@ ], "lookupKey" : {"HLA-A": "No Result", "HLA-B": "*15:02 positive"}, "otherPrescribingGuidance" : false, - "population" : "CBZ-no alternatives", + "population" : "CBZ naive", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448785", "name" : "carbamazepine", - "version" : 14 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105008", "name" : "Annotation of CPIC Guideline for carbamazepine and HLA-A, HLA-B", - "version" : 52 + "version" : 115 }, "text" : { - "id" : 1452059904, + "id" : 1452059895, "html" : "

If patient is carbamazepine-naïve, do not use carbamazepine.

\n

Other Considerations

\n

Other aromatic anticonvulsants have weaker evidence linking SJS/TEN with the HLA-B*15:02 allele; however, caution should still be used in choosing an alternative agent. Previous tolerance of carbamazepine is not indicative of tolerance to other aromatic anticonvulsants. Aromatic anticonvulsants include carbamazepine, oxcarbazepine, eslicarbazepine, lamotrigine, phenytoin, fosphenytoin, and phenobarbital. In addition to HLA-B*15:02, risk for carbamazepine-induced SJS/TEN has been reported in association with the most common B75 serotype alleles in Southeast Asia, HLA-B*15:08, HLA-B*15:11, and HLA-B*15:21. Although not described, the possibility of carbamazepine-induced SJS/TEN in association with less frequently carried B75 serotype alleles, such as HLA-B*15:30 and HLA-B*15:31, should also be considered.

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Use carbamazepine per standard dosing guidelines.

\n

Other Considerations

\n

HLA-B*15:02 has a 100% negative predictive value for carbamazepine-induced SJS/TEN, and its use is currently recommended to guide use of carbamazepine and oxcarbazepine only. Because there is a much weaker association and less than 100% negative predictive value of HLA-B*15:02 for SJS/TEN associated with other aromatic anticonvulsants, using these drugs instead of carbamazepine or oxcarbazepine in the setting of a negative HLA-B*15:02 test in Southeast Asians will not result in prevention of anticonvulsant-associated SJS/TEN (PMID 25355835).

\n", + "id" : 1452059897, + "html" : "

If patient is carbamazepine-naïve and alternative agents are available, do not use carbamazepine.

\n

Other Considerations

\n

Other aromatic anticonvulsants have very limited evidence, if any, linking SJS/TEN, DRESS, and/or MPE with the HLA-A*31:01 allele, and thus no recommendation can be made with respect to choosing another aromatic anticonvulsant as an alternative agent. Aromatic anticonvulsants include carbamazepine, oxcarbazepine, eslicarbazepine, lamotrigine, phenytoin, fosphenytoin, and phenobarbital. Previous tolerance of carbamazepine is not indicative of tolerance to other aromatic anticonvulsants.

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The latency period for cutaneous adverse drug reactions is variable depending on phenotype; however, all usually occur within three months of regular dosing. Therefore, if the patient has previously used carbamazepine consistently for longer than three months without incidence of cutaneous adverse reactions, cautiously consider use of carbamazepine.

\n

Other Considerations

\n

Previous tolerance of carbamazepine is not indicative of tolerance to other aromatic anticonvulsants. Aromatic anticonvulsants include carbamazepine, oxcarbazepine, eslicarbazepine, lamotrigine, phenytoin, fosphenytoin, and phenobarbital.

\n", + "id" : 1452059902, + "html" : "

If patient is carbamazepine-naïve, do not use carbamazepine.

\n

Other Considerations

\n

Other aromatic anticonvulsants have weaker evidence linking SJS/TEN with the HLA-B*15:02 allele; however, caution should still be used in choosing an alternative agent. Previous tolerance of carbamazepine is not indicative of tolerance to other aromatic anticonvulsants. Aromatic anticonvulsants include carbamazepine, oxcarbazepine, eslicarbazepine, lamotrigine, phenytoin, fosphenytoin, and phenobarbital. In addition to HLA-B*15:02, risk for carbamazepine-induced SJS/TEN has been reported in association with the most common B75 serotype alleles in Southeast Asia, HLA-B*15:08, HLA-B*15:11, and HLA-B*15:21. Although not described, the possibility of carbamazepine-induced SJS/TEN in association with less frequently carried B75 serotype alleles, such as HLA-B*15:30 and HLA-B*15:31, should also be considered.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297293", - "name" : "Recommendation PA166297293", + "id" : "PA166297301", + "name" : "Recommendation PA166297301", "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, @@ -17568,28 +17654,28 @@ }, "dosingInformation" : false, "implications" : [ - "HLA-A: n/a", + "HLA-A: Greater risk of carbamazepine-induced SJS/TEN, DRESS, and MPE", "HLA-B: Greater risk of carbamazepine-induced SJS/TEN" ], - "lookupKey" : {"HLA-A": "No Result", "HLA-B": "*15:02 positive"}, + "lookupKey" : {"HLA-A": "*31:01 positive", "HLA-B": "*15:02 positive"}, "otherPrescribingGuidance" : false, - "population" : "CBZ naive", + "population" : "CBZ-no alternatives", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448785", "name" : "carbamazepine", - "version" : 14 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105008", "name" : "Annotation of CPIC Guideline for carbamazepine and HLA-A, HLA-B", - "version" : 52 + "version" : 115 }, "text" : { - "id" : 1452059895, + "id" : 1452059903, "html" : "

If patient is carbamazepine-naïve, do not use carbamazepine.

\n

Other Considerations

\n

Other aromatic anticonvulsants have weaker evidence linking SJS/TEN with the HLA-B*15:02 allele; however, caution should still be used in choosing an alternative agent. Previous tolerance of carbamazepine is not indicative of tolerance to other aromatic anticonvulsants. Aromatic anticonvulsants include carbamazepine, oxcarbazepine, eslicarbazepine, lamotrigine, phenytoin, fosphenytoin, and phenobarbital. In addition to HLA-B*15:02, risk for carbamazepine-induced SJS/TEN has been reported in association with the most common B75 serotype alleles in Southeast Asia, HLA-B*15:08, HLA-B*15:11, and HLA-B*15:21. Although not described, the possibility of carbamazepine-induced SJS/TEN in association with less frequently carried B75 serotype alleles, such as HLA-B*15:30 and HLA-B*15:31, should also be considered.

\n", "version" : 0 }, @@ -17597,51 +17683,51 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297312", - "name" : "Recommendation PA166297312", - "alternateDrugAvailable" : false, + "id" : "PA166297302", + "name" : "Recommendation PA166297302", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "HLA-A: Greater risk of carbamazepine-induced SJS/TEN, DRESS, and MPE", - "HLA-B: n/a" + "HLA-A: n/a", + "HLA-B: Greater risk of carbamazepine-induced SJS/TEN" ], - "lookupKey" : {"HLA-A": "*31:01 positive", "HLA-B": "No Result"}, - "otherPrescribingGuidance" : true, - "population" : "CBZ use >3mos", + "lookupKey" : {"HLA-A": "No Result", "HLA-B": "*15:02 positive"}, + "otherPrescribingGuidance" : false, + "population" : "CBZ-no alternatives", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448785", "name" : "carbamazepine", - "version" : 14 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105008", "name" : "Annotation of CPIC Guideline for carbamazepine and HLA-A, HLA-B", - "version" : 52 + "version" : 115 }, "text" : { - "id" : 1452059914, - "html" : "

The latency period for cutaneous adverse drug reactions is variable depending on phenotype; however, all usually occur within three months of regular dosing. Therefore, if the patient has previously used carbamazepine consistently for longer than three months without incidence of cutaneous adverse reactions, cautiously consider use of carbamazepine.

\n

Other Considerations

\n

Previous tolerance of carbamazepine is not indicative of tolerance to other aromatic anticonvulsants. Aromatic anticonvulsants include carbamazepine, oxcarbazepine, eslicarbazepine, lamotrigine, phenytoin, fosphenytoin, and phenobarbital.

\n", + "id" : 1452059904, + "html" : "

If patient is carbamazepine-naïve, do not use carbamazepine.

\n

Other Considerations

\n

Other aromatic anticonvulsants have weaker evidence linking SJS/TEN with the HLA-B*15:02 allele; however, caution should still be used in choosing an alternative agent. Previous tolerance of carbamazepine is not indicative of tolerance to other aromatic anticonvulsants. Aromatic anticonvulsants include carbamazepine, oxcarbazepine, eslicarbazepine, lamotrigine, phenytoin, fosphenytoin, and phenobarbital. In addition to HLA-B*15:02, risk for carbamazepine-induced SJS/TEN has been reported in association with the most common B75 serotype alleles in Southeast Asia, HLA-B*15:08, HLA-B*15:11, and HLA-B*15:21. Although not described, the possibility of carbamazepine-induced SJS/TEN in association with less frequently carried B75 serotype alleles, such as HLA-B*15:30 and HLA-B*15:31, should also be considered.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297294", - "name" : "Recommendation PA166297294", + "id" : "PA166297290", + "name" : "Recommendation PA166297290", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -17654,10 +17740,10 @@ }, "dosingInformation" : false, "implications" : [ - "HLA-A: Normal risk of carbamazepine-induced SJS/TEN, DRESS, and MPE", - "HLA-B: n/a" + "HLA-A: n/a", + "HLA-B: Normal risk of carbamazepine-induced SJS/TEN" ], - "lookupKey" : {"HLA-A": "*31:01 negative", "HLA-B": "No Result"}, + "lookupKey" : {"HLA-A": "No Result", "HLA-B": "*15:02 negative"}, "otherPrescribingGuidance" : false, "population" : "CBZ naive", "relatedChemicals" : [ @@ -17665,27 +17751,27 @@ "objCls" : "Chemical", "id" : "PA448785", "name" : "carbamazepine", - "version" : 14 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105008", "name" : "Annotation of CPIC Guideline for carbamazepine and HLA-A, HLA-B", - "version" : 52 + "version" : 115 }, "text" : { - "id" : 1452059896, + "id" : 1452059892, "html" : "

Use carbamazepine per standard dosing guidelines.

\n

Other Considerations

\n

HLA-B*15:02 has a 100% negative predictive value for carbamazepine-induced SJS/TEN, and its use is currently recommended to guide use of carbamazepine and oxcarbazepine only. Because there is a much weaker association and less than 100% negative predictive value of HLA-B*15:02 for SJS/TEN associated with other aromatic anticonvulsants, using these drugs instead of carbamazepine or oxcarbazepine in the setting of a negative HLA-B*15:02 test in Southeast Asians will not result in prevention of anticonvulsant-associated SJS/TEN (PMID 25355835).

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297289", - "name" : "Recommendation PA166297289", - "alternateDrugAvailable" : true, + "id" : "PA166297294", + "name" : "Recommendation PA166297294", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, "parents" : [], @@ -17697,10 +17783,10 @@ }, "dosingInformation" : false, "implications" : [ - "HLA-A: Greater risk of carbamazepine-induced SJS/TEN, DRESS, and MPE", - "HLA-B: Normal risk of carbamazepine-induced SJS/TEN" + "HLA-A: Normal risk of carbamazepine-induced SJS/TEN, DRESS, and MPE", + "HLA-B: n/a" ], - "lookupKey" : {"HLA-A": "*31:01 positive", "HLA-B": "*15:02 negative"}, + "lookupKey" : {"HLA-A": "*31:01 negative", "HLA-B": "No Result"}, "otherPrescribingGuidance" : false, "population" : "CBZ naive", "relatedChemicals" : [ @@ -17708,26 +17794,26 @@ "objCls" : "Chemical", "id" : "PA448785", "name" : "carbamazepine", - "version" : 14 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105008", "name" : "Annotation of CPIC Guideline for carbamazepine and HLA-A, HLA-B", - "version" : 52 + "version" : 115 }, "text" : { - "id" : 1452059891, - "html" : "

If patient is carbamazepine-naïve and alternative agents are available, do not use carbamazepine.

\n

Other Considerations

\n

Other aromatic anticonvulsants have very limited evidence, if any, linking SJS/TEN, DRESS, and/or MPE with the HLA-A*31:01 allele, and thus no recommendation can be made with respect to choosing another aromatic anticonvulsant as an alternative agent. Aromatic anticonvulsants include carbamazepine, oxcarbazepine, eslicarbazepine, lamotrigine, phenytoin, fosphenytoin, and phenobarbital. Previous tolerance of carbamazepine is not indicative of tolerance to other aromatic anticonvulsants.

\n", + "id" : 1452059896, + "html" : "

Use carbamazepine per standard dosing guidelines.

\n

Other Considerations

\n

HLA-B*15:02 has a 100% negative predictive value for carbamazepine-induced SJS/TEN, and its use is currently recommended to guide use of carbamazepine and oxcarbazepine only. Because there is a much weaker association and less than 100% negative predictive value of HLA-B*15:02 for SJS/TEN associated with other aromatic anticonvulsants, using these drugs instead of carbamazepine or oxcarbazepine in the setting of a negative HLA-B*15:02 test in Southeast Asians will not result in prevention of anticonvulsant-associated SJS/TEN (PMID 25355835).

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297307", - "name" : "Recommendation PA166297307", + "id" : "PA166297296", + "name" : "Recommendation PA166297296", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -17740,37 +17826,37 @@ }, "dosingInformation" : false, "implications" : [ - "HLA-A: n/a", + "HLA-A: Normal risk of carbamazepine-induced SJS/TEN, DRESS, and MPE", "HLA-B: Normal risk of carbamazepine-induced SJS/TEN" ], - "lookupKey" : {"HLA-A": "No Result", "HLA-B": "*15:02 negative"}, + "lookupKey" : {"HLA-A": "*31:01 negative", "HLA-B": "*15:02 negative"}, "otherPrescribingGuidance" : false, - "population" : "CBZ use >3mos", + "population" : "CBZ naive", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448785", "name" : "carbamazepine", - "version" : 14 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105008", "name" : "Annotation of CPIC Guideline for carbamazepine and HLA-A, HLA-B", - "version" : 52 + "version" : 115 }, "text" : { - "id" : 1452059909, + "id" : 1452059898, "html" : "

Use carbamazepine per standard dosing guidelines.

\n

Other Considerations

\n

HLA-B*15:02 has a 100% negative predictive value for carbamazepine-induced SJS/TEN, and its use is currently recommended to guide use of carbamazepine and oxcarbazepine only. Because there is a much weaker association and less than 100% negative predictive value of HLA-B*15:02 for SJS/TEN associated with other aromatic anticonvulsants, using these drugs instead of carbamazepine or oxcarbazepine in the setting of a negative HLA-B*15:02 test in Southeast Asians will not result in prevention of anticonvulsant-associated SJS/TEN (PMID 25355835).

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297303", - "name" : "Recommendation PA166297303", + "id" : "PA166297297", + "name" : "Recommendation PA166297297", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -17784,9 +17870,9 @@ "dosingInformation" : false, "implications" : [ "HLA-A: Normal risk of carbamazepine-induced SJS/TEN, DRESS, and MPE", - "HLA-B: n/a" + "HLA-B: Normal risk of carbamazepine-induced SJS/TEN" ], - "lookupKey" : {"HLA-A": "*31:01 negative", "HLA-B": "No Result"}, + "lookupKey" : {"HLA-A": "*31:01 negative", "HLA-B": "*15:02 negative"}, "otherPrescribingGuidance" : false, "population" : "CBZ-no alternatives", "relatedChemicals" : [ @@ -17794,21 +17880,21 @@ "objCls" : "Chemical", "id" : "PA448785", "name" : "carbamazepine", - "version" : 14 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105008", "name" : "Annotation of CPIC Guideline for carbamazepine and HLA-A, HLA-B", - "version" : 52 + "version" : 115 }, "text" : { - "id" : 1452059905, + "id" : 1452059899, "html" : "

Use carbamazepine per standard dosing guidelines.

\n

Other Considerations

\n

HLA-B*15:02 has a 100% negative predictive value for carbamazepine-induced SJS/TEN, and its use is currently recommended to guide use of carbamazepine and oxcarbazepine only. Because there is a much weaker association and less than 100% negative predictive value of HLA-B*15:02 for SJS/TEN associated with other aromatic anticonvulsants, using these drugs instead of carbamazepine or oxcarbazepine in the setting of a negative HLA-B*15:02 test in Southeast Asians will not result in prevention of anticonvulsant-associated SJS/TEN (PMID 25355835).

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -17837,69 +17923,26 @@ "objCls" : "Chemical", "id" : "PA448785", "name" : "carbamazepine", - "version" : 14 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105008", "name" : "Annotation of CPIC Guideline for carbamazepine and HLA-A, HLA-B", - "version" : 52 + "version" : 115 }, "text" : { "id" : 1452059900, "html" : "

If patient is carbamazepine-naïve and alternative agents are not available, consider the use of carbamazepine with increased frequency of clinical monitoring. Discontinue therapy at first evidence of a cutaneous adverse reaction.

\n", "version" : 0 }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166297308", - "name" : "Recommendation PA166297308", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 981565059, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "HLA-A: Normal risk of carbamazepine-induced SJS/TEN, DRESS, and MPE", - "HLA-B: Greater risk of carbamazepine-induced SJS/TEN" - ], - "lookupKey" : {"HLA-A": "*31:01 negative", "HLA-B": "*15:02 positive"}, - "otherPrescribingGuidance" : true, - "population" : "CBZ use >3mos", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA448785", - "name" : "carbamazepine", - "version" : 14 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166105008", - "name" : "Annotation of CPIC Guideline for carbamazepine and HLA-A, HLA-B", - "version" : 52 - }, - "text" : { - "id" : 1452059910, - "html" : "

The latency period for drug-induced SJS/TEN is short with continuous dosing and adherence to therapy (~4-28 days), and cases usually occur within three months of dosing; therefore, if the patient has previously used carbamazepine consistently for longer than three months without incidence of cutaneous adverse reactions, cautiously consider use of carbamazepine in the future.

\n

Other Considerations

\n

Previous tolerance of carbamazepine is not indicative of tolerance to other aromatic anticonvulsants. Aromatic anticonvulsants include carbamazepine, oxcarbazepine, eslicarbazepine, lamotrigine, phenytoin, fosphenytoin, and phenobarbital. In addition to HLA-B*15:02, risk for carbamazepine-induced SJS/TEN has been reported in association with the most common B75 serotype alleles in Southeast Asia, HLA-B*15:08, HLA-B*15:11, and HLA-B*15:21. Although not described, the possibility of carbamazepine-induced SJS/TEN in association with less frequently carried B75 serotype alleles, such as HLA-B*15:30 and HLA-B*15:31, should also be considered.

\n", - "version" : 0 - }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297290", - "name" : "Recommendation PA166297290", + "id" : "PA166297299", + "name" : "Recommendation PA166297299", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -17917,33 +17960,33 @@ ], "lookupKey" : {"HLA-A": "No Result", "HLA-B": "*15:02 negative"}, "otherPrescribingGuidance" : false, - "population" : "CBZ naive", + "population" : "CBZ-no alternatives", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448785", "name" : "carbamazepine", - "version" : 14 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105008", "name" : "Annotation of CPIC Guideline for carbamazepine and HLA-A, HLA-B", - "version" : 52 + "version" : 115 }, "text" : { - "id" : 1452059892, + "id" : 1452059901, "html" : "

Use carbamazepine per standard dosing guidelines.

\n

Other Considerations

\n

HLA-B*15:02 has a 100% negative predictive value for carbamazepine-induced SJS/TEN, and its use is currently recommended to guide use of carbamazepine and oxcarbazepine only. Because there is a much weaker association and less than 100% negative predictive value of HLA-B*15:02 for SJS/TEN associated with other aromatic anticonvulsants, using these drugs instead of carbamazepine or oxcarbazepine in the setting of a negative HLA-B*15:02 test in Southeast Asians will not result in prevention of anticonvulsant-associated SJS/TEN (PMID 25355835).

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297295", - "name" : "Recommendation PA166297295", - "alternateDrugAvailable" : true, + "id" : "PA166297303", + "name" : "Recommendation PA166297303", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, "parents" : [], @@ -17955,80 +17998,80 @@ }, "dosingInformation" : false, "implications" : [ - "HLA-A: Greater risk of carbamazepine-induced SJS/TEN, DRESS, and MPE", + "HLA-A: Normal risk of carbamazepine-induced SJS/TEN, DRESS, and MPE", "HLA-B: n/a" ], - "lookupKey" : {"HLA-A": "*31:01 positive", "HLA-B": "No Result"}, + "lookupKey" : {"HLA-A": "*31:01 negative", "HLA-B": "No Result"}, "otherPrescribingGuidance" : false, - "population" : "CBZ naive", + "population" : "CBZ-no alternatives", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448785", "name" : "carbamazepine", - "version" : 14 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105008", "name" : "Annotation of CPIC Guideline for carbamazepine and HLA-A, HLA-B", - "version" : 52 + "version" : 115 }, "text" : { - "id" : 1452059897, - "html" : "

If patient is carbamazepine-naïve and alternative agents are available, do not use carbamazepine.

\n

Other Considerations

\n

Other aromatic anticonvulsants have very limited evidence, if any, linking SJS/TEN, DRESS, and/or MPE with the HLA-A*31:01 allele, and thus no recommendation can be made with respect to choosing another aromatic anticonvulsant as an alternative agent. Aromatic anticonvulsants include carbamazepine, oxcarbazepine, eslicarbazepine, lamotrigine, phenytoin, fosphenytoin, and phenobarbital. Previous tolerance of carbamazepine is not indicative of tolerance to other aromatic anticonvulsants.

\n", + "id" : 1452059905, + "html" : "

Use carbamazepine per standard dosing guidelines.

\n

Other Considerations

\n

HLA-B*15:02 has a 100% negative predictive value for carbamazepine-induced SJS/TEN, and its use is currently recommended to guide use of carbamazepine and oxcarbazepine only. Because there is a much weaker association and less than 100% negative predictive value of HLA-B*15:02 for SJS/TEN associated with other aromatic anticonvulsants, using these drugs instead of carbamazepine or oxcarbazepine in the setting of a negative HLA-B*15:02 test in Southeast Asians will not result in prevention of anticonvulsant-associated SJS/TEN (PMID 25355835).

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297300", - "name" : "Recommendation PA166297300", - "alternateDrugAvailable" : true, + "id" : "PA166297304", + "name" : "Recommendation PA166297304", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "HLA-A: Normal risk of carbamazepine-induced SJS/TEN, DRESS, and MPE", - "HLA-B: Greater risk of carbamazepine-induced SJS/TEN" + "HLA-A: Greater risk of carbamazepine-induced SJS/TEN, DRESS, and MPE", + "HLA-B: n/a" ], - "lookupKey" : {"HLA-A": "*31:01 negative", "HLA-B": "*15:02 positive"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"HLA-A": "*31:01 positive", "HLA-B": "No Result"}, + "otherPrescribingGuidance" : true, "population" : "CBZ-no alternatives", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448785", "name" : "carbamazepine", - "version" : 14 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105008", "name" : "Annotation of CPIC Guideline for carbamazepine and HLA-A, HLA-B", - "version" : 52 + "version" : 115 }, "text" : { - "id" : 1452059902, - "html" : "

If patient is carbamazepine-naïve, do not use carbamazepine.

\n

Other Considerations

\n

Other aromatic anticonvulsants have weaker evidence linking SJS/TEN with the HLA-B*15:02 allele; however, caution should still be used in choosing an alternative agent. Previous tolerance of carbamazepine is not indicative of tolerance to other aromatic anticonvulsants. Aromatic anticonvulsants include carbamazepine, oxcarbazepine, eslicarbazepine, lamotrigine, phenytoin, fosphenytoin, and phenobarbital. In addition to HLA-B*15:02, risk for carbamazepine-induced SJS/TEN has been reported in association with the most common B75 serotype alleles in Southeast Asia, HLA-B*15:08, HLA-B*15:11, and HLA-B*15:21. Although not described, the possibility of carbamazepine-induced SJS/TEN in association with less frequently carried B75 serotype alleles, such as HLA-B*15:30 and HLA-B*15:31, should also be considered.

\n", + "id" : 1452059906, + "html" : "

If patient is carbamazepine-naïve and alternative agents are not available, consider the use of carbamazepine with increased frequency of clinical monitoring. Discontinue therapy at first evidence of a cutaneous adverse reaction.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297299", - "name" : "Recommendation PA166297299", + "id" : "PA166297305", + "name" : "Recommendation PA166297305", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -18041,37 +18084,37 @@ }, "dosingInformation" : false, "implications" : [ - "HLA-A: n/a", + "HLA-A: Normal risk of carbamazepine-induced SJS/TEN, DRESS, and MPE", "HLA-B: Normal risk of carbamazepine-induced SJS/TEN" ], - "lookupKey" : {"HLA-A": "No Result", "HLA-B": "*15:02 negative"}, + "lookupKey" : {"HLA-A": "*31:01 negative", "HLA-B": "*15:02 negative"}, "otherPrescribingGuidance" : false, - "population" : "CBZ-no alternatives", + "population" : "CBZ use >3mos", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448785", "name" : "carbamazepine", - "version" : 14 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105008", "name" : "Annotation of CPIC Guideline for carbamazepine and HLA-A, HLA-B", - "version" : 52 + "version" : 115 }, "text" : { - "id" : 1452059901, + "id" : 1452059907, "html" : "

Use carbamazepine per standard dosing guidelines.

\n

Other Considerations

\n

HLA-B*15:02 has a 100% negative predictive value for carbamazepine-induced SJS/TEN, and its use is currently recommended to guide use of carbamazepine and oxcarbazepine only. Because there is a much weaker association and less than 100% negative predictive value of HLA-B*15:02 for SJS/TEN associated with other aromatic anticonvulsants, using these drugs instead of carbamazepine or oxcarbazepine in the setting of a negative HLA-B*15:02 test in Southeast Asians will not result in prevention of anticonvulsant-associated SJS/TEN (PMID 25355835).

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297304", - "name" : "Recommendation PA166297304", + "id" : "PA166297306", + "name" : "Recommendation PA166297306", "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, @@ -18085,36 +18128,36 @@ "dosingInformation" : false, "implications" : [ "HLA-A: Greater risk of carbamazepine-induced SJS/TEN, DRESS, and MPE", - "HLA-B: n/a" + "HLA-B: Normal risk of carbamazepine-induced SJS/TEN" ], - "lookupKey" : {"HLA-A": "*31:01 positive", "HLA-B": "No Result"}, + "lookupKey" : {"HLA-A": "*31:01 positive", "HLA-B": "*15:02 negative"}, "otherPrescribingGuidance" : true, - "population" : "CBZ-no alternatives", + "population" : "CBZ use >3mos", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448785", "name" : "carbamazepine", - "version" : 14 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105008", "name" : "Annotation of CPIC Guideline for carbamazepine and HLA-A, HLA-B", - "version" : 52 + "version" : 115 }, "text" : { - "id" : 1452059906, - "html" : "

If patient is carbamazepine-naïve and alternative agents are not available, consider the use of carbamazepine with increased frequency of clinical monitoring. Discontinue therapy at first evidence of a cutaneous adverse reaction.

\n", + "id" : 1452059908, + "html" : "

The latency period for cutaneous adverse drug reactions is variable depending on phenotype; however, all usually occur within three months of regular dosing. Therefore, if the patient has previously used carbamazepine consistently for longer than three months without incidence of cutaneous adverse reactions, cautiously consider use of carbamazepine.

\n

Other Considerations

\n

Previous tolerance of carbamazepine is not indicative of tolerance to other aromatic anticonvulsants. Aromatic anticonvulsants include carbamazepine, oxcarbazepine, eslicarbazepine, lamotrigine, phenytoin, fosphenytoin, and phenobarbital.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297309", - "name" : "Recommendation PA166297309", + "id" : "PA166297308", + "name" : "Recommendation PA166297308", "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, @@ -18127,10 +18170,10 @@ }, "dosingInformation" : false, "implications" : [ - "HLA-A: Greater risk of carbamazepine-induced SJS/TEN, DRESS, and MPE", + "HLA-A: Normal risk of carbamazepine-induced SJS/TEN, DRESS, and MPE", "HLA-B: Greater risk of carbamazepine-induced SJS/TEN" ], - "lookupKey" : {"HLA-A": "*31:01 positive", "HLA-B": "*15:02 positive"}, + "lookupKey" : {"HLA-A": "*31:01 negative", "HLA-B": "*15:02 positive"}, "otherPrescribingGuidance" : true, "population" : "CBZ use >3mos", "relatedChemicals" : [ @@ -18138,155 +18181,112 @@ "objCls" : "Chemical", "id" : "PA448785", "name" : "carbamazepine", - "version" : 14 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105008", "name" : "Annotation of CPIC Guideline for carbamazepine and HLA-A, HLA-B", - "version" : 52 + "version" : 115 }, "text" : { - "id" : 1452059911, + "id" : 1452059910, "html" : "

The latency period for drug-induced SJS/TEN is short with continuous dosing and adherence to therapy (~4-28 days), and cases usually occur within three months of dosing; therefore, if the patient has previously used carbamazepine consistently for longer than three months without incidence of cutaneous adverse reactions, cautiously consider use of carbamazepine in the future.

\n

Other Considerations

\n

Previous tolerance of carbamazepine is not indicative of tolerance to other aromatic anticonvulsants. Aromatic anticonvulsants include carbamazepine, oxcarbazepine, eslicarbazepine, lamotrigine, phenytoin, fosphenytoin, and phenobarbital. In addition to HLA-B*15:02, risk for carbamazepine-induced SJS/TEN has been reported in association with the most common B75 serotype alleles in Southeast Asia, HLA-B*15:08, HLA-B*15:11, and HLA-B*15:21. Although not described, the possibility of carbamazepine-induced SJS/TEN in association with less frequently carried B75 serotype alleles, such as HLA-B*15:30 and HLA-B*15:31, should also be considered.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297291", - "name" : "Recommendation PA166297291", - "alternateDrugAvailable" : true, + "id" : "PA166297309", + "name" : "Recommendation PA166297309", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "HLA-A: Normal risk of carbamazepine-induced SJS/TEN, DRESS, and MPE", + "HLA-A: Greater risk of carbamazepine-induced SJS/TEN, DRESS, and MPE", "HLA-B: Greater risk of carbamazepine-induced SJS/TEN" ], - "lookupKey" : {"HLA-A": "*31:01 negative", "HLA-B": "*15:02 positive"}, - "otherPrescribingGuidance" : false, - "population" : "CBZ naive", + "lookupKey" : {"HLA-A": "*31:01 positive", "HLA-B": "*15:02 positive"}, + "otherPrescribingGuidance" : true, + "population" : "CBZ use >3mos", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448785", "name" : "carbamazepine", - "version" : 14 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105008", "name" : "Annotation of CPIC Guideline for carbamazepine and HLA-A, HLA-B", - "version" : 52 + "version" : 115 }, "text" : { - "id" : 1452059893, - "html" : "

If patient is carbamazepine-naïve, do not use carbamazepine.

\n

Other Considerations

\n

Other aromatic anticonvulsants have weaker evidence linking SJS/TEN with the HLA-B*15:02 allele; however, caution should still be used in choosing an alternative agent. Previous tolerance of carbamazepine is not indicative of tolerance to other aromatic anticonvulsants. Aromatic anticonvulsants include carbamazepine, oxcarbazepine, eslicarbazepine, lamotrigine, phenytoin, fosphenytoin, and phenobarbital. In addition to HLA-B*15:02, risk for carbamazepine-induced SJS/TEN has been reported in association with the most common B75 serotype alleles in Southeast Asia, HLA-B*15:08, HLA-B*15:11, and HLA-B*15:21. Although not described, the possibility of carbamazepine-induced SJS/TEN in association with less frequently carried B75 serotype alleles, such as HLA-B*15:30 and HLA-B*15:31, should also be considered.

\n", + "id" : 1452059911, + "html" : "

The latency period for drug-induced SJS/TEN is short with continuous dosing and adherence to therapy (~4-28 days), and cases usually occur within three months of dosing; therefore, if the patient has previously used carbamazepine consistently for longer than three months without incidence of cutaneous adverse reactions, cautiously consider use of carbamazepine in the future.

\n

Other Considerations

\n

Previous tolerance of carbamazepine is not indicative of tolerance to other aromatic anticonvulsants. Aromatic anticonvulsants include carbamazepine, oxcarbazepine, eslicarbazepine, lamotrigine, phenytoin, fosphenytoin, and phenobarbital. In addition to HLA-B*15:02, risk for carbamazepine-induced SJS/TEN has been reported in association with the most common B75 serotype alleles in Southeast Asia, HLA-B*15:08, HLA-B*15:11, and HLA-B*15:21. Although not described, the possibility of carbamazepine-induced SJS/TEN in association with less frequently carried B75 serotype alleles, such as HLA-B*15:30 and HLA-B*15:31, should also be considered.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297296", - "name" : "Recommendation PA166297296", + "id" : "PA166297310", + "name" : "Recommendation PA166297310", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "HLA-A: Normal risk of carbamazepine-induced SJS/TEN, DRESS, and MPE", - "HLA-B: Normal risk of carbamazepine-induced SJS/TEN" - ], - "lookupKey" : {"HLA-A": "*31:01 negative", "HLA-B": "*15:02 negative"}, - "otherPrescribingGuidance" : false, - "population" : "CBZ naive", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA448785", - "name" : "carbamazepine", - "version" : 14 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166105008", - "name" : "Annotation of CPIC Guideline for carbamazepine and HLA-A, HLA-B", - "version" : 52 - }, - "text" : { - "id" : 1452059898, - "html" : "

Use carbamazepine per standard dosing guidelines.

\n

Other Considerations

\n

HLA-B*15:02 has a 100% negative predictive value for carbamazepine-induced SJS/TEN, and its use is currently recommended to guide use of carbamazepine and oxcarbazepine only. Because there is a much weaker association and less than 100% negative predictive value of HLA-B*15:02 for SJS/TEN associated with other aromatic anticonvulsants, using these drugs instead of carbamazepine or oxcarbazepine in the setting of a negative HLA-B*15:02 test in Southeast Asians will not result in prevention of anticonvulsant-associated SJS/TEN (PMID 25355835).

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166297301", - "name" : "Recommendation PA166297301", - "alternateDrugAvailable" : true, - "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "HLA-A: Greater risk of carbamazepine-induced SJS/TEN, DRESS, and MPE", + "HLA-A: n/a", "HLA-B: Greater risk of carbamazepine-induced SJS/TEN" ], - "lookupKey" : {"HLA-A": "*31:01 positive", "HLA-B": "*15:02 positive"}, - "otherPrescribingGuidance" : false, - "population" : "CBZ-no alternatives", + "lookupKey" : {"HLA-A": "No Result", "HLA-B": "*15:02 positive"}, + "otherPrescribingGuidance" : true, + "population" : "CBZ use >3mos", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448785", "name" : "carbamazepine", - "version" : 14 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105008", "name" : "Annotation of CPIC Guideline for carbamazepine and HLA-A, HLA-B", - "version" : 52 + "version" : 115 }, "text" : { - "id" : 1452059903, - "html" : "

If patient is carbamazepine-naïve, do not use carbamazepine.

\n

Other Considerations

\n

Other aromatic anticonvulsants have weaker evidence linking SJS/TEN with the HLA-B*15:02 allele; however, caution should still be used in choosing an alternative agent. Previous tolerance of carbamazepine is not indicative of tolerance to other aromatic anticonvulsants. Aromatic anticonvulsants include carbamazepine, oxcarbazepine, eslicarbazepine, lamotrigine, phenytoin, fosphenytoin, and phenobarbital. In addition to HLA-B*15:02, risk for carbamazepine-induced SJS/TEN has been reported in association with the most common B75 serotype alleles in Southeast Asia, HLA-B*15:08, HLA-B*15:11, and HLA-B*15:21. Although not described, the possibility of carbamazepine-induced SJS/TEN in association with less frequently carried B75 serotype alleles, such as HLA-B*15:30 and HLA-B*15:31, should also be considered.

\n", + "id" : 1452059912, + "html" : "

The latency period for drug-induced SJS/TEN is short with continuous dosing and adherence to therapy (~4-28 days), and cases usually occur within three months of dosing; therefore, if the patient has previously used carbamazepine consistently for longer than three months without incidence of cutaneous adverse reactions, cautiously consider use of carbamazepine in the future.

\n

Other Considerations

\n

Previous tolerance of carbamazepine is not indicative of tolerance to other aromatic anticonvulsants. Aromatic anticonvulsants include carbamazepine, oxcarbazepine, eslicarbazepine, lamotrigine, phenytoin, fosphenytoin, and phenobarbital. In addition to HLA-B*15:02, risk for carbamazepine-induced SJS/TEN has been reported in association with the most common B75 serotype alleles in Southeast Asia, HLA-B*15:08, HLA-B*15:11, and HLA-B*15:21. Although not described, the possibility of carbamazepine-induced SJS/TEN in association with less frequently carried B75 serotype alleles, such as HLA-B*15:30 and HLA-B*15:31, should also be considered.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297305", - "name" : "Recommendation PA166297305", + "id" : "PA166297311", + "name" : "Recommendation PA166297311", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -18300,9 +18300,9 @@ "dosingInformation" : false, "implications" : [ "HLA-A: Normal risk of carbamazepine-induced SJS/TEN, DRESS, and MPE", - "HLA-B: Normal risk of carbamazepine-induced SJS/TEN" + "HLA-B: n/a" ], - "lookupKey" : {"HLA-A": "*31:01 negative", "HLA-B": "*15:02 negative"}, + "lookupKey" : {"HLA-A": "*31:01 negative", "HLA-B": "No Result"}, "otherPrescribingGuidance" : false, "population" : "CBZ use >3mos", "relatedChemicals" : [ @@ -18310,26 +18310,26 @@ "objCls" : "Chemical", "id" : "PA448785", "name" : "carbamazepine", - "version" : 14 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105008", "name" : "Annotation of CPIC Guideline for carbamazepine and HLA-A, HLA-B", - "version" : 52 + "version" : 115 }, "text" : { - "id" : 1452059907, + "id" : 1452059913, "html" : "

Use carbamazepine per standard dosing guidelines.

\n

Other Considerations

\n

HLA-B*15:02 has a 100% negative predictive value for carbamazepine-induced SJS/TEN, and its use is currently recommended to guide use of carbamazepine and oxcarbazepine only. Because there is a much weaker association and less than 100% negative predictive value of HLA-B*15:02 for SJS/TEN associated with other aromatic anticonvulsants, using these drugs instead of carbamazepine or oxcarbazepine in the setting of a negative HLA-B*15:02 test in Southeast Asians will not result in prevention of anticonvulsant-associated SJS/TEN (PMID 25355835).

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297310", - "name" : "Recommendation PA166297310", + "id" : "PA166297312", + "name" : "Recommendation PA166297312", "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, @@ -18342,10 +18342,10 @@ }, "dosingInformation" : false, "implications" : [ - "HLA-A: n/a", - "HLA-B: Greater risk of carbamazepine-induced SJS/TEN" + "HLA-A: Greater risk of carbamazepine-induced SJS/TEN, DRESS, and MPE", + "HLA-B: n/a" ], - "lookupKey" : {"HLA-A": "No Result", "HLA-B": "*15:02 positive"}, + "lookupKey" : {"HLA-A": "*31:01 positive", "HLA-B": "No Result"}, "otherPrescribingGuidance" : true, "population" : "CBZ use >3mos", "relatedChemicals" : [ @@ -18353,27 +18353,27 @@ "objCls" : "Chemical", "id" : "PA448785", "name" : "carbamazepine", - "version" : 14 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105008", "name" : "Annotation of CPIC Guideline for carbamazepine and HLA-A, HLA-B", - "version" : 52 + "version" : 115 }, "text" : { - "id" : 1452059912, - "html" : "

The latency period for drug-induced SJS/TEN is short with continuous dosing and adherence to therapy (~4-28 days), and cases usually occur within three months of dosing; therefore, if the patient has previously used carbamazepine consistently for longer than three months without incidence of cutaneous adverse reactions, cautiously consider use of carbamazepine in the future.

\n

Other Considerations

\n

Previous tolerance of carbamazepine is not indicative of tolerance to other aromatic anticonvulsants. Aromatic anticonvulsants include carbamazepine, oxcarbazepine, eslicarbazepine, lamotrigine, phenytoin, fosphenytoin, and phenobarbital. In addition to HLA-B*15:02, risk for carbamazepine-induced SJS/TEN has been reported in association with the most common B75 serotype alleles in Southeast Asia, HLA-B*15:08, HLA-B*15:11, and HLA-B*15:21. Although not described, the possibility of carbamazepine-induced SJS/TEN in association with less frequently carried B75 serotype alleles, such as HLA-B*15:30 and HLA-B*15:31, should also be considered.

\n", + "id" : 1452059914, + "html" : "

The latency period for cutaneous adverse drug reactions is variable depending on phenotype; however, all usually occur within three months of regular dosing. Therefore, if the patient has previously used carbamazepine consistently for longer than three months without incidence of cutaneous adverse reactions, cautiously consider use of carbamazepine.

\n

Other Considerations

\n

Previous tolerance of carbamazepine is not indicative of tolerance to other aromatic anticonvulsants. Aromatic anticonvulsants include carbamazepine, oxcarbazepine, eslicarbazepine, lamotrigine, phenytoin, fosphenytoin, and phenobarbital.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297292", - "name" : "Recommendation PA166297292", - "alternateDrugAvailable" : true, + "id" : "PA166297307", + "name" : "Recommendation PA166297307", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, "parents" : [], @@ -18385,32 +18385,32 @@ }, "dosingInformation" : false, "implications" : [ - "HLA-A: Greater risk of carbamazepine-induced SJS/TEN, DRESS, and MPE", - "HLA-B: Greater risk of carbamazepine-induced SJS/TEN" + "HLA-A: n/a", + "HLA-B: Normal risk of carbamazepine-induced SJS/TEN" ], - "lookupKey" : {"HLA-A": "*31:01 positive", "HLA-B": "*15:02 positive"}, + "lookupKey" : {"HLA-A": "No Result", "HLA-B": "*15:02 negative"}, "otherPrescribingGuidance" : false, - "population" : "CBZ naive", + "population" : "CBZ use >3mos", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448785", "name" : "carbamazepine", - "version" : 14 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105008", "name" : "Annotation of CPIC Guideline for carbamazepine and HLA-A, HLA-B", - "version" : 52 + "version" : 115 }, "text" : { - "id" : 1452059894, - "html" : "

If patient is carbamazepine-naïve, do not use carbamazepine.

\n

Other Considerations

\n

Other aromatic anticonvulsants have weaker evidence linking SJS/TEN with the HLA-B*15:02 allele; however, caution should still be used in choosing an alternative agent. Previous tolerance of carbamazepine is not indicative of tolerance to other aromatic anticonvulsants. Aromatic anticonvulsants include carbamazepine, oxcarbazepine, eslicarbazepine, lamotrigine, phenytoin, fosphenytoin, and phenobarbital. In addition to HLA-B*15:02, risk for carbamazepine-induced SJS/TEN has been reported in association with the most common B75 serotype alleles in Southeast Asia, HLA-B*15:08, HLA-B*15:11, and HLA-B*15:21. Although not described, the possibility of carbamazepine-induced SJS/TEN in association with less frequently carried B75 serotype alleles, such as HLA-B*15:30 and HLA-B*15:31, should also be considered.

\n", + "id" : 1452059909, + "html" : "

Use carbamazepine per standard dosing guidelines.

\n

Other Considerations

\n

HLA-B*15:02 has a 100% negative predictive value for carbamazepine-induced SJS/TEN, and its use is currently recommended to guide use of carbamazepine and oxcarbazepine only. Because there is a much weaker association and less than 100% negative predictive value of HLA-B*15:02 for SJS/TEN associated with other aromatic anticonvulsants, using these drugs instead of carbamazepine or oxcarbazepine in the setting of a negative HLA-B*15:02 test in Southeast Asians will not result in prevention of anticonvulsant-associated SJS/TEN (PMID 25355835).

\n", "version" : 0 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166105008" @@ -18749,25 +18749,25 @@ "objCls" : "Chemical", "id" : "PA448871", "name" : "celecoxib", - "version" : 22 + "version" : 43 }, { "objCls" : "Chemical", "id" : "PA449683", "name" : "flurbiprofen", - "version" : 12 + "version" : 35 }, { "objCls" : "Chemical", "id" : "PA449957", "name" : "ibuprofen", - "version" : 13 + "version" : 43 }, { "objCls" : "Chemical", "id" : "PA165958395", "name" : "lornoxicam", - "version" : 7 + "version" : 12 } ], "relatedGenes" : [ @@ -18776,29 +18776,29 @@ "id" : "PA126", "symbol" : "CYP2C9", "name" : "cytochrome P450 family 2 subfamily C member 9", - "version" : 7877 + "version" : 7952 } ], "source" : "CPIC", "summaryMarkdown" : { "id" : 1450983460, "html" : "

The CPIC Dosing Guideline for celecoxib, flurbiprofen, ibuprofen and lornoxicam recommends initiating therapy with 25-50% of\nthe lowest recommended starting dose for CYP2C9 poor metabolizers and initiating therapy with lowest recommended starting dose for CYP2C9 intermediate metabolizers with activity score of 1. See full guideline for further details and supporting evidence.

\n", - "version" : 0 + "version" : 1 }, "terms" : [], "textMarkdown" : { "id" : 1451433677, "html" : "

This annotation is based on the CPIC® guideline for Nonsteroidal Anti-inflammatory Drugs and CYP2C9.

\n

March 2020

\n

Advance online publication March 2020.

\n\n\n

Adapted from Tables 1 and 2 of the 2020 guideline.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
PhenotypeaActivity ScoreGenotypeExamples of genotypesbImplicationsTherapeutic recommendationscClassification of recommendationsdOther considerations
CYP2C9 Normal metabolizer2cAn individual carrying two normal function alleles*1/*1Normal metabolismInitiate therapy with recommended starting dose. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals.Strong
CYP2C9 Intermediate metabolizerf1.5cAn individual carrying one normal function and one decreased function allele.*1/*2Mildly reduced metabolismInitiate therapy with recommended starting dose. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals.ModerateIMs might have a higher than normal risk of adverse events especially in individuals with other factors affecting clearance of these drugs such as hepatic impairment or advanced age.Further caution should be taken with ibuprofen use in individuals carrying the CYP2C9*2 allele as it is in linkage disequilibrium with CYP2C8*3 and ibuprofen is also metabolized by CYP2C8.
CYP2C9 Intermediate metabolizerf1cAn individual carrying one normal function allele plus one no function allele OR two decreased function alleles.*1/*3, *2/*2Moderately reduced metabolism; higher plasma concentrations may increase probability of toxicitiesInitiate therapy with lowest recommended starting dose. Titrate dose upward to clinical effect or maximum recommended dose with caution. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals. Carefully monitor adverse events such as blood pressure and kidney function during course of therapy.ModerateIMs might have a higher than normal risk of adverse events especially in individuals with other factors affecting clearance of these drugs such as hepatic impairment or advanced age. Further caution should be taken with ibuprofen use in individuals carrying the CYP2C9*2 allele as it is in linkage
CYP2C9 Poor metabolizer0 or 0.5cAn individual carrying one no function allele plus one decreased function allele; OR two no function alleles*2/*3, *3/*3Significantly reduced metabolism and prolonged half life; higher plasma concentrations may increase probability and/or severity of toxicitiesInitiate therapy with 25-50% of the lowest recommended starting dose. Titrate dose upward to clinical effect or 25-50% of the maximum recommended dose with caution. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals.Upward dose titration should not occur until after steady state is reached (at least 8 days for celecoxib and 5 days for ibuprofen, flurbiprofen and lornoxicam after first dose in PMs). Carefully monitor adverse events such as blood pressure and kidney function during course of therapy. Alternatively, consider an alternate therapy not metabolized by CYP2C9 or not significantly impacted by CYP2C9 genetic variants in vivo.ModerateAlternative therapies not primarily metabolized by CYP2C9 include aspirin, ketorolac, naproxen and sulindac. Selection of therapy will depend on individual patient treatment goals and risks for toxicity.
Indeterminaten/acAn individual carrying allele combinations with uncertain and/or unknown function alleles*1/*7, *1/*10, *7/*10, *1/*57n/aNo recommendation.n/a
\n

a See the CYP2C9 frequency table for race-specific allele and phenotype frequencies.
\nb For a complete list of CYP2C9 diplotypes and resulting phenotypes, see the CYP2C9 genotype to phenotype table.

\n

c CPIC assigned each allele functional status an activity value ranging from 0 to 1 (e.g., 0 for no function, 0.5 for decreased, and 1.0 for normal function), which are summed to calculate the activity score (AS) for each diplotype. The CYP2C9 AS has been translated into the phenotype classification system as follows: individuals with an AS of 0 or 0.5 are poor\nmetabolizers (PMs), those with a score of 1 or 1.5 are intermediate metabolizers (IMs), and those with a score of 2 are normal metabolizers (NMs).
\nd Rating scheme described in Supplement.

\n", - "version" : 1 + "version" : 2 }, "userId" : "lgong", - "version" : 10 + "version" : 118 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166297315", - "name" : "Recommendation PA166297315", + "id" : "PA166297314", + "name" : "Recommendation PA166297314", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -18809,11 +18809,11 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C9: Moderately reduced metabolism; higher plasma concentrations may increase probability of toxicities" + "CYP2C9: Mildly reduced metabolism" ], - "lookupKey" : {"CYP2C9": "1.0"}, + "lookupKey" : {"CYP2C9": "1.5"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -18821,21 +18821,21 @@ "objCls" : "Chemical", "id" : "PA448871", "name" : "celecoxib", - "version" : 22 + "version" : 43 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166191841", "name" : "Annotation of CPIC Guideline for celecoxib, flurbiprofen, ibuprofen, lornoxicam and CYP2C9", - "version" : 10 + "version" : 118 }, "text" : { - "id" : 1452059917, - "html" : "

Initiate therapy with lowest recommended starting dose. Titrate dose upward to clinical effect or maximum recommended dose with caution. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals. Carefully monitor adverse events such as blood pressure and kidney function during course of therapy.

\n

Other Considerations

\n

IMs might have a higher than normal risk of adverse events especially in individuals with other factors affecting clearance of these drugs such as hepatic impairment or advanced age. Further caution should be taken with ibuprofen use in individuals carrying the CYP2C9*2 allele as it is in linkage disequilibrium with CYP2C8*3 and ibuprofen is also metabolized by CYP2C8.

\n", + "id" : 1452059916, + "html" : "

Initiate therapy with recommended starting dose. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals.

\n

Other Considerations

\n

IMs might have a higher than normal risk of adverse events especially in individuals with other factors affecting clearance of these drugs such as hepatic impairment or advanced age. Further caution should be taken with ibuprofen use in individuals carrying the CYP2C9*2 allele as it is in linkage disequilibrium with CYP2C8*3 and ibuprofen is also metabolized by CYP2C8.

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", @@ -18863,83 +18863,83 @@ "objCls" : "Chemical", "id" : "PA449683", "name" : "flurbiprofen", - "version" : 12 + "version" : 35 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166191841", "name" : "Annotation of CPIC Guideline for celecoxib, flurbiprofen, ibuprofen, lornoxicam and CYP2C9", - "version" : 10 + "version" : 118 }, "text" : { "id" : 1452059926, "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297319", - "name" : "Recommendation PA166297319", + "id" : "PA166297318", + "name" : "Recommendation PA166297318", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2C9: Normal metabolism" + "CYP2C9: n/a" ], - "lookupKey" : {"CYP2C9": "2.0"}, + "lookupKey" : {"CYP2C9": "n/a"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA449683", - "name" : "flurbiprofen", - "version" : 12 + "id" : "PA448871", + "name" : "celecoxib", + "version" : 43 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166191841", "name" : "Annotation of CPIC Guideline for celecoxib, flurbiprofen, ibuprofen, lornoxicam and CYP2C9", - "version" : 10 + "version" : 118 }, "text" : { - "id" : 1452059921, - "html" : "

Initiate therapy with recommended starting dose. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals.

\n", + "id" : 1452059920, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297328", - "name" : "Recommendation PA166297328", - "alternateDrugAvailable" : true, + "id" : "PA166297329", + "name" : "Recommendation PA166297329", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C9: Significantly reduced metabolism and prolonged half-life; higher plasma concentrations may increase probability and/or severity of toxicities" + "CYP2C9: n/a" ], - "lookupKey" : {"CYP2C9": "0.0"}, + "lookupKey" : {"CYP2C9": "n/a"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -18947,41 +18947,41 @@ "objCls" : "Chemical", "id" : "PA449957", "name" : "ibuprofen", - "version" : 13 + "version" : 43 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166191841", "name" : "Annotation of CPIC Guideline for celecoxib, flurbiprofen, ibuprofen, lornoxicam and CYP2C9", - "version" : 10 + "version" : 118 }, "text" : { - "id" : 1452059930, - "html" : "

Initiate therapy with 25-50% of the lowest recommended starting dose. Titrate dose upward to clinical effect or 25-50% of the maximum recommended dose with caution. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals. Upward dose titration should not occur until after steady state is reached (at least 8 days for celecoxib after first dose in PMs). Carefully monitor adverse events such as blood pressure and kidney function during course of therapy. Alternatively, consider an alternate therapy not metabolized by CYP2C9 or not significantly impacted by CYP2C9 genetic variants in vivo.

\n

Other Considerations

\n

Alternative therapies not primarily metabolized by CYP2C9 include aspirin, ketorolac, naproxen and sulindac. Selection of therapy will depend on individual patient treatment goals and risks for toxicity.

\n", + "id" : 1452059931, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297333", - "name" : "Recommendation PA166297333", - "alternateDrugAvailable" : true, + "id" : "PA166297335", + "name" : "Recommendation PA166297335", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C9: Significantly reduced metabolism and prolonged half-life; higher plasma concentrations may increase probability and/or severity of toxicities" + "CYP2C9: n/a" ], - "lookupKey" : {"CYP2C9": "0.5"}, + "lookupKey" : {"CYP2C9": "n/a"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -18989,41 +18989,41 @@ "objCls" : "Chemical", "id" : "PA165958395", "name" : "lornoxicam", - "version" : 7 + "version" : 12 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166191841", "name" : "Annotation of CPIC Guideline for celecoxib, flurbiprofen, ibuprofen, lornoxicam and CYP2C9", - "version" : 10 + "version" : 118 }, "text" : { - "id" : 1452059935, - "html" : "

Initiate therapy with 25-50% of the lowest recommended starting dose. Titrate dose upward to clinical effect or 25-50% of the maximum recommended dose with caution. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals. Upward dose titration should not occur until after steady state is reached (at least 8 days for celecoxib after first dose in PMs). Carefully monitor adverse events such as blood pressure and kidney function during course of therapy. Alternatively, consider an alternate therapy not metabolized by CYP2C9 or not significantly impacted by CYP2C9 genetic variants in vivo.

\n

Other Considerations

\n

Alternative therapies not primarily metabolized by CYP2C9 include aspirin, ketorolac, naproxen and sulindac. Selection of therapy will depend on individual patient treatment goals and risks for toxicity.

\n", + "id" : 1452059937, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297320", - "name" : "Recommendation PA166297320", + "id" : "PA166297319", + "name" : "Recommendation PA166297319", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2C9: Mildly reduced metabolism" + "CYP2C9: Normal metabolism" ], - "lookupKey" : {"CYP2C9": "1.5"}, + "lookupKey" : {"CYP2C9": "2.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -19031,26 +19031,26 @@ "objCls" : "Chemical", "id" : "PA449683", "name" : "flurbiprofen", - "version" : 12 + "version" : 35 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166191841", "name" : "Annotation of CPIC Guideline for celecoxib, flurbiprofen, ibuprofen, lornoxicam and CYP2C9", - "version" : 10 + "version" : 118 }, "text" : { - "id" : 1452059922, - "html" : "

Initiate therapy with recommended starting dose. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals.

\n

Other Considerations

\n

IMs might have a higher than normal risk of adverse events especially in individuals with other factors affecting clearance of these drugs such as hepatic impairment or advanced age. Further caution should be taken with ibuprofen use in individuals carrying the CYP2C9*2 allele as it is in linkage disequilibrium with CYP2C8*3 and ibuprofen is also metabolized by CYP2C8.

\n", + "id" : 1452059921, + "html" : "

Initiate therapy with recommended starting dose. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals.

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297285", - "name" : "Recommendation PA166297285", + "id" : "PA166297320", + "name" : "Recommendation PA166297320", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -19061,122 +19061,122 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C9: Moderately reduced metabolism; higher plasma concentrations may increase probability of toxicities" + "CYP2C9: Mildly reduced metabolism" ], - "lookupKey" : {"CYP2C9": "1.0"}, + "lookupKey" : {"CYP2C9": "1.5"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA449957", - "name" : "ibuprofen", - "version" : 13 + "id" : "PA449683", + "name" : "flurbiprofen", + "version" : 35 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166191841", "name" : "Annotation of CPIC Guideline for celecoxib, flurbiprofen, ibuprofen, lornoxicam and CYP2C9", - "version" : 10 + "version" : 118 }, "text" : { - "id" : 1452059887, - "html" : "

Initiate therapy with lowest recommended starting dose. Titrate dose upward to clinical effect or maximum recommended dose with caution. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals. Carefully monitor adverse events such as blood pressure and kidney function during course of therapy.

\n

Other Considerations

\n

IMs might have a higher than normal risk of adverse events especially in individuals with other factors affecting clearance of these drugs such as hepatic impairment or advanced age. Further caution should be taken with ibuprofen use in individuals carrying the CYP2C9*2 allele as it is in linkage disequilibrium with CYP2C8*3 and ibuprofen is also metabolized by CYP2C8.

\n", + "id" : 1452059922, + "html" : "

Initiate therapy with recommended starting dose. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals.

\n

Other Considerations

\n

IMs might have a higher than normal risk of adverse events especially in individuals with other factors affecting clearance of these drugs such as hepatic impairment or advanced age. Further caution should be taken with ibuprofen use in individuals carrying the CYP2C9*2 allele as it is in linkage disequilibrium with CYP2C8*3 and ibuprofen is also metabolized by CYP2C8.

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297325", - "name" : "Recommendation PA166297325", - "alternateDrugAvailable" : false, + "id" : "PA166297316", + "name" : "Recommendation PA166297316", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C9: Normal metabolism" + "CYP2C9: Significantly reduced metabolism and prolonged half-life; higher plasma concentrations may increase probability and/or severity of toxicities" ], - "lookupKey" : {"CYP2C9": "2.0"}, + "lookupKey" : {"CYP2C9": "0.5"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA449957", - "name" : "ibuprofen", - "version" : 13 + "id" : "PA448871", + "name" : "celecoxib", + "version" : 43 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166191841", "name" : "Annotation of CPIC Guideline for celecoxib, flurbiprofen, ibuprofen, lornoxicam and CYP2C9", - "version" : 10 + "version" : 118 }, "text" : { - "id" : 1452059927, - "html" : "

Initiate therapy with recommended starting dose. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals.

\n", + "id" : 1452059918, + "html" : "

Initiate therapy with 25-50% of the lowest recommended starting dose. Titrate dose upward to clinical effect or 25-50% of the maximum recommended dose with caution. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals. Upward dose titration should not occur until after steady state is reached (at least 8 days for celecoxib after first dose in PMs). Carefully monitor adverse events such as blood pressure and kidney function during course of therapy. Alternatively, consider an alternate therapy not metabolized by CYP2C9 or not significantly impacted by CYP2C9 genetic variants in vivo.

\n

Other Considerations

\n

Alternative therapies not primarily metabolized by CYP2C9 include aspirin, ketorolac, naproxen and sulindac. Selection of therapy will depend on individual patient treatment goals and risks for toxicity.

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297329", - "name" : "Recommendation PA166297329", + "id" : "PA166297321", + "name" : "Recommendation PA166297321", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C9: n/a" + "CYP2C9: Moderately reduced metabolism; higher plasma concentrations may increase probability of toxicities" ], - "lookupKey" : {"CYP2C9": "n/a"}, + "lookupKey" : {"CYP2C9": "1.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA449957", - "name" : "ibuprofen", - "version" : 13 + "id" : "PA449683", + "name" : "flurbiprofen", + "version" : 35 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166191841", "name" : "Annotation of CPIC Guideline for celecoxib, flurbiprofen, ibuprofen, lornoxicam and CYP2C9", - "version" : 10 + "version" : 118 }, "text" : { - "id" : 1452059931, - "html" : "

No recommendation

\n", + "id" : 1452059923, + "html" : "

Initiate therapy with lowest recommended starting dose. Titrate dose upward to clinical effect or maximum recommended dose with caution. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals. Carefully monitor adverse events such as blood pressure and kidney function during course of therapy.

\n

Other Considerations

\n

IMs might have a higher than normal risk of adverse events especially in individuals with other factors affecting clearance of these drugs such as hepatic impairment or advanced age. Further caution should be taken with ibuprofen use in individuals carrying the CYP2C9*2 allele as it is in linkage disequilibrium with CYP2C8*3 and ibuprofen is also metabolized by CYP2C8.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297316", - "name" : "Recommendation PA166297316", + "id" : "PA166297317", + "name" : "Recommendation PA166297317", "alternateDrugAvailable" : true, "classification" : { "id" : 981501931, @@ -19191,7 +19191,7 @@ "implications" : [ "CYP2C9: Significantly reduced metabolism and prolonged half-life; higher plasma concentrations may increase probability and/or severity of toxicities" ], - "lookupKey" : {"CYP2C9": "0.5"}, + "lookupKey" : {"CYP2C9": "0.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -19199,26 +19199,26 @@ "objCls" : "Chemical", "id" : "PA448871", "name" : "celecoxib", - "version" : 22 + "version" : 43 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166191841", "name" : "Annotation of CPIC Guideline for celecoxib, flurbiprofen, ibuprofen, lornoxicam and CYP2C9", - "version" : 10 + "version" : 118 }, "text" : { - "id" : 1452059918, + "id" : 1452059919, "html" : "

Initiate therapy with 25-50% of the lowest recommended starting dose. Titrate dose upward to clinical effect or 25-50% of the maximum recommended dose with caution. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals. Upward dose titration should not occur until after steady state is reached (at least 8 days for celecoxib after first dose in PMs). Carefully monitor adverse events such as blood pressure and kidney function during course of therapy. Alternatively, consider an alternate therapy not metabolized by CYP2C9 or not significantly impacted by CYP2C9 genetic variants in vivo.

\n

Other Considerations

\n

Alternative therapies not primarily metabolized by CYP2C9 include aspirin, ketorolac, naproxen and sulindac. Selection of therapy will depend on individual patient treatment goals and risks for toxicity.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297330", - "name" : "Recommendation PA166297330", + "id" : "PA166297325", + "name" : "Recommendation PA166297325", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -19239,29 +19239,29 @@ "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA165958395", - "name" : "lornoxicam", - "version" : 7 + "id" : "PA449957", + "name" : "ibuprofen", + "version" : 43 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166191841", "name" : "Annotation of CPIC Guideline for celecoxib, flurbiprofen, ibuprofen, lornoxicam and CYP2C9", - "version" : 10 + "version" : 118 }, "text" : { - "id" : 1452059932, + "id" : 1452059927, "html" : "

Initiate therapy with recommended starting dose. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals.

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297334", - "name" : "Recommendation PA166297334", - "alternateDrugAvailable" : true, + "id" : "PA166297315", + "name" : "Recommendation PA166297315", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, "parents" : [], @@ -19273,37 +19273,37 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C9: Significantly reduced metabolism and prolonged half-life; higher plasma concentrations may increase probability and/or severity of toxicities" + "CYP2C9: Moderately reduced metabolism; higher plasma concentrations may increase probability of toxicities" ], - "lookupKey" : {"CYP2C9": "0.0"}, + "lookupKey" : {"CYP2C9": "1.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA165958395", - "name" : "lornoxicam", - "version" : 7 + "id" : "PA448871", + "name" : "celecoxib", + "version" : 43 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166191841", "name" : "Annotation of CPIC Guideline for celecoxib, flurbiprofen, ibuprofen, lornoxicam and CYP2C9", - "version" : 10 + "version" : 118 }, "text" : { - "id" : 1452059936, - "html" : "

Initiate therapy with 25-50% of the lowest recommended starting dose. Titrate dose upward to clinical effect or 25-50% of the maximum recommended dose with caution. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals. Upward dose titration should not occur until after steady state is reached (at least 8 days for celecoxib after first dose in PMs). Carefully monitor adverse events such as blood pressure and kidney function during course of therapy. Alternatively, consider an alternate therapy not metabolized by CYP2C9 or not significantly impacted by CYP2C9 genetic variants in vivo.

\n

Other Considerations

\n

Alternative therapies not primarily metabolized by CYP2C9 include aspirin, ketorolac, naproxen and sulindac. Selection of therapy will depend on individual patient treatment goals and risks for toxicity.

\n", + "id" : 1452059917, + "html" : "

Initiate therapy with lowest recommended starting dose. Titrate dose upward to clinical effect or maximum recommended dose with caution. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals. Carefully monitor adverse events such as blood pressure and kidney function during course of therapy.

\n

Other Considerations

\n

IMs might have a higher than normal risk of adverse events especially in individuals with other factors affecting clearance of these drugs such as hepatic impairment or advanced age. Further caution should be taken with ibuprofen use in individuals carrying the CYP2C9*2 allele as it is in linkage disequilibrium with CYP2C8*3 and ibuprofen is also metabolized by CYP2C8.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297321", - "name" : "Recommendation PA166297321", - "alternateDrugAvailable" : false, + "id" : "PA166297322", + "name" : "Recommendation PA166297322", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501931, "parents" : [], @@ -19315,9 +19315,9 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C9: Moderately reduced metabolism; higher plasma concentrations may increase probability of toxicities" + "CYP2C9: Significantly reduced metabolism and prolonged half-life; higher plasma concentrations may increase probability and/or severity of toxicities" ], - "lookupKey" : {"CYP2C9": "1.0"}, + "lookupKey" : {"CYP2C9": "0.5"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -19325,63 +19325,63 @@ "objCls" : "Chemical", "id" : "PA449683", "name" : "flurbiprofen", - "version" : 12 + "version" : 35 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166191841", "name" : "Annotation of CPIC Guideline for celecoxib, flurbiprofen, ibuprofen, lornoxicam and CYP2C9", - "version" : 10 + "version" : 118 }, "text" : { - "id" : 1452059923, - "html" : "

Initiate therapy with lowest recommended starting dose. Titrate dose upward to clinical effect or maximum recommended dose with caution. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals. Carefully monitor adverse events such as blood pressure and kidney function during course of therapy.

\n

Other Considerations

\n

IMs might have a higher than normal risk of adverse events especially in individuals with other factors affecting clearance of these drugs such as hepatic impairment or advanced age. Further caution should be taken with ibuprofen use in individuals carrying the CYP2C9*2 allele as it is in linkage disequilibrium with CYP2C8*3 and ibuprofen is also metabolized by CYP2C8.

\n", + "id" : 1452059924, + "html" : "

Initiate therapy with 25-50% of the lowest recommended starting dose. Titrate dose upward to clinical effect or 25-50% of the maximum recommended dose with caution. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals. Upward dose titration should not occur until after steady state is reached (at least 8 days for celecoxib after first dose in PMs). Carefully monitor adverse events such as blood pressure and kidney function during course of therapy. Alternatively, consider an alternate therapy not metabolized by CYP2C9 or not significantly impacted by CYP2C9 genetic variants in vivo.

\n

Other Considerations

\n

Alternative therapies not primarily metabolized by CYP2C9 include aspirin, ketorolac, naproxen and sulindac. Selection of therapy will depend on individual patient treatment goals and risks for toxicity.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297313", - "name" : "Recommendation PA166297313", - "alternateDrugAvailable" : false, + "id" : "PA166297323", + "name" : "Recommendation PA166297323", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C9: Normal metabolism" + "CYP2C9: Significantly reduced metabolism and prolonged half-life; higher plasma concentrations may increase probability and/or severity of toxicities" ], - "lookupKey" : {"CYP2C9": "2.0"}, + "lookupKey" : {"CYP2C9": "0.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA448871", - "name" : "celecoxib", - "version" : 22 + "id" : "PA449683", + "name" : "flurbiprofen", + "version" : 35 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166191841", "name" : "Annotation of CPIC Guideline for celecoxib, flurbiprofen, ibuprofen, lornoxicam and CYP2C9", - "version" : 10 + "version" : 118 }, "text" : { - "id" : 1452059915, - "html" : "

Initiate therapy with recommended starting dose. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals.

\n", + "id" : 1452059925, + "html" : "

Initiate therapy with 25-50% of the lowest recommended starting dose. Titrate dose upward to clinical effect or 25-50% of the maximum recommended dose with caution. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals. Upward dose titration should not occur until after steady state is reached (at least 8 days for celecoxib after first dose in PMs). Carefully monitor adverse events such as blood pressure and kidney function during course of therapy. Alternatively, consider an alternate therapy not metabolized by CYP2C9 or not significantly impacted by CYP2C9 genetic variants in vivo.

\n

Other Considerations

\n

Alternative therapies not primarily metabolized by CYP2C9 include aspirin, ketorolac, naproxen and sulindac. Selection of therapy will depend on individual patient treatment goals and risks for toxicity.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", @@ -19409,111 +19409,111 @@ "objCls" : "Chemical", "id" : "PA449957", "name" : "ibuprofen", - "version" : 13 + "version" : 43 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166191841", "name" : "Annotation of CPIC Guideline for celecoxib, flurbiprofen, ibuprofen, lornoxicam and CYP2C9", - "version" : 10 + "version" : 118 }, "text" : { "id" : 1452059928, "html" : "

Initiate therapy with recommended starting dose. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals.

\n

Other Considerations

\n

IMs might have a higher than normal risk of adverse events especially in individuals with other factors affecting clearance of these drugs such as hepatic impairment or advanced age. Further caution should be taken with ibuprofen use in individuals carrying the CYP2C9*2 allele as it is in linkage disequilibrium with CYP2C8*3 and ibuprofen is also metabolized by CYP2C8.

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297335", - "name" : "Recommendation PA166297335", - "alternateDrugAvailable" : false, + "id" : "PA166297327", + "name" : "Recommendation PA166297327", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C9: n/a" + "CYP2C9: Significantly reduced metabolism and prolonged half-life; higher plasma concentrations may increase probability and/or severity of toxicities" ], - "lookupKey" : {"CYP2C9": "n/a"}, + "lookupKey" : {"CYP2C9": "0.5"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA165958395", - "name" : "lornoxicam", - "version" : 7 + "id" : "PA449957", + "name" : "ibuprofen", + "version" : 43 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166191841", "name" : "Annotation of CPIC Guideline for celecoxib, flurbiprofen, ibuprofen, lornoxicam and CYP2C9", - "version" : 10 + "version" : 118 }, "text" : { - "id" : 1452059937, - "html" : "

No recommendation

\n", + "id" : 1452059929, + "html" : "

Initiate therapy with 25-50% of the lowest recommended starting dose. Titrate dose upward to clinical effect or 25-50% of the maximum recommended dose with caution. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals. Upward dose titration should not occur until after steady state is reached (at least 8 days for celecoxib after first dose in PMs). Carefully monitor adverse events such as blood pressure and kidney function during course of therapy. Alternatively, consider an alternate therapy not metabolized by CYP2C9 or not significantly impacted by CYP2C9 genetic variants in vivo.

\n

Other Considerations

\n

Alternative therapies not primarily metabolized by CYP2C9 include aspirin, ketorolac, naproxen and sulindac. Selection of therapy will depend on individual patient treatment goals and risks for toxicity.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297317", - "name" : "Recommendation PA166297317", - "alternateDrugAvailable" : true, + "id" : "PA166297330", + "name" : "Recommendation PA166297330", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C9: Significantly reduced metabolism and prolonged half-life; higher plasma concentrations may increase probability and/or severity of toxicities" + "CYP2C9: Normal metabolism" ], - "lookupKey" : {"CYP2C9": "0.0"}, + "lookupKey" : {"CYP2C9": "2.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA448871", - "name" : "celecoxib", - "version" : 22 + "id" : "PA165958395", + "name" : "lornoxicam", + "version" : 12 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166191841", "name" : "Annotation of CPIC Guideline for celecoxib, flurbiprofen, ibuprofen, lornoxicam and CYP2C9", - "version" : 10 + "version" : 118 }, "text" : { - "id" : 1452059919, - "html" : "

Initiate therapy with 25-50% of the lowest recommended starting dose. Titrate dose upward to clinical effect or 25-50% of the maximum recommended dose with caution. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals. Upward dose titration should not occur until after steady state is reached (at least 8 days for celecoxib after first dose in PMs). Carefully monitor adverse events such as blood pressure and kidney function during course of therapy. Alternatively, consider an alternate therapy not metabolized by CYP2C9 or not significantly impacted by CYP2C9 genetic variants in vivo.

\n

Other Considerations

\n

Alternative therapies not primarily metabolized by CYP2C9 include aspirin, ketorolac, naproxen and sulindac. Selection of therapy will depend on individual patient treatment goals and risks for toxicity.

\n", + "id" : 1452059932, + "html" : "

Initiate therapy with recommended starting dose. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals.

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297322", - "name" : "Recommendation PA166297322", - "alternateDrugAvailable" : true, + "id" : "PA166297285", + "name" : "Recommendation PA166297285", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, "parents" : [], @@ -19525,37 +19525,37 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C9: Significantly reduced metabolism and prolonged half-life; higher plasma concentrations may increase probability and/or severity of toxicities" + "CYP2C9: Moderately reduced metabolism; higher plasma concentrations may increase probability of toxicities" ], - "lookupKey" : {"CYP2C9": "0.5"}, + "lookupKey" : {"CYP2C9": "1.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA449683", - "name" : "flurbiprofen", - "version" : 12 + "id" : "PA449957", + "name" : "ibuprofen", + "version" : 43 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166191841", "name" : "Annotation of CPIC Guideline for celecoxib, flurbiprofen, ibuprofen, lornoxicam and CYP2C9", - "version" : 10 + "version" : 118 }, "text" : { - "id" : 1452059924, - "html" : "

Initiate therapy with 25-50% of the lowest recommended starting dose. Titrate dose upward to clinical effect or 25-50% of the maximum recommended dose with caution. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals. Upward dose titration should not occur until after steady state is reached (at least 8 days for celecoxib after first dose in PMs). Carefully monitor adverse events such as blood pressure and kidney function during course of therapy. Alternatively, consider an alternate therapy not metabolized by CYP2C9 or not significantly impacted by CYP2C9 genetic variants in vivo.

\n

Other Considerations

\n

Alternative therapies not primarily metabolized by CYP2C9 include aspirin, ketorolac, naproxen and sulindac. Selection of therapy will depend on individual patient treatment goals and risks for toxicity.

\n", + "id" : 1452059887, + "html" : "

Initiate therapy with lowest recommended starting dose. Titrate dose upward to clinical effect or maximum recommended dose with caution. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals. Carefully monitor adverse events such as blood pressure and kidney function during course of therapy.

\n

Other Considerations

\n

IMs might have a higher than normal risk of adverse events especially in individuals with other factors affecting clearance of these drugs such as hepatic impairment or advanced age. Further caution should be taken with ibuprofen use in individuals carrying the CYP2C9*2 allele as it is in linkage disequilibrium with CYP2C8*3 and ibuprofen is also metabolized by CYP2C8.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297331", - "name" : "Recommendation PA166297331", - "alternateDrugAvailable" : false, + "id" : "PA166297328", + "name" : "Recommendation PA166297328", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501931, "parents" : [], @@ -19565,38 +19565,38 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C9: Mildly reduced metabolism" + "CYP2C9: Significantly reduced metabolism and prolonged half-life; higher plasma concentrations may increase probability and/or severity of toxicities" ], - "lookupKey" : {"CYP2C9": "1.5"}, + "lookupKey" : {"CYP2C9": "0.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA165958395", - "name" : "lornoxicam", - "version" : 7 + "id" : "PA449957", + "name" : "ibuprofen", + "version" : 43 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166191841", "name" : "Annotation of CPIC Guideline for celecoxib, flurbiprofen, ibuprofen, lornoxicam and CYP2C9", - "version" : 10 + "version" : 118 }, "text" : { - "id" : 1452059933, - "html" : "

Initiate therapy with recommended starting dose. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals.

\n

Other Considerations

\n

IMs might have a higher than normal risk of adverse events especially in individuals with other factors affecting clearance of these drugs such as hepatic impairment or advanced age. Further caution should be taken with ibuprofen use in individuals carrying the CYP2C9*2 allele as it is in linkage disequilibrium with CYP2C8*3 and ibuprofen is also metabolized by CYP2C8.

\n", + "id" : 1452059930, + "html" : "

Initiate therapy with 25-50% of the lowest recommended starting dose. Titrate dose upward to clinical effect or 25-50% of the maximum recommended dose with caution. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals. Upward dose titration should not occur until after steady state is reached (at least 8 days for celecoxib after first dose in PMs). Carefully monitor adverse events such as blood pressure and kidney function during course of therapy. Alternatively, consider an alternate therapy not metabolized by CYP2C9 or not significantly impacted by CYP2C9 genetic variants in vivo.

\n

Other Considerations

\n

Alternative therapies not primarily metabolized by CYP2C9 include aspirin, ketorolac, naproxen and sulindac. Selection of therapy will depend on individual patient treatment goals and risks for toxicity.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297314", - "name" : "Recommendation PA166297314", + "id" : "PA166297331", + "name" : "Recommendation PA166297331", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -19617,29 +19617,29 @@ "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA448871", - "name" : "celecoxib", - "version" : 22 + "id" : "PA165958395", + "name" : "lornoxicam", + "version" : 12 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166191841", "name" : "Annotation of CPIC Guideline for celecoxib, flurbiprofen, ibuprofen, lornoxicam and CYP2C9", - "version" : 10 + "version" : 118 }, "text" : { - "id" : 1452059916, + "id" : 1452059933, "html" : "

Initiate therapy with recommended starting dose. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals.

\n

Other Considerations

\n

IMs might have a higher than normal risk of adverse events especially in individuals with other factors affecting clearance of these drugs such as hepatic impairment or advanced age. Further caution should be taken with ibuprofen use in individuals carrying the CYP2C9*2 allele as it is in linkage disequilibrium with CYP2C8*3 and ibuprofen is also metabolized by CYP2C8.

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297327", - "name" : "Recommendation PA166297327", - "alternateDrugAvailable" : true, + "id" : "PA166297332", + "name" : "Recommendation PA166297332", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, "parents" : [], @@ -19651,36 +19651,36 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C9: Significantly reduced metabolism and prolonged half-life; higher plasma concentrations may increase probability and/or severity of toxicities" + "CYP2C9: Moderately reduced metabolism; higher plasma concentrations may increase probability of toxicities" ], - "lookupKey" : {"CYP2C9": "0.5"}, + "lookupKey" : {"CYP2C9": "1.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA449957", - "name" : "ibuprofen", - "version" : 13 + "id" : "PA165958395", + "name" : "lornoxicam", + "version" : 12 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166191841", "name" : "Annotation of CPIC Guideline for celecoxib, flurbiprofen, ibuprofen, lornoxicam and CYP2C9", - "version" : 10 + "version" : 118 }, "text" : { - "id" : 1452059929, - "html" : "

Initiate therapy with 25-50% of the lowest recommended starting dose. Titrate dose upward to clinical effect or 25-50% of the maximum recommended dose with caution. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals. Upward dose titration should not occur until after steady state is reached (at least 8 days for celecoxib after first dose in PMs). Carefully monitor adverse events such as blood pressure and kidney function during course of therapy. Alternatively, consider an alternate therapy not metabolized by CYP2C9 or not significantly impacted by CYP2C9 genetic variants in vivo.

\n

Other Considerations

\n

Alternative therapies not primarily metabolized by CYP2C9 include aspirin, ketorolac, naproxen and sulindac. Selection of therapy will depend on individual patient treatment goals and risks for toxicity.

\n", + "id" : 1452059934, + "html" : "

Initiate therapy with lowest recommended starting dose. Titrate dose upward to clinical effect or maximum recommended dose with caution. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals. Carefully monitor adverse events such as blood pressure and kidney function during course of therapy.

\n

Other Considerations

\n

IMs might have a higher than normal risk of adverse events especially in individuals with other factors affecting clearance of these drugs such as hepatic impairment or advanced age. Further caution should be taken with ibuprofen use in individuals carrying the CYP2C9*2 allele as it is in linkage disequilibrium with CYP2C8*3 and ibuprofen is also metabolized by CYP2C8.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297323", - "name" : "Recommendation PA166297323", + "id" : "PA166297333", + "name" : "Recommendation PA166297333", "alternateDrugAvailable" : true, "classification" : { "id" : 981501931, @@ -19695,14 +19695,14 @@ "implications" : [ "CYP2C9: Significantly reduced metabolism and prolonged half-life; higher plasma concentrations may increase probability and/or severity of toxicities" ], - "lookupKey" : {"CYP2C9": "0.0"}, + "lookupKey" : {"CYP2C9": "0.5"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA449683", - "name" : "flurbiprofen", + "id" : "PA165958395", + "name" : "lornoxicam", "version" : 12 } ], @@ -19710,98 +19710,98 @@ "objCls" : "Guideline Annotation", "id" : "PA166191841", "name" : "Annotation of CPIC Guideline for celecoxib, flurbiprofen, ibuprofen, lornoxicam and CYP2C9", - "version" : 10 + "version" : 118 }, "text" : { - "id" : 1452059925, + "id" : 1452059935, "html" : "

Initiate therapy with 25-50% of the lowest recommended starting dose. Titrate dose upward to clinical effect or 25-50% of the maximum recommended dose with caution. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals. Upward dose titration should not occur until after steady state is reached (at least 8 days for celecoxib after first dose in PMs). Carefully monitor adverse events such as blood pressure and kidney function during course of therapy. Alternatively, consider an alternate therapy not metabolized by CYP2C9 or not significantly impacted by CYP2C9 genetic variants in vivo.

\n

Other Considerations

\n

Alternative therapies not primarily metabolized by CYP2C9 include aspirin, ketorolac, naproxen and sulindac. Selection of therapy will depend on individual patient treatment goals and risks for toxicity.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297318", - "name" : "Recommendation PA166297318", - "alternateDrugAvailable" : false, + "id" : "PA166297334", + "name" : "Recommendation PA166297334", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C9: n/a" + "CYP2C9: Significantly reduced metabolism and prolonged half-life; higher plasma concentrations may increase probability and/or severity of toxicities" ], - "lookupKey" : {"CYP2C9": "n/a"}, + "lookupKey" : {"CYP2C9": "0.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA448871", - "name" : "celecoxib", - "version" : 22 + "id" : "PA165958395", + "name" : "lornoxicam", + "version" : 12 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166191841", "name" : "Annotation of CPIC Guideline for celecoxib, flurbiprofen, ibuprofen, lornoxicam and CYP2C9", - "version" : 10 + "version" : 118 }, "text" : { - "id" : 1452059920, - "html" : "

No recommendation

\n", + "id" : 1452059936, + "html" : "

Initiate therapy with 25-50% of the lowest recommended starting dose. Titrate dose upward to clinical effect or 25-50% of the maximum recommended dose with caution. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals. Upward dose titration should not occur until after steady state is reached (at least 8 days for celecoxib after first dose in PMs). Carefully monitor adverse events such as blood pressure and kidney function during course of therapy. Alternatively, consider an alternate therapy not metabolized by CYP2C9 or not significantly impacted by CYP2C9 genetic variants in vivo.

\n

Other Considerations

\n

Alternative therapies not primarily metabolized by CYP2C9 include aspirin, ketorolac, naproxen and sulindac. Selection of therapy will depend on individual patient treatment goals and risks for toxicity.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297332", - "name" : "Recommendation PA166297332", + "id" : "PA166297313", + "name" : "Recommendation PA166297313", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C9: Moderately reduced metabolism; higher plasma concentrations may increase probability of toxicities" + "CYP2C9: Normal metabolism" ], - "lookupKey" : {"CYP2C9": "1.0"}, + "lookupKey" : {"CYP2C9": "2.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA165958395", - "name" : "lornoxicam", - "version" : 7 + "id" : "PA448871", + "name" : "celecoxib", + "version" : 43 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166191841", "name" : "Annotation of CPIC Guideline for celecoxib, flurbiprofen, ibuprofen, lornoxicam and CYP2C9", - "version" : 10 + "version" : 118 }, "text" : { - "id" : 1452059934, - "html" : "

Initiate therapy with lowest recommended starting dose. Titrate dose upward to clinical effect or maximum recommended dose with caution. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals. Carefully monitor adverse events such as blood pressure and kidney function during course of therapy.

\n

Other Considerations

\n

IMs might have a higher than normal risk of adverse events especially in individuals with other factors affecting clearance of these drugs such as hepatic impairment or advanced age. Further caution should be taken with ibuprofen use in individuals carrying the CYP2C9*2 allele as it is in linkage disequilibrium with CYP2C8*3 and ibuprofen is also metabolized by CYP2C8.

\n", + "id" : 1452059915, + "html" : "

Initiate therapy with recommended starting dose. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals.

\n", "version" : 0 }, - "version" : 0 + "version" : 3 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166191841" @@ -19965,6 +19965,7 @@ "version" : 1 } ], + "descriptiveVideoId" : "db-jvGg3T2I", "dosingInformation" : true, "hasTestingInfo" : false, "history" : [ @@ -19986,7 +19987,7 @@ "date" : "2020-04-21T00:00:00-07:00", "description" : "Updated link to CYP2C19 and CYP2D6 gene information tables page, drug resource mappings and pre and post test alerts.", "type" : "Update", - "version" : 1 + "version" : 2 }, { "id" : 1452064981, @@ -19994,6 +19995,13 @@ "description" : "added CPIC guideline publication", "type" : "Update", "version" : 0 + }, + { + "id" : 1452507020, + "date" : "2024-06-25T02:03:45.234-07:00", + "description" : "Added video", + "type" : "Update", + "version" : 0 } ], "literature" : [ @@ -20014,13 +20022,13 @@ "objCls" : "Chemical", "id" : "PA449015", "name" : "citalopram", - "version" : 21 + "version" : 49 }, { "objCls" : "Chemical", "id" : "PA10074", "name" : "escitalopram", - "version" : 11 + "version" : 28 } ], "relatedGenes" : [ @@ -20029,71 +20037,29 @@ "id" : "PA124", "symbol" : "CYP2C19", "name" : "cytochrome P450 family 2 subfamily C member 19", - "version" : 7210 + "version" : 7266 } ], "source" : "CPIC", "summaryMarkdown" : { "id" : 1447982401, "html" : "

The CPIC Dosing Guideline for the selective serotonin reuptake inhibitors citalopram and escitalopram recommends to consider a clinically appropriate antidepressant not predominantly metabolized by CYP2C19 for CYP2C19 ultrarapid, likely poor, and poor metabolizers. In case citalopram or escitalopram are clinically appropriate, dose alterations are recommended.

\n", - "version" : 1 + "version" : 2 }, "terms" : [], "textMarkdown" : { "id" : 1451433707, "html" : "

This annotation is based on the CPIC® guideline for CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A Genotypes and Serotonin Reuptake Inhibitor Antidepressants. This is an update to the previous CPIC® guideline for Selective Serotonin Reuptake Inhibitors and CYP2D6 and CYP2C19.

\n

February 2023

\n\n

Table 1: Dosing recommendations for citalopram and escitalopram based on CYP2C19 phenotype

\n

Adapted from Tables 1 and 3a of the guideline.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
PhenotypeGenotypesExamplesImplicationsTherapeutic
Recommendations		Classification of
Recommendations a		Considerations
Ultrarapid MetabolizerAn individual carrying two increased function alleles.*17/*17Increased metabolism of citalopram and escitalopram to less active compounds when compared to CYP2C19 rapid and normal metabolizers. Lower plasma concentrations decrease the probability of clinical benefit.Consider a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2C19. If citalopram or escitalopram are clinically appropriate, and adequate efficacy is not achieved at standard maintenance dosing, consider titrating to a higher maintenance dose.StrongDrug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when adjusting dose or selecting an alternative therapy.
Rapid MetabolizerAn individual carrying one normal function allele and one increased function allele.*1/*17Increase in metabolism of citalopram and escitalopram to less active compounds when compared to CYP2C19 normal metabolizers. Lower plasma concentrations decrease the probability of clinical benefit.Initiate therapy with recommended starting dose. If patient does not adequately respond to recommended maintenance dosing, consider titrating to a higher maintenance dose or switching to a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2C19.OptionalDrug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when adjusting dose or selecting an alternative therapy.
Normal MetabolizerAn individual carrying two normal function alleles.*1/*1Normal metabolismInitiate therapy with recommended starting dose.Strong
Likely Intermediate MetabolizerAn individual carrying one normal function allele and one decreased b function allele or one increased function allele and one decreased b function allele or two decreased b function alleles.*1/*9, *9/*17, *9/*9Reduced metabolism when compared to CYP2C19 normal metabolizers. Higher plasma concentrations may increase the probability of side effects.Initiate therapy with recommended starting dose. Consider a slower titration schedule and lower maintenance dose than normal metabolizers.ModerateDrug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when adjusting dose.
Intermediate MetabolizerAn individual carrying one normal function allele and one no function allele or one increased function allele and one no function allele.*1/*2, *1/*3, *2/*17, *3/*17Reduced metabolism when compared to CYP2C19 normal metabolizers. Higher plasma concentrations may increase the probability of side effects.Initiate therapy with recommended starting dose. Consider a slower titration schedule and lower maintenance dose than normal metabolizers.ModerateDrug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when adjusting dose.
Likely Poor MetabolizerAn individual carrying one decreased b function allele and one no function allele.*2/*9, *3/*9Reduced metabolism of citalopram and escitalopram to less active compounds when compared to CYP2C19 normal and intermediate metabolizers. Higher plasma concentrations may increase the probability of side effects.Consider a clinically appropriate antidepressant not predominantly metabolized by CYP2C19. If citalopram or escitalopram are clinically appropriate, consider a lower starting dose, slower titration schedule and 50% reduction of the standard maintenance dose as compared to normal metabolizers.StrongPer the FDA warning, citalopram 20 mg/day is the maximum recommended dose in CYP2C19 poor metabolizers due to the risk of QT prolongation. FDA product labeling additionally cautions that citalopram dose should be limited to 20 mg/day in patients with hepatic impairment, those taking a CYP2C19 inhibitor, and patients greater than 60 years of age.
Poor MetabolizerAn individual carrying two no function alleles.*2/*2, *2/*3, *3/*3Reduced metabolism of citalopram and escitalopram to less active compounds when compared to CYP2C19 normal and intermediate metabolizers. Higher plasma concentrations may increase the probability of side effects.Consider a clinically appropriate antidepressant not predominantly metabolized by CYP2C19. If citalopram or escitalopram are clinically appropriate, consider a lower starting dose, slower titration schedule and 50% reduction of the standard maintenance dose as compared to normal metabolizers.StrongPer the FDA warning, citalopram 20 mg/day is the maximum recommended dose in CYP2C19 poor metabolizers due to the risk of QT prolongation. FDA product labeling additionally cautions that citalopram dose should be limited to 20 mg/day in patients with hepatic impairment, those taking a CYP2C19 inhibitor, and patients greater than 60 years of age.
IndeterminateAn individual carrying one or two uncertain function alleles.*1/*12, *2/*12, *12/*14No recommendationNo recommendation
\n

a Rating scheme described in Supplement.\nb There are limited data to characterize the function of decreased function alleles.

\n

August 2015

\n

Advanced online publication May 2015

\n\n

Table 1: Dosing recommendations for citalopram and escitalopram based on CYP2C19 phenotype:

\n

Adapted from Tables 1 and 3a of the 2015 guideline manuscript.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Likely phenotypeGenotypesExamples of CYP2C19 diplotypesImplications for citalopram/escitalopram metabolismTherapeutic RecommendationsClassification of recommendations a
Ultrarapid metabolizer (~5-30% of patients) bAn individual carrying two increased function alleles or one normal function allele and one increased function allele*17/*17, *1/*17Increased metabolism when compared to extensive metabolizers. Lower plasma concentrations will increase probability of pharmacotherapy failure.Consider an alternative drug not predominantly metabolized by CYP2C19.cModerate
Extensive metabolizer (~35-50% of patients)An individual carrying two normal function alleles*1/*1Normal metabolismInitiate therapy with recommended starting dose.Strong
Intermediate metabolizer (~18-45% of patients)An individual carrying one normal function allele or one increased function allele and one no function allele*1/*2, *1/*3, *2/*17 dReduced metabolism when compared to extensive metabolizers.Initiate therapy with recommended starting dose.Strong
Poor metabolizer (~2-15% of patients)An individual carrying two no function alleles*2/*2, *2/*3, *3/*3Greatly reduced metabolism when compared to extensive metabolizers. Higher plasma concentrations may increase the probability of side effects.Consider a 50% reduction e,f of recommended starting dose and titrate to response or select alternative drug not predominantly metabolized by CYP2C19.cModerate
\n

a Rating scheme described in Supplement.

\n

b CYP2C19 metabolizer status frequencies are based on average multi-ethnic frequency.

\n

c Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when selecting an alternative therapy.

\n

d The predicted metabolizer phenotype for the*2/*17 genotypes is a provisional classification. The currently available evidence indicates that the CYP2C19*17 increased function allele is unable to completely compensate for the no function CYP2C19*2. See Supplemental Materials for a more comprehensive list of predicted metabolizer phenotypes.

\n

e Per the FDA warning, citalopram 20 mg/day is the maximum recommended dose in CYP2C19 poor metabolizers due to the risk of QT prolongation. FDA product labeling additionally cautions that citalopram dose should be limited to 20 mg/day in patients with hepatic impairment, those taking a CYP2C19 inhibitor, and patients greater than 60 years of age.

\n

f Percent dose adjustments corresponding to percent difference in oral clearances have been calculated/estimated by Stingl et al. [Article:22565785].

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Initiate therapy with recommended starting dose. If patient does not adequately respond to recommended maintenance dosing, consider titrating to a higher maintenance dose or switching to a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2C19.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when adjusting dose or selecting an alternative therapy.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166297350", - "name" : "Recommendation PA166297350", + "id" : "PA166297341", + "name" : "Recommendation PA166297341", "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, @@ -20108,29 +20074,29 @@ "implications" : [ "CYP2C19: Reduced metabolism of citalopram and escitalopram to less active compounds when compared to CYP2C19 normal and intermediate metabolizers. Higher plasma concentrations may increase the probability of side effects." ], - "lookupKey" : {"CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA10074", - "name" : "escitalopram", - "version" : 11 + "id" : "PA449015", + "name" : "citalopram", + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127638", "name" : "Annotation of CPIC Guideline for citalopram, escitalopram and CYP2C19", - "version" : 48 + "version" : 140 }, "text" : { - "id" : 1452093816, + "id" : 1452093805, "html" : "

Consider a clinically appropriate antidepressant not predominantly metabolized by CYP2C19. If citalopram or escitalopram are clinically appropriate, consider a lower starting dose, slower titration schedule and 50% reduction of the standard maintenance dose as compared to normal metabolizers.

\n

Other Considerations

\n

Per the FDA warning, citalopram 20 mg/day is the maximum recommended dose in CYP2C19 poor metabolizers due to the risk of QT prolongation. FDA product labeling additionally cautions that citalopram dose should be limited to 20 mg/day in patients with hepatic impairment, those taking a CYP2C19 inhibitor, and patients greater than 60 years of age.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -20158,26 +20124,26 @@ "objCls" : "Chemical", "id" : "PA449015", "name" : "citalopram", - "version" : 21 + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127638", "name" : "Annotation of CPIC Guideline for citalopram, escitalopram and CYP2C19", - "version" : 48 + "version" : 140 }, "text" : { "id" : 1452093806, "html" : "

Consider a clinically appropriate antidepressant not predominantly metabolized by CYP2C19. If citalopram or escitalopram are clinically appropriate, consider a lower starting dose, slower titration schedule and 50% reduction of the standard maintenance dose as compared to normal metabolizers.

\n

Other Considerations

\n

Per the FDA warning, citalopram 20 mg/day is the maximum recommended dose in CYP2C19 poor metabolizers due to the risk of QT prolongation. FDA product labeling additionally cautions that citalopram dose should be limited to 20 mg/day in patients with hepatic impairment, those taking a CYP2C19 inhibitor, and patients greater than 60 years of age.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297351", - "name" : "Recommendation PA166297351", + "id" : "PA166297343", + "name" : "Recommendation PA166297343", "alternateDrugAvailable" : false, "classification" : { "id" : 1448526251, @@ -20198,29 +20164,29 @@ "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA10074", - "name" : "escitalopram", - "version" : 11 + "id" : "PA449015", + "name" : "citalopram", + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127638", "name" : "Annotation of CPIC Guideline for citalopram, escitalopram and CYP2C19", - "version" : 48 + "version" : 140 }, "text" : { - "id" : 1452093809, + "id" : 1452093807, "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297346", - "name" : "Recommendation PA166297346", - "alternateDrugAvailable" : false, + "id" : "PA166297349", + "name" : "Recommendation PA166297349", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, "parents" : [], @@ -20230,11 +20196,11 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism" + "CYP2C19: Reduced metabolism of citalopram and escitalopram to less active compounds when compared to CYP2C19 normal and intermediate metabolizers. Higher plasma concentrations may increase the probability of side effects." ], - "lookupKey" : {"CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -20242,27 +20208,27 @@ "objCls" : "Chemical", "id" : "PA10074", "name" : "escitalopram", - "version" : 11 + "version" : 28 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127638", "name" : "Annotation of CPIC Guideline for citalopram, escitalopram and CYP2C19", - "version" : 48 + "version" : 140 }, "text" : { - "id" : 1452093812, - "html" : "

Initiate therapy with recommended starting dose

\n", + "id" : 1452093815, + "html" : "

Consider a clinically appropriate antidepressant not predominantly metabolized by CYP2C19. If citalopram or escitalopram are clinically appropriate, consider a lower starting dose, slower titration schedule and 50% reduction of the standard maintenance dose as compared to normal metabolizers.

\n

Other Considerations

\n

Per the FDA warning, citalopram 20 mg/day is the maximum recommended dose in CYP2C19 poor metabolizers due to the risk of QT prolongation. FDA product labeling additionally cautions that citalopram dose should be limited to 20 mg/day in patients with hepatic impairment, those taking a CYP2C19 inhibitor, and patients greater than 60 years of age.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297338", - "name" : "Recommendation PA166297338", - "alternateDrugAvailable" : false, + "id" : "PA166297350", + "name" : "Recommendation PA166297350", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, "parents" : [], @@ -20272,38 +20238,38 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism" + "CYP2C19: Reduced metabolism of citalopram and escitalopram to less active compounds when compared to CYP2C19 normal and intermediate metabolizers. Higher plasma concentrations may increase the probability of side effects." ], - "lookupKey" : {"CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA449015", - "name" : "citalopram", - "version" : 21 + "id" : "PA10074", + "name" : "escitalopram", + "version" : 28 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127638", "name" : "Annotation of CPIC Guideline for citalopram, escitalopram and CYP2C19", - "version" : 48 + "version" : 140 }, "text" : { - "id" : 1452093802, - "html" : "

Initiate therapy with recommended starting dose

\n", + "id" : 1452093816, + "html" : "

Consider a clinically appropriate antidepressant not predominantly metabolized by CYP2C19. If citalopram or escitalopram are clinically appropriate, consider a lower starting dose, slower titration schedule and 50% reduction of the standard maintenance dose as compared to normal metabolizers.

\n

Other Considerations

\n

Per the FDA warning, citalopram 20 mg/day is the maximum recommended dose in CYP2C19 poor metabolizers due to the risk of QT prolongation. FDA product labeling additionally cautions that citalopram dose should be limited to 20 mg/day in patients with hepatic impairment, those taking a CYP2C19 inhibitor, and patients greater than 60 years of age.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297347", - "name" : "Recommendation PA166297347", + "id" : "PA166297348", + "name" : "Recommendation PA166297348", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -20318,7 +20284,7 @@ "implications" : [ "CYP2C19: Reduced metabolism when compared to CYP2C19 normal metabolizers. Higher plasma concentrations may increase the probability of side effects." ], - "lookupKey" : {"CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -20326,41 +20292,41 @@ "objCls" : "Chemical", "id" : "PA10074", "name" : "escitalopram", - "version" : 11 + "version" : 28 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127638", "name" : "Annotation of CPIC Guideline for citalopram, escitalopram and CYP2C19", - "version" : 48 + "version" : 140 }, "text" : { - "id" : 1452093813, + "id" : 1452093814, "html" : "

Initiate therapy with recommended starting dose. Consider a slower titration schedule and lower maintenance dose than normal metabolizers.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when adjusting dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 4 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297343", - "name" : "Recommendation PA166297343", + "id" : "PA166297339", + "name" : "Recommendation PA166297339", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a" + "CYP2C19: Reduced metabolism when compared to CYP2C19 normal metabolizers. Higher plasma concentrations may increase the probability of side effects." ], - "lookupKey" : {"CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -20368,41 +20334,41 @@ "objCls" : "Chemical", "id" : "PA449015", "name" : "citalopram", - "version" : 21 + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127638", "name" : "Annotation of CPIC Guideline for citalopram, escitalopram and CYP2C19", - "version" : 48 + "version" : 140 }, "text" : { - "id" : 1452093807, - "html" : "

No recommendation

\n", + "id" : 1452093803, + "html" : "

Initiate therapy with recommended starting dose. Consider a slower titration schedule and lower maintenance dose than normal metabolizers.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when adjusting dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297339", - "name" : "Recommendation PA166297339", + "id" : "PA166297338", + "name" : "Recommendation PA166297338", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Reduced metabolism when compared to CYP2C19 normal metabolizers. Higher plasma concentrations may increase the probability of side effects." + "CYP2C19: Normal metabolism" ], - "lookupKey" : {"CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -20410,41 +20376,41 @@ "objCls" : "Chemical", "id" : "PA449015", "name" : "citalopram", - "version" : 21 + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127638", "name" : "Annotation of CPIC Guideline for citalopram, escitalopram and CYP2C19", - "version" : 48 + "version" : 140 }, "text" : { - "id" : 1452093803, - "html" : "

Initiate therapy with recommended starting dose. Consider a slower titration schedule and lower maintenance dose than normal metabolizers.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when adjusting dose.

\n", + "id" : 1452093802, + "html" : "

Initiate therapy with recommended starting dose

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297348", - "name" : "Recommendation PA166297348", - "alternateDrugAvailable" : false, + "id" : "PA166297344", + "name" : "Recommendation PA166297344", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501931, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism when compared to CYP2C19 normal metabolizers. Higher plasma concentrations may increase the probability of side effects." + "CYP2C19: Increased metabolism of citalopram and escitalopram to less active compounds when compared to CYP2C19 rapid and normal metabolizers. Lower plasma concentrations decrease the probability of clinical benefit." ], - "lookupKey" : {"CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -20452,41 +20418,41 @@ "objCls" : "Chemical", "id" : "PA10074", "name" : "escitalopram", - "version" : 11 + "version" : 28 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127638", "name" : "Annotation of CPIC Guideline for citalopram, escitalopram and CYP2C19", - "version" : 48 + "version" : 140 }, "text" : { - "id" : 1452093814, - "html" : "

Initiate therapy with recommended starting dose. Consider a slower titration schedule and lower maintenance dose than normal metabolizers.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when adjusting dose.

\n", + "id" : 1452093810, + "html" : "

Consider a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2C19. If citalopram or escitalopram are clinically appropriate, and adequate efficacy is not achieved at standard maintenance dosing, consider titrating to a higher maintenance dose.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when adjusting dose or selecting an alternative therapy.

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297340", - "name" : "Recommendation PA166297340", - "alternateDrugAvailable" : false, + "id" : "PA166297336", + "name" : "Recommendation PA166297336", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501931, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism when compared to CYP2C19 normal metabolizers. Higher plasma concentrations may increase the probability of side effects." + "CYP2C19: Increased metabolism of citalopram and escitalopram to less active compounds when compared to CYP2C19 rapid and normal metabolizers. Lower plasma concentrations decrease the probability of clinical benefit." ], - "lookupKey" : {"CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -20494,125 +20460,125 @@ "objCls" : "Chemical", "id" : "PA449015", "name" : "citalopram", - "version" : 21 + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127638", "name" : "Annotation of CPIC Guideline for citalopram, escitalopram and CYP2C19", - "version" : 48 + "version" : 140 }, "text" : { - "id" : 1452093804, - "html" : "

Initiate therapy with recommended starting dose. Consider a slower titration schedule and lower maintenance dose than normal metabolizers.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when adjusting dose.

\n", + "id" : 1452093800, + "html" : "

Consider a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2C19. If citalopram or escitalopram are clinically appropriate, and adequate efficacy is not achieved at standard maintenance dosing, consider titrating to a higher maintenance dose.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when adjusting dose or selecting an alternative therapy.

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297344", - "name" : "Recommendation PA166297344", + "id" : "PA166297337", + "name" : "Recommendation PA166297337", "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of citalopram and escitalopram to less active compounds when compared to CYP2C19 rapid and normal metabolizers. Lower plasma concentrations decrease the probability of clinical benefit." + "CYP2C19: Increase in metabolism of citalopram and escitalopram to less active compounds when compared to CYP2C19 normal metabolizers. Lower plasma concentrations decrease the probability of clinical benefit." ], - "lookupKey" : {"CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA10074", - "name" : "escitalopram", - "version" : 11 + "id" : "PA449015", + "name" : "citalopram", + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127638", "name" : "Annotation of CPIC Guideline for citalopram, escitalopram and CYP2C19", - "version" : 48 + "version" : 140 }, "text" : { - "id" : 1452093810, - "html" : "

Consider a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2C19. If citalopram or escitalopram are clinically appropriate, and adequate efficacy is not achieved at standard maintenance dosing, consider titrating to a higher maintenance dose.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when adjusting dose or selecting an alternative therapy.

\n", + "id" : 1452093801, + "html" : "

Initiate therapy with recommended starting dose. If patient does not adequately respond to recommended maintenance dosing, consider titrating to a higher maintenance dose or switching to a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2C19.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when adjusting dose or selecting an alternative therapy.

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297336", - "name" : "Recommendation PA166297336", + "id" : "PA166297345", + "name" : "Recommendation PA166297345", "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of citalopram and escitalopram to less active compounds when compared to CYP2C19 rapid and normal metabolizers. Lower plasma concentrations decrease the probability of clinical benefit." + "CYP2C19: Increase in metabolism of citalopram and escitalopram to less active compounds when compared to CYP2C19 normal metabolizers. Lower plasma concentrations decrease the probability of clinical benefit." ], - "lookupKey" : {"CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA449015", - "name" : "citalopram", - "version" : 21 + "id" : "PA10074", + "name" : "escitalopram", + "version" : 28 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127638", "name" : "Annotation of CPIC Guideline for citalopram, escitalopram and CYP2C19", - "version" : 48 + "version" : 140 }, "text" : { - "id" : 1452093800, - "html" : "

Consider a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2C19. If citalopram or escitalopram are clinically appropriate, and adequate efficacy is not achieved at standard maintenance dosing, consider titrating to a higher maintenance dose.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when adjusting dose or selecting an alternative therapy.

\n", + "id" : 1452093811, + "html" : "

Initiate therapy with recommended starting dose. If patient does not adequately respond to recommended maintenance dosing, consider titrating to a higher maintenance dose or switching to a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2C19.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when adjusting dose or selecting an alternative therapy.

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297349", - "name" : "Recommendation PA166297349", - "alternateDrugAvailable" : true, + "id" : "PA166297347", + "name" : "Recommendation PA166297347", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of citalopram and escitalopram to less active compounds when compared to CYP2C19 normal and intermediate metabolizers. Higher plasma concentrations may increase the probability of side effects." + "CYP2C19: Reduced metabolism when compared to CYP2C19 normal metabolizers. Higher plasma concentrations may increase the probability of side effects." ], - "lookupKey" : {"CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -20620,41 +20586,41 @@ "objCls" : "Chemical", "id" : "PA10074", "name" : "escitalopram", - "version" : 11 + "version" : 28 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127638", "name" : "Annotation of CPIC Guideline for citalopram, escitalopram and CYP2C19", - "version" : 48 + "version" : 140 }, "text" : { - "id" : 1452093815, - "html" : "

Consider a clinically appropriate antidepressant not predominantly metabolized by CYP2C19. If citalopram or escitalopram are clinically appropriate, consider a lower starting dose, slower titration schedule and 50% reduction of the standard maintenance dose as compared to normal metabolizers.

\n

Other Considerations

\n

Per the FDA warning, citalopram 20 mg/day is the maximum recommended dose in CYP2C19 poor metabolizers due to the risk of QT prolongation. FDA product labeling additionally cautions that citalopram dose should be limited to 20 mg/day in patients with hepatic impairment, those taking a CYP2C19 inhibitor, and patients greater than 60 years of age.

\n", + "id" : 1452093813, + "html" : "

Initiate therapy with recommended starting dose. Consider a slower titration schedule and lower maintenance dose than normal metabolizers.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when adjusting dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297341", - "name" : "Recommendation PA166297341", - "alternateDrugAvailable" : true, + "id" : "PA166297340", + "name" : "Recommendation PA166297340", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of citalopram and escitalopram to less active compounds when compared to CYP2C19 normal and intermediate metabolizers. Higher plasma concentrations may increase the probability of side effects." + "CYP2C19: Reduced metabolism when compared to CYP2C19 normal metabolizers. Higher plasma concentrations may increase the probability of side effects." ], - "lookupKey" : {"CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -20662,41 +20628,41 @@ "objCls" : "Chemical", "id" : "PA449015", "name" : "citalopram", - "version" : 21 + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127638", "name" : "Annotation of CPIC Guideline for citalopram, escitalopram and CYP2C19", - "version" : 48 + "version" : 140 }, "text" : { - "id" : 1452093805, - "html" : "

Consider a clinically appropriate antidepressant not predominantly metabolized by CYP2C19. If citalopram or escitalopram are clinically appropriate, consider a lower starting dose, slower titration schedule and 50% reduction of the standard maintenance dose as compared to normal metabolizers.

\n

Other Considerations

\n

Per the FDA warning, citalopram 20 mg/day is the maximum recommended dose in CYP2C19 poor metabolizers due to the risk of QT prolongation. FDA product labeling additionally cautions that citalopram dose should be limited to 20 mg/day in patients with hepatic impairment, those taking a CYP2C19 inhibitor, and patients greater than 60 years of age.

\n", + "id" : 1452093804, + "html" : "

Initiate therapy with recommended starting dose. Consider a slower titration schedule and lower maintenance dose than normal metabolizers.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when adjusting dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297345", - "name" : "Recommendation PA166297345", - "alternateDrugAvailable" : true, + "id" : "PA166297351", + "name" : "Recommendation PA166297351", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Increase in metabolism of citalopram and escitalopram to less active compounds when compared to CYP2C19 normal metabolizers. Lower plasma concentrations decrease the probability of clinical benefit." + "CYP2C19: n/a" ], - "lookupKey" : {"CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -20704,21 +20670,63 @@ "objCls" : "Chemical", "id" : "PA10074", "name" : "escitalopram", - "version" : 11 + "version" : 28 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127638", "name" : "Annotation of CPIC Guideline for citalopram, escitalopram and CYP2C19", - "version" : 48 + "version" : 140 }, "text" : { - "id" : 1452093811, - "html" : "

Initiate therapy with recommended starting dose. If patient does not adequately respond to recommended maintenance dosing, consider titrating to a higher maintenance dose or switching to a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2C19.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when adjusting dose or selecting an alternative therapy.

\n", + "id" : 1452093809, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 2 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166297346", + "name" : "Recommendation PA166297346", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501930, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : false, + "implications" : [ + "CYP2C19: Normal metabolism" + ], + "lookupKey" : {"CYP2C19": "Normal Metabolizer"}, + "otherPrescribingGuidance" : false, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA10074", + "name" : "escitalopram", + "version" : 28 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166127638", + "name" : "Annotation of CPIC Guideline for citalopram, escitalopram and CYP2C19", + "version" : 140 + }, + "text" : { + "id" : 1452093812, + "html" : "

Initiate therapy with recommended starting dose

\n", + "version" : 0 + }, + "version" : 2 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166127638" @@ -20959,7 +20967,7 @@ "pediatricMarkdown" : { "id" : 1451266662, "html" : "

Guideline excerpt: "There are scarce studies focusing solely on CYP2D6 or CYP2C19 genotype and association with pharmacokinetic parameters or treatment outcomes of TCAs in pediatric patients. CYP2D6 activity is fully mature by early childhood, but CYP2C19 activity may be increased in children relative to adults. Although further genomic ontogeny studies are needed, there is a lack of evidence suggesting that this guideline cannot be extrapolated to pediatric patients."

\n", - "version" : 0 + "version" : 1 }, "recommendation" : true, "relatedAlleles" : [], @@ -20968,7 +20976,7 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "relatedGenes" : [ @@ -20977,21 +20985,21 @@ "id" : "PA124", "symbol" : "CYP2C19", "name" : "cytochrome P450 family 2 subfamily C member 19", - "version" : 7210 + "version" : 7266 }, { "objCls" : "Gene", "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "CPIC", "summaryMarkdown" : { "id" : 1447981968, "html" : "

Tricyclic antidepressants have comparable pharmacokinetic properties, it may be reasonable to apply the CPIC Dosing Guideline for amitriptyline and CYP2C19, CYP2D6 to other tricyclics including clomipramine. The CPIC Dosing Guideline update for amitriptyline recommends an alternative drug for CYP2D6 ultrarapid or poor metabolizers and CYP2C19 ultrarapid, rapid or poor metabolizers. If amitriptyline is warranted, consider a 50% dose reduction in CYP2D6 or CYP2C19 poor metabolizers. For CYP2D6 intermediate metabolizers, a 25% dose reduction should be considered.

\n", - "version" : 1 + "version" : 2 }, "terms" : [], "textMarkdown" : { @@ -21000,228 +21008,283 @@ "version" : 1 }, "userId" : "whaleyr", - "version" : 45 + "version" : 93 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166297491", - "name" : "Recommendation PA166297491", - "alternateDrugAvailable" : true, - "classification" : { - "id" : 981565059, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : true, - "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" - ], - "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Ultrarapid Metabolizer"}, + "id" : "PA166301342", + "name" : "Recommendation Annotation PA166301342", + "alternateDrugAvailable" : false, + "dosingInformation" : false, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, - "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060093, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452095661, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297394", - "name" : "Recommendation PA166297394", + "id" : "PA166301343", + "name" : "Recommendation Annotation PA166301343", "alternateDrugAvailable" : false, - "classification" : { - "id" : 981565059, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", - "valid" : true, + "dosingInformation" : false, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Likely Intermediate Metabolizer"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA449048", + "name" : "clomipramine", + "version" : 41 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166105007", + "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", + "version" : 93 + }, + "text" : { + "id" : 1452095662, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", "version" : 0 }, - "dosingInformation" : true, - "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" - ], - "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "No Result"}, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166301344", + "name" : "Recommendation Annotation PA166301344", + "alternateDrugAvailable" : false, + "dosingInformation" : false, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, - "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452059996, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452095663, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297531", - "name" : "Recommendation PA166297531", - "alternateDrugAvailable" : true, - "classification" : { - "id" : 981565059, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", - "valid" : true, + "id" : "PA166301345", + "name" : "Recommendation Annotation PA166301345", + "alternateDrugAvailable" : false, + "dosingInformation" : false, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "No Result"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA449048", + "name" : "clomipramine", + "version" : 41 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166105007", + "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", + "version" : 93 + }, + "text" : { + "id" : 1452095664, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", "version" : 0 }, - "dosingInformation" : true, - "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" - ], - "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Likely Poor Metabolizer"}, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166301346", + "name" : "Recommendation Annotation PA166301346", + "alternateDrugAvailable" : false, + "dosingInformation" : false, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, - "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060133, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452095665, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297434", - "name" : "Recommendation PA166297434", + "id" : "PA166301347", + "name" : "Recommendation Annotation PA166301347", "alternateDrugAvailable" : false, - "classification" : { - "id" : 981501930, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", - "valid" : true, + "dosingInformation" : false, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Ultrarapid Metabolizer"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA449048", + "name" : "clomipramine", + "version" : 41 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166105007", + "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", + "version" : 93 + }, + "text" : { + "id" : 1452095666, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", "version" : 0 }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166301361", + "name" : "Recommendation Annotation PA166301361", + "alternateDrugAvailable" : false, "dosingInformation" : false, - "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Normal metabolism of TCAs" - ], - "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "No Result"}, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, - "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060036, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452095680, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297381", - "name" : "Recommendation PA166297381", + "id" : "PA166301362", + "name" : "Recommendation Annotation PA166301362", "alternateDrugAvailable" : false, - "classification" : { - "id" : 981565059, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", - "valid" : true, + "dosingInformation" : false, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Poor Metabolizer"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA449048", + "name" : "clomipramine", + "version" : 41 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166105007", + "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", + "version" : 93 + }, + "text" : { + "id" : 1452095681, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", "version" : 0 }, - "dosingInformation" : true, - "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" - ], - "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Indeterminate"}, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166301363", + "name" : "Recommendation Annotation PA166301363", + "alternateDrugAvailable" : false, + "dosingInformation" : false, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, - "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452059983, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452095682, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297544", - "name" : "Recommendation PA166297544", + "id" : "PA166297447", + "name" : "Recommendation PA166297447", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -21234,10 +21297,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -21245,26 +21308,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060146, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060049, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297447", - "name" : "Recommendation PA166297447", + "id" : "PA166297522", + "name" : "Recommendation PA166297522", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -21280,7 +21343,7 @@ "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -21288,26 +21351,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060049, + "id" : 1452060124, "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297421", - "name" : "Recommendation PA166297421", + "id" : "PA166297114", + "name" : "Recommendation PA166297114", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -21320,10 +21383,10 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Normal metabolism of tertiary amines", "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -21331,42 +21394,42 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060023, - "html" : "

No recommendation

\n", + "id" : 1452059716, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297553", - "name" : "Recommendation PA166297553", - "alternateDrugAvailable" : true, + "id" : "PA166297263", + "name" : "Recommendation PA166297263", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: n/a" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -21374,26 +21437,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060155, - "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. For tertiary amines, consider a 50% reduction of the recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452059865, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297456", - "name" : "Recommendation PA166297456", + "id" : "PA166297363", + "name" : "Recommendation PA166297363", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -21406,10 +21469,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -21417,26 +21480,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060058, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", + "id" : 1452059965, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297469", - "name" : "Recommendation PA166297469", + "id" : "PA166297364", + "name" : "Recommendation PA166297364", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -21450,9 +21513,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -21460,27 +21523,27 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060071, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059966, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297398", - "name" : "Recommendation PA166297398", - "alternateDrugAvailable" : false, + "id" : "PA166297365", + "name" : "Recommendation PA166297365", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -21490,12 +21553,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -21503,26 +21566,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060000, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452059967, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297495", - "name" : "Recommendation PA166297495", + "id" : "PA166297368", + "name" : "Recommendation PA166297368", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -21535,10 +21598,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -21546,26 +21609,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060097, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452059970, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297548", - "name" : "Recommendation PA166297548", + "id" : "PA166297369", + "name" : "Recommendation PA166297369", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -21578,10 +21641,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: n/a" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -21589,26 +21652,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060150, - "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. For tertiary amines, consider a 50% reduction of the recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452059971, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297416", - "name" : "Recommendation PA166297416", + "id" : "PA166297370", + "name" : "Recommendation PA166297370", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -21622,9 +21685,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -21632,27 +21695,27 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060018, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452059972, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297385", - "name" : "Recommendation PA166297385", - "alternateDrugAvailable" : false, + "id" : "PA166297371", + "name" : "Recommendation PA166297371", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -21664,10 +21727,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -21675,26 +21738,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452059987, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059973, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297513", - "name" : "Recommendation PA166297513", + "id" : "PA166297372", + "name" : "Recommendation PA166297372", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -21707,10 +21770,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -21718,26 +21781,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060115, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059974, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297482", - "name" : "Recommendation PA166297482", + "id" : "PA166297374", + "name" : "Recommendation PA166297374", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -21751,9 +21814,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -21761,56 +21824,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166105007", - "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 - }, - "text" : { - "id" : 1452060084, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166301347", - "name" : "Recommendation Annotation PA166301347", - "alternateDrugAvailable" : false, - "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Ultrarapid Metabolizer"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA449048", - "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452095666, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "id" : 1452059976, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297500", - "name" : "Recommendation PA166297500", + "id" : "PA166297375", + "name" : "Recommendation PA166297375", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -21824,9 +21857,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -21834,26 +21867,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060102, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452059977, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297403", - "name" : "Recommendation PA166297403", + "id" : "PA166297376", + "name" : "Recommendation PA166297376", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -21866,10 +21899,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -21877,26 +21910,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060005, - "html" : "

Avoid clomipramine use. If clomipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452059978, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297372", - "name" : "Recommendation PA166297372", + "id" : "PA166297377", + "name" : "Recommendation PA166297377", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -21912,7 +21945,7 @@ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -21920,17 +21953,17 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452059974, + "id" : 1452059979, "html" : "

Consider alternative drug not metabolized by CYP2C19; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, @@ -21938,8 +21971,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297438", - "name" : "Recommendation PA166297438", + "id" : "PA166297386", + "name" : "Recommendation PA166297386", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -21953,9 +21986,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -21963,26 +21996,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060040, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059988, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297412", - "name" : "Recommendation PA166297412", + "id" : "PA166297387", + "name" : "Recommendation PA166297387", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -21995,10 +22028,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -22006,26 +22039,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060014, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452059989, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297535", - "name" : "Recommendation PA166297535", + "id" : "PA166297388", + "name" : "Recommendation PA166297388", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -22039,9 +22072,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -22049,26 +22082,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060137, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059990, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297522", - "name" : "Recommendation PA166297522", + "id" : "PA166297389", + "name" : "Recommendation PA166297389", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -22081,10 +22114,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -22092,27 +22125,27 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060124, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059991, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297425", - "name" : "Recommendation PA166297425", - "alternateDrugAvailable" : false, + "id" : "PA166297402", + "name" : "Recommendation PA166297402", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -22122,12 +22155,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -22135,26 +22168,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060027, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060004, + "html" : "

Avoid clomipramine use. If clomipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297487", - "name" : "Recommendation PA166297487", + "id" : "PA166297403", + "name" : "Recommendation PA166297403", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -22167,10 +22200,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -22178,26 +22211,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060089, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452060005, + "html" : "

Avoid clomipramine use. If clomipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297408", - "name" : "Recommendation PA166297408", + "id" : "PA166297352", + "name" : "Recommendation PA166297352", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -22210,10 +22243,10 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Normal metabolism of tertiary amines", "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -22221,27 +22254,27 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060010, + "id" : 1452059954, "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297377", - "name" : "Recommendation PA166297377", - "alternateDrugAvailable" : true, + "id" : "PA166297366", + "name" : "Recommendation PA166297366", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -22251,12 +22284,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -22264,27 +22297,27 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452059979, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059968, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297474", - "name" : "Recommendation PA166297474", - "alternateDrugAvailable" : true, + "id" : "PA166297399", + "name" : "Recommendation PA166297399", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -22294,12 +22327,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -22307,42 +22340,42 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060076, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060001, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297505", - "name" : "Recommendation PA166297505", - "alternateDrugAvailable" : true, + "id" : "PA166297373", + "name" : "Recommendation PA166297373", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -22350,57 +22383,70 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060107, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452059975, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301342", - "name" : "Recommendation Annotation PA166301342", + "id" : "PA166297398", + "name" : "Recommendation PA166297398", "alternateDrugAvailable" : false, + "classification" : { + "id" : 981565059, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", + "valid" : true, + "version" : 0 + }, "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Intermediate Metabolizer"}, + "implications" : [ + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Normal metabolism of TCAs" + ], + "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, + "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452095661, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "id" : 1452060000, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297514", - "name" : "Recommendation PA166297514", - "alternateDrugAvailable" : true, + "id" : "PA166297397", + "name" : "Recommendation PA166297397", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -22410,12 +22456,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -22423,42 +22469,42 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060116, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059999, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297461", - "name" : "Recommendation PA166297461", - "alternateDrugAvailable" : true, + "id" : "PA166297401", + "name" : "Recommendation PA166297401", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -22466,27 +22512,27 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060063, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", + "id" : 1452060003, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297364", - "name" : "Recommendation PA166297364", - "alternateDrugAvailable" : true, + "id" : "PA166297396", + "name" : "Recommendation PA166297396", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -22496,12 +22542,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -22509,42 +22555,42 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452059966, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059998, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297501", - "name" : "Recommendation PA166297501", - "alternateDrugAvailable" : true, + "id" : "PA166297400", + "name" : "Recommendation PA166297400", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -22552,26 +22598,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060103, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060002, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297399", - "name" : "Recommendation PA166297399", + "id" : "PA166297395", + "name" : "Recommendation PA166297395", "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, @@ -22587,7 +22633,7 @@ "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -22595,27 +22641,27 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060001, + "id" : 1452059997, "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297496", - "name" : "Recommendation PA166297496", - "alternateDrugAvailable" : true, + "id" : "PA166297362", + "name" : "Recommendation PA166297362", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -22627,10 +22673,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -22638,27 +22684,27 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060098, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452059964, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297527", - "name" : "Recommendation PA166297527", - "alternateDrugAvailable" : true, + "id" : "PA166297394", + "name" : "Recommendation PA166297394", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -22670,10 +22716,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: n/a", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -22681,27 +22727,27 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060129, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059996, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297417", - "name" : "Recommendation PA166297417", - "alternateDrugAvailable" : true, + "id" : "PA166297385", + "name" : "Recommendation PA166297385", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -22713,10 +22759,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -22724,27 +22770,27 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060019, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452059987, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297443", - "name" : "Recommendation PA166297443", - "alternateDrugAvailable" : true, + "id" : "PA166297357", + "name" : "Recommendation PA166297357", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -22756,10 +22802,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -22767,26 +22813,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060045, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059959, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297390", - "name" : "Recommendation PA166297390", + "id" : "PA166297381", + "name" : "Recommendation PA166297381", "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, @@ -22802,7 +22848,7 @@ "CYP2C19: n/a", "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -22810,26 +22856,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452059992, + "id" : 1452059983, "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297359", - "name" : "Recommendation PA166297359", + "id" : "PA166297361", + "name" : "Recommendation PA166297361", "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, @@ -22845,7 +22891,7 @@ "CYP2C19: Normal metabolism of tertiary amines", "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -22853,27 +22899,27 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452059961, + "id" : 1452059963, "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297478", - "name" : "Recommendation PA166297478", - "alternateDrugAvailable" : true, + "id" : "PA166297393", + "name" : "Recommendation PA166297393", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -22885,10 +22931,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: n/a", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -22896,27 +22942,27 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060080, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059995, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297509", - "name" : "Recommendation PA166297509", - "alternateDrugAvailable" : true, + "id" : "PA166297384", + "name" : "Recommendation PA166297384", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -22928,10 +22974,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -22939,27 +22985,27 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060111, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452059986, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297430", - "name" : "Recommendation PA166297430", - "alternateDrugAvailable" : true, + "id" : "PA166297356", + "name" : "Recommendation PA166297356", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -22971,10 +23017,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -22982,27 +23028,27 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060032, - "html" : "

Avoid clomipramine use. If clomipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452059958, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297540", - "name" : "Recommendation PA166297540", - "alternateDrugAvailable" : true, + "id" : "PA166297380", + "name" : "Recommendation PA166297380", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -23015,9 +23061,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -23025,27 +23071,27 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060142, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452059982, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297518", - "name" : "Recommendation PA166297518", - "alternateDrugAvailable" : true, + "id" : "PA166297359", + "name" : "Recommendation PA166297359", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -23057,10 +23103,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -23068,27 +23114,27 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060120, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059961, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297465", - "name" : "Recommendation PA166297465", - "alternateDrugAvailable" : true, + "id" : "PA166297392", + "name" : "Recommendation PA166297392", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -23100,10 +23146,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: n/a", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -23111,27 +23157,27 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060067, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", + "id" : 1452059994, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297368", - "name" : "Recommendation PA166297368", - "alternateDrugAvailable" : true, + "id" : "PA166297383", + "name" : "Recommendation PA166297383", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -23143,10 +23189,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -23154,27 +23200,27 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452059970, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059985, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297452", - "name" : "Recommendation PA166297452", - "alternateDrugAvailable" : true, + "id" : "PA166297355", + "name" : "Recommendation PA166297355", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -23187,9 +23233,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -23197,26 +23243,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060054, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059957, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297355", - "name" : "Recommendation PA166297355", + "id" : "PA166297379", + "name" : "Recommendation PA166297379", "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, @@ -23229,10 +23275,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: n/a", "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -23240,26 +23286,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452059957, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059981, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297562", - "name" : "Recommendation PA166297562", + "id" : "PA166297358", + "name" : "Recommendation PA166297358", "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, @@ -23270,12 +23316,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: n/a" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -23283,42 +23329,42 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060164, - "html" : "

No recommendation

\n", + "id" : 1452059960, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297435", - "name" : "Recommendation PA166297435", + "id" : "PA166297390", + "name" : "Recommendation PA166297390", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ "CYP2C19: n/a", - "CYP2D6: Normal metabolism of TCAs" + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -23326,21 +23372,21 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060037, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452059992, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -23369,27 +23415,27 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { "id" : 1452059984, "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297448", - "name" : "Recommendation PA166297448", - "alternateDrugAvailable" : true, + "id" : "PA166297354", + "name" : "Recommendation PA166297354", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -23402,9 +23448,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -23412,42 +23458,42 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060050, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452059956, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297422", - "name" : "Recommendation PA166297422", + "id" : "PA166297378", + "name" : "Recommendation PA166297378", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ "CYP2C19: n/a", - "CYP2D6: Normal metabolism of TCAs" + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -23455,26 +23501,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060024, - "html" : "

No recommendation

\n", + "id" : 1452059980, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297532", - "name" : "Recommendation PA166297532", + "id" : "PA166297404", + "name" : "Recommendation PA166297404", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -23488,9 +23534,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -23498,26 +23544,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060134, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060006, + "html" : "

Avoid clomipramine use. If clomipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297541", - "name" : "Recommendation PA166297541", + "id" : "PA166297405", + "name" : "Recommendation PA166297405", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -23530,10 +23576,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -23541,26 +23587,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060143, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060007, + "html" : "

Avoid clomipramine use. If clomipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297444", - "name" : "Recommendation PA166297444", + "id" : "PA166297406", + "name" : "Recommendation PA166297406", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -23573,10 +23619,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -23584,27 +23630,27 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060046, - "html" : "

Avoid tricyclic use due to potential for side effects. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452060008, + "html" : "

Avoid clomipramine use. If clomipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297554", - "name" : "Recommendation PA166297554", - "alternateDrugAvailable" : false, + "id" : "PA166297407", + "name" : "Recommendation PA166297407", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -23614,12 +23660,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: n/a" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -23627,26 +23673,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060156, - "html" : "

No recommendation

\n", + "id" : 1452060009, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297386", - "name" : "Recommendation PA166297386", + "id" : "PA166297409", + "name" : "Recommendation PA166297409", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -23659,10 +23705,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -23670,26 +23716,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452059988, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060011, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297536", - "name" : "Recommendation PA166297536", + "id" : "PA166297410", + "name" : "Recommendation PA166297410", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -23702,10 +23748,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -23713,26 +23759,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060138, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060012, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297483", - "name" : "Recommendation PA166297483", + "id" : "PA166297411", + "name" : "Recommendation PA166297411", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -23746,9 +23792,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -23756,26 +23802,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060085, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452060013, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297523", - "name" : "Recommendation PA166297523", + "id" : "PA166297412", + "name" : "Recommendation PA166297412", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -23788,10 +23834,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -23799,26 +23845,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060125, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060014, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297404", - "name" : "Recommendation PA166297404", + "id" : "PA166297413", + "name" : "Recommendation PA166297413", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -23831,10 +23877,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -23842,26 +23888,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060006, - "html" : "

Avoid clomipramine use. If clomipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060015, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297549", - "name" : "Recommendation PA166297549", + "id" : "PA166297414", + "name" : "Recommendation PA166297414", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -23875,9 +23921,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: n/a" + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -23885,26 +23931,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060151, - "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. If a tertiary amine is warranted, utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060016, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297470", - "name" : "Recommendation PA166297470", + "id" : "PA166297415", + "name" : "Recommendation PA166297415", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -23917,10 +23963,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Normal metabolism of tertiary amines", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -23928,42 +23974,42 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060072, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060017, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297373", - "name" : "Recommendation PA166297373", - "alternateDrugAvailable" : false, + "id" : "PA166297416", + "name" : "Recommendation PA166297416", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -23971,26 +24017,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452059975, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060018, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297439", - "name" : "Recommendation PA166297439", + "id" : "PA166297417", + "name" : "Recommendation PA166297417", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -24004,9 +24050,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -24014,26 +24060,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060041, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060019, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297413", - "name" : "Recommendation PA166297413", + "id" : "PA166297418", + "name" : "Recommendation PA166297418", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -24049,7 +24095,7 @@ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -24057,17 +24103,17 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060015, + "id" : 1452060020, "html" : "

Consider alternative drug not metabolized by CYP2C19; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, @@ -24075,24 +24121,24 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297263", - "name" : "Recommendation PA166297263", - "alternateDrugAvailable" : false, + "id" : "PA166297428", + "name" : "Recommendation PA166297428", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -24100,56 +24146,69 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452059865, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060030, + "html" : "

Avoid clomipramine use. If clomipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301346", - "name" : "Recommendation Annotation PA166301346", - "alternateDrugAvailable" : false, - "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Normal Metabolizer"}, + "id" : "PA166297429", + "name" : "Recommendation PA166297429", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981565059, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" + ], + "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, + "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452095665, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "id" : 1452060031, + "html" : "

Avoid clomipramine use. If clomipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297545", - "name" : "Recommendation PA166297545", + "id" : "PA166297430", + "name" : "Recommendation PA166297430", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -24162,10 +24221,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -24173,27 +24232,27 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060147, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060032, + "html" : "

Avoid clomipramine use. If clomipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297426", - "name" : "Recommendation PA166297426", - "alternateDrugAvailable" : false, + "id" : "PA166297431", + "name" : "Recommendation PA166297431", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -24203,12 +24262,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -24216,42 +24275,42 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060028, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060033, + "html" : "

Avoid clomipramine use. If clomipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297400", - "name" : "Recommendation PA166297400", - "alternateDrugAvailable" : false, + "id" : "PA166297432", + "name" : "Recommendation PA166297432", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -24259,27 +24318,27 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060002, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060034, + "html" : "

Avoid clomipramine use. If clomipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297395", - "name" : "Recommendation PA166297395", - "alternateDrugAvailable" : false, + "id" : "PA166297436", + "name" : "Recommendation PA166297436", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -24289,12 +24348,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Normal metabolism of TCAs" + "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -24302,26 +24361,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452059997, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060038, + "html" : "

Avoid clomipramine use. If a clomipramine is warranted, consider a 50% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297492", - "name" : "Recommendation PA166297492", + "id" : "PA166297437", + "name" : "Recommendation PA166297437", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -24334,10 +24393,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -24345,26 +24404,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060094, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452060039, + "html" : "

Avoid clomipramine use. If a clomipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297510", - "name" : "Recommendation PA166297510", + "id" : "PA166297438", + "name" : "Recommendation PA166297438", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -24377,10 +24436,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -24388,26 +24447,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060112, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060040, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297528", - "name" : "Recommendation PA166297528", + "id" : "PA166297439", + "name" : "Recommendation PA166297439", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -24420,10 +24479,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -24431,26 +24490,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060130, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060041, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297475", - "name" : "Recommendation PA166297475", + "id" : "PA166297440", + "name" : "Recommendation PA166297440", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -24463,10 +24522,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -24474,27 +24533,27 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060077, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060042, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297378", - "name" : "Recommendation PA166297378", - "alternateDrugAvailable" : false, + "id" : "PA166297441", + "name" : "Recommendation PA166297441", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -24507,9 +24566,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: n/a", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -24517,26 +24576,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452059980, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452060043, + "html" : "

Avoid tricyclic use due to potential for side effects. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297462", - "name" : "Recommendation PA166297462", + "id" : "PA166297442", + "name" : "Recommendation PA166297442", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -24549,10 +24608,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -24560,26 +24619,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060064, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", + "id" : 1452060044, + "html" : "

Avoid clomipramine use. If a clomipramine is warranted, consider a 50% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297365", - "name" : "Recommendation PA166297365", + "id" : "PA166297443", + "name" : "Recommendation PA166297443", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -24593,9 +24652,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -24603,26 +24662,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452059967, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060045, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297502", - "name" : "Recommendation PA166297502", + "id" : "PA166297444", + "name" : "Recommendation PA166297444", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -24636,9 +24695,52 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: n/a", + "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + ], + "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "No Result"}, + "otherPrescribingGuidance" : false, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA449048", + "name" : "clomipramine", + "version" : 41 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166105007", + "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", + "version" : 93 + }, + "text" : { + "id" : 1452060046, + "html" : "

Avoid tricyclic use due to potential for side effects. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166297445", + "name" : "Recommendation PA166297445", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981565059, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -24646,26 +24748,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060104, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060047, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297497", - "name" : "Recommendation PA166297497", + "id" : "PA166297446", + "name" : "Recommendation PA166297446", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -24678,10 +24780,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -24689,42 +24791,42 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060099, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452060048, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297352", - "name" : "Recommendation PA166297352", - "alternateDrugAvailable" : false, + "id" : "PA166297448", + "name" : "Recommendation PA166297448", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -24732,26 +24834,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452059954, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060050, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297418", - "name" : "Recommendation PA166297418", + "id" : "PA166297449", + "name" : "Recommendation PA166297449", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -24764,10 +24866,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -24775,26 +24877,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060020, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060051, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297387", - "name" : "Recommendation PA166297387", + "id" : "PA166297450", + "name" : "Recommendation PA166297450", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -24807,10 +24909,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -24818,26 +24920,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452059989, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060052, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297484", - "name" : "Recommendation PA166297484", + "id" : "PA166297451", + "name" : "Recommendation PA166297451", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -24850,10 +24952,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -24861,26 +24963,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060086, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452060053, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297515", - "name" : "Recommendation PA166297515", + "id" : "PA166297452", + "name" : "Recommendation PA166297452", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -24896,7 +24998,7 @@ "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -24904,17 +25006,17 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060117, + "id" : 1452060054, "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, @@ -24922,8 +25024,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297405", - "name" : "Recommendation PA166297405", + "id" : "PA166297454", + "name" : "Recommendation PA166297454", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -24936,10 +25038,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -24947,26 +25049,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060007, - "html" : "

Avoid clomipramine use. If clomipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060056, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297479", - "name" : "Recommendation PA166297479", + "id" : "PA166297455", + "name" : "Recommendation PA166297455", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -24979,10 +25081,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -24990,26 +25092,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060081, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452060057, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297431", - "name" : "Recommendation PA166297431", + "id" : "PA166297456", + "name" : "Recommendation PA166297456", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -25022,10 +25124,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -25033,27 +25135,27 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060033, - "html" : "

Avoid clomipramine use. If clomipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060058, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297563", - "name" : "Recommendation PA166297563", - "alternateDrugAvailable" : false, + "id" : "PA166297459", + "name" : "Recommendation PA166297459", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -25063,12 +25165,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: n/a" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -25076,26 +25178,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060165, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060061, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297466", - "name" : "Recommendation PA166297466", + "id" : "PA166297460", + "name" : "Recommendation PA166297460", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -25111,7 +25213,7 @@ "CYP2C19: Normal metabolism of tertiary amines", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -25119,17 +25221,17 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060068, + "id" : 1452060062, "html" : "

Avoid clomipramine use; If clomipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", "version" : 0 }, @@ -25137,38 +25239,51 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301363", - "name" : "Recommendation Annotation PA166301363", - "alternateDrugAvailable" : false, - "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Rapid Metabolizer"}, + "id" : "PA166297461", + "name" : "Recommendation PA166297461", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981565059, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + ], + "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, + "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452095682, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "id" : 1452060063, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297369", - "name" : "Recommendation PA166297369", + "id" : "PA166297462", + "name" : "Recommendation PA166297462", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -25181,10 +25296,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -25192,26 +25307,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452059971, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060064, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297506", - "name" : "Recommendation PA166297506", + "id" : "PA166297463", + "name" : "Recommendation PA166297463", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -25224,10 +25339,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Normal metabolism of tertiary amines", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -25235,18 +25350,61 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060108, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060065, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166297465", + "name" : "Recommendation PA166297465", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981565059, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + ], + "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Normal Metabolizer"}, + "otherPrescribingGuidance" : false, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA449048", + "name" : "clomipramine", + "version" : 41 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166105007", + "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", + "version" : 93 + }, + "text" : { + "id" : 1452060067, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", "version" : 0 }, "version" : 0 @@ -25278,27 +25436,27 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { "id" : 1452060055, "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297356", - "name" : "Recommendation PA166297356", - "alternateDrugAvailable" : false, + "id" : "PA166297458", + "name" : "Recommendation PA166297458", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -25310,10 +25468,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -25321,42 +25479,42 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452059958, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060060, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297114", - "name" : "Recommendation PA166297114", - "alternateDrugAvailable" : false, + "id" : "PA166297464", + "name" : "Recommendation PA166297464", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Normal metabolism of TCAs" + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -25364,42 +25522,42 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452059716, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060066, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297488", - "name" : "Recommendation PA166297488", - "alternateDrugAvailable" : true, + "id" : "PA166297408", + "name" : "Recommendation PA166297408", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: n/a", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -25407,42 +25565,42 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060090, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452060010, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297519", - "name" : "Recommendation PA166297519", - "alternateDrugAvailable" : true, + "id" : "PA166297423", + "name" : "Recommendation PA166297423", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: n/a", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -25450,27 +25608,27 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060121, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060025, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297440", - "name" : "Recommendation PA166297440", - "alternateDrugAvailable" : true, + "id" : "PA166297427", + "name" : "Recommendation PA166297427", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -25480,12 +25638,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -25493,42 +25651,42 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060042, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060029, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297409", - "name" : "Recommendation PA166297409", - "alternateDrugAvailable" : true, + "id" : "PA166297422", + "name" : "Recommendation PA166297422", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: n/a", "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -25536,42 +25694,42 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060011, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060024, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297550", - "name" : "Recommendation PA166297550", - "alternateDrugAvailable" : true, + "id" : "PA166297435", + "name" : "Recommendation PA166297435", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: n/a" + "CYP2C19: n/a", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -25579,27 +25737,27 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060152, - "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. If a tertiary amine is warranted, utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060037, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297370", - "name" : "Recommendation PA166297370", - "alternateDrugAvailable" : true, + "id" : "PA166297426", + "name" : "Recommendation PA166297426", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -25609,12 +25767,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -25622,26 +25780,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452059972, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060028, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297423", - "name" : "Recommendation PA166297423", + "id" : "PA166297421", + "name" : "Recommendation PA166297421", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -25657,7 +25815,7 @@ "CYP2C19: n/a", "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -25665,42 +25823,42 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060025, + "id" : 1452060023, "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297555", - "name" : "Recommendation PA166297555", + "id" : "PA166297434", + "name" : "Recommendation PA166297434", "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: n/a" + "CYP2C19: n/a", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -25708,27 +25866,27 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060157, + "id" : 1452060036, "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297436", - "name" : "Recommendation PA166297436", - "alternateDrugAvailable" : true, + "id" : "PA166297425", + "name" : "Recommendation PA166297425", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -25738,12 +25896,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -25751,42 +25909,42 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060038, - "html" : "

Avoid clomipramine use. If a clomipramine is warranted, consider a 50% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060027, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297410", - "name" : "Recommendation PA166297410", - "alternateDrugAvailable" : true, + "id" : "PA166297420", + "name" : "Recommendation PA166297420", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: n/a", "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -25794,42 +25952,42 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060012, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060022, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297520", - "name" : "Recommendation PA166297520", - "alternateDrugAvailable" : true, + "id" : "PA166297433", + "name" : "Recommendation PA166297433", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: n/a", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -25837,27 +25995,27 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060122, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060035, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297445", - "name" : "Recommendation PA166297445", - "alternateDrugAvailable" : true, + "id" : "PA166297424", + "name" : "Recommendation PA166297424", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -25867,12 +26025,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -25880,42 +26038,42 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060047, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060026, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297392", - "name" : "Recommendation PA166297392", + "id" : "PA166297419", + "name" : "Recommendation PA166297419", "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ "CYP2C19: n/a", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -25923,26 +26081,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452059994, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452060021, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297458", - "name" : "Recommendation PA166297458", + "id" : "PA166297466", + "name" : "Recommendation PA166297466", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -25958,7 +26116,7 @@ "CYP2C19: Normal metabolism of tertiary amines", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -25966,17 +26124,17 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060060, + "id" : 1452060068, "html" : "

Avoid clomipramine use; If clomipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", "version" : 0 }, @@ -25984,8 +26142,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297432", - "name" : "Recommendation PA166297432", + "id" : "PA166297467", + "name" : "Recommendation PA166297467", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -25999,9 +26157,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -26009,26 +26167,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060034, - "html" : "

Avoid clomipramine use. If clomipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060069, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297542", - "name" : "Recommendation PA166297542", + "id" : "PA166297469", + "name" : "Recommendation PA166297469", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -26041,10 +26199,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -26052,26 +26210,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060144, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060071, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297374", - "name" : "Recommendation PA166297374", + "id" : "PA166297471", + "name" : "Recommendation PA166297471", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -26084,10 +26242,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -26095,26 +26253,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452059976, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060073, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297524", - "name" : "Recommendation PA166297524", + "id" : "PA166297472", + "name" : "Recommendation PA166297472", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -26127,10 +26285,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -26138,26 +26296,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060126, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060074, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297471", - "name" : "Recommendation PA166297471", + "id" : "PA166297473", + "name" : "Recommendation PA166297473", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -26173,7 +26331,7 @@ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -26181,17 +26339,17 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060073, + "id" : 1452060075, "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, @@ -26199,8 +26357,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297511", - "name" : "Recommendation PA166297511", + "id" : "PA166297474", + "name" : "Recommendation PA166297474", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -26213,10 +26371,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -26224,27 +26382,27 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060113, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060076, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297361", - "name" : "Recommendation PA166297361", - "alternateDrugAvailable" : false, + "id" : "PA166297475", + "name" : "Recommendation PA166297475", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -26256,10 +26414,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -26267,42 +26425,42 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452059963, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452060077, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297537", - "name" : "Recommendation PA166297537", - "alternateDrugAvailable" : false, + "id" : "PA166297477", + "name" : "Recommendation PA166297477", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: n/a" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -26310,27 +26468,27 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060139, - "html" : "

No recommendation

\n", + "id" : 1452060079, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297427", - "name" : "Recommendation PA166297427", - "alternateDrugAvailable" : false, + "id" : "PA166297478", + "name" : "Recommendation PA166297478", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -26340,12 +26498,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -26353,27 +26511,27 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060029, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060080, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297396", - "name" : "Recommendation PA166297396", - "alternateDrugAvailable" : false, + "id" : "PA166297479", + "name" : "Recommendation PA166297479", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -26383,12 +26541,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -26396,42 +26554,42 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452059998, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060081, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297401", - "name" : "Recommendation PA166297401", - "alternateDrugAvailable" : false, + "id" : "PA166297480", + "name" : "Recommendation PA166297480", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -26439,26 +26597,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060003, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060082, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297546", - "name" : "Recommendation PA166297546", + "id" : "PA166297482", + "name" : "Recommendation PA166297482", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -26471,10 +26629,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -26482,26 +26640,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060148, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060084, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297493", - "name" : "Recommendation PA166297493", + "id" : "PA166297483", + "name" : "Recommendation PA166297483", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -26517,7 +26675,7 @@ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -26525,17 +26683,17 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060095, + "id" : 1452060085, "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, @@ -26543,8 +26701,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297533", - "name" : "Recommendation PA166297533", + "id" : "PA166297484", + "name" : "Recommendation PA166297484", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -26557,10 +26715,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -26568,26 +26726,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060135, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060086, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297414", - "name" : "Recommendation PA166297414", + "id" : "PA166297485", + "name" : "Recommendation PA166297485", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -26601,9 +26759,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -26611,56 +26769,69 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060016, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060087, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301345", - "name" : "Recommendation Annotation PA166301345", - "alternateDrugAvailable" : false, - "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "No Result"}, + "id" : "PA166297486", + "name" : "Recommendation PA166297486", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981565059, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + ], + "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, + "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452095664, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "id" : 1452060088, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297559", - "name" : "Recommendation PA166297559", + "id" : "PA166297488", + "name" : "Recommendation PA166297488", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -26673,10 +26844,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: n/a" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -26684,26 +26855,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060161, - "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. For tertiary amines, consider a 50% reduction of the recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060090, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297480", - "name" : "Recommendation PA166297480", + "id" : "PA166297489", + "name" : "Recommendation PA166297489", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -26719,7 +26890,7 @@ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -26727,17 +26898,17 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060082, + "id" : 1452060091, "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, @@ -26745,9 +26916,9 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297383", - "name" : "Recommendation PA166297383", - "alternateDrugAvailable" : false, + "id" : "PA166297490", + "name" : "Recommendation PA166297490", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -26759,10 +26930,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -26770,26 +26941,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452059985, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060092, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297449", - "name" : "Recommendation PA166297449", + "id" : "PA166297491", + "name" : "Recommendation PA166297491", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -26802,10 +26973,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -26813,56 +26984,69 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060051, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060093, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301344", - "name" : "Recommendation Annotation PA166301344", - "alternateDrugAvailable" : false, - "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Likely Poor Metabolizer"}, + "id" : "PA166297493", + "name" : "Recommendation PA166297493", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981565059, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + ], + "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, + "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452095663, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "id" : 1452060095, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297463", - "name" : "Recommendation PA166297463", + "id" : "PA166297494", + "name" : "Recommendation PA166297494", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -26875,10 +27059,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -26886,26 +27070,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060065, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", + "id" : 1452060096, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297516", - "name" : "Recommendation PA166297516", + "id" : "PA166297495", + "name" : "Recommendation PA166297495", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -26918,10 +27102,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -26929,27 +27113,27 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060118, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060097, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297366", - "name" : "Recommendation PA166297366", - "alternateDrugAvailable" : false, + "id" : "PA166297496", + "name" : "Recommendation PA166297496", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -26959,12 +27143,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -26972,26 +27156,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452059968, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060098, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297529", - "name" : "Recommendation PA166297529", + "id" : "PA166297497", + "name" : "Recommendation PA166297497", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -27004,10 +27188,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -27015,26 +27199,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060131, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060099, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297498", - "name" : "Recommendation PA166297498", + "id" : "PA166297499", + "name" : "Recommendation PA166297499", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -27050,7 +27234,7 @@ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -27058,17 +27242,17 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060100, + "id" : 1452060101, "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, @@ -27076,8 +27260,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297450", - "name" : "Recommendation PA166297450", + "id" : "PA166297500", + "name" : "Recommendation PA166297500", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -27090,10 +27274,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -27101,42 +27285,42 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060052, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060102, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297419", - "name" : "Recommendation PA166297419", - "alternateDrugAvailable" : false, + "id" : "PA166297501", + "name" : "Recommendation PA166297501", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ "CYP2C19: n/a", - "CYP2D6: Normal metabolism of TCAs" + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -27144,26 +27328,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060021, - "html" : "

No recommendation

\n", + "id" : 1452060103, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297560", - "name" : "Recommendation PA166297560", + "id" : "PA166297502", + "name" : "Recommendation PA166297502", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -27176,10 +27360,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: n/a" + "CYP2C19: n/a", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -27187,26 +27371,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060162, - "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. If a tertiary amine is warranted, utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060104, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297388", - "name" : "Recommendation PA166297388", + "id" : "PA166297504", + "name" : "Recommendation PA166297504", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -27219,10 +27403,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: n/a", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -27230,26 +27414,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452059990, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060106, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297485", - "name" : "Recommendation PA166297485", + "id" : "PA166297505", + "name" : "Recommendation PA166297505", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -27262,10 +27446,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -27273,26 +27457,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060087, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452060107, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297538", - "name" : "Recommendation PA166297538", + "id" : "PA166297506", + "name" : "Recommendation PA166297506", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -27308,7 +27492,7 @@ "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -27316,17 +27500,17 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060140, + "id" : 1452060108, "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, @@ -27334,8 +27518,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297406", - "name" : "Recommendation PA166297406", + "id" : "PA166297508", + "name" : "Recommendation PA166297508", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -27348,10 +27532,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: n/a", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -27359,26 +27543,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060008, - "html" : "

Avoid clomipramine use. If clomipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060110, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297375", - "name" : "Recommendation PA166297375", + "id" : "PA166297509", + "name" : "Recommendation PA166297509", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -27391,10 +27575,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: n/a", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -27402,26 +27586,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452059977, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060111, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297503", - "name" : "Recommendation PA166297503", + "id" : "PA166297511", + "name" : "Recommendation PA166297511", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -27437,7 +27621,7 @@ "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -27445,17 +27629,17 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060105, + "id" : 1452060113, "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, @@ -27463,8 +27647,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297472", - "name" : "Recommendation PA166297472", + "id" : "PA166297512", + "name" : "Recommendation PA166297512", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -27477,10 +27661,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -27488,26 +27672,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060074, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060114, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297467", - "name" : "Recommendation PA166297467", + "id" : "PA166297513", + "name" : "Recommendation PA166297513", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -27520,10 +27704,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -27531,27 +27715,27 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060069, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060115, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297551", - "name" : "Recommendation PA166297551", - "alternateDrugAvailable" : false, + "id" : "PA166297514", + "name" : "Recommendation PA166297514", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -27561,12 +27745,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: n/a" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -27574,26 +27758,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060153, - "html" : "

No recommendation

\n", + "id" : 1452060116, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297454", - "name" : "Recommendation PA166297454", + "id" : "PA166297516", + "name" : "Recommendation PA166297516", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -27606,10 +27790,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -27617,27 +27801,27 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060056, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060118, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297357", - "name" : "Recommendation PA166297357", - "alternateDrugAvailable" : false, + "id" : "PA166297517", + "name" : "Recommendation PA166297517", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -27650,9 +27834,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -27660,26 +27844,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452059959, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060119, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297564", - "name" : "Recommendation PA166297564", + "id" : "PA166297518", + "name" : "Recommendation PA166297518", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -27692,10 +27876,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: n/a" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -27703,26 +27887,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060166, - "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. For tertiary amines, consider a 50% reduction of the recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060120, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297489", - "name" : "Recommendation PA166297489", + "id" : "PA166297519", + "name" : "Recommendation PA166297519", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -27735,10 +27919,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -27746,26 +27930,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060091, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452060121, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297441", - "name" : "Recommendation PA166297441", + "id" : "PA166297520", + "name" : "Recommendation PA166297520", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -27778,10 +27962,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -27789,56 +27973,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166105007", - "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 - }, - "text" : { - "id" : 1452060043, - "html" : "

Avoid tricyclic use due to potential for side effects. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166301362", - "name" : "Recommendation Annotation PA166301362", - "alternateDrugAvailable" : false, - "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Poor Metabolizer"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA449048", - "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452095681, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "id" : 1452060122, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297476", - "name" : "Recommendation PA166297476", + "id" : "PA166297521", + "name" : "Recommendation PA166297521", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -27851,10 +28005,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -27862,27 +28016,27 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060078, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060123, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297379", - "name" : "Recommendation PA166297379", - "alternateDrugAvailable" : false, + "id" : "PA166297523", + "name" : "Recommendation PA166297523", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -27894,10 +28048,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -27905,26 +28059,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452059981, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452060125, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297411", - "name" : "Recommendation PA166297411", + "id" : "PA166297524", + "name" : "Recommendation PA166297524", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -27937,10 +28091,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -27948,26 +28102,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060013, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060126, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297543", - "name" : "Recommendation PA166297543", + "id" : "PA166297525", + "name" : "Recommendation PA166297525", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -27980,10 +28134,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -27991,26 +28145,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060145, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060127, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297446", - "name" : "Recommendation PA166297446", + "id" : "PA166297526", + "name" : "Recommendation PA166297526", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -28023,10 +28177,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -28034,26 +28188,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060048, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060128, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297490", - "name" : "Recommendation PA166297490", + "id" : "PA166297470", + "name" : "Recommendation PA166297470", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -28066,10 +28220,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -28077,27 +28231,27 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060092, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452060072, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297393", - "name" : "Recommendation PA166297393", - "alternateDrugAvailable" : false, + "id" : "PA166297476", + "name" : "Recommendation PA166297476", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -28109,53 +28263,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" - ], - "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "No Result"}, - "otherPrescribingGuidance" : false, - "population" : "general", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA449048", - "name" : "clomipramine", - "version" : 7 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166105007", - "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 - }, - "text" : { - "id" : 1452059995, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166297556", - "name" : "Recommendation PA166297556", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 981501930, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: n/a" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -28163,26 +28274,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060158, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060078, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297459", - "name" : "Recommendation PA166297459", + "id" : "PA166297481", + "name" : "Recommendation PA166297481", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -28195,10 +28306,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -28206,42 +28317,42 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060061, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", + "id" : 1452060083, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297433", - "name" : "Recommendation PA166297433", - "alternateDrugAvailable" : false, + "id" : "PA166297487", + "name" : "Recommendation PA166297487", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -28249,27 +28360,27 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060035, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060089, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297380", - "name" : "Recommendation PA166297380", - "alternateDrugAvailable" : false, + "id" : "PA166297492", + "name" : "Recommendation PA166297492", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -28281,10 +28392,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -28292,42 +28403,42 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452059982, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452060094, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297420", - "name" : "Recommendation PA166297420", - "alternateDrugAvailable" : false, + "id" : "PA166297498", + "name" : "Recommendation PA166297498", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -28335,26 +28446,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060022, - "html" : "

No recommendation

\n", + "id" : 1452060100, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297530", - "name" : "Recommendation PA166297530", + "id" : "PA166297503", + "name" : "Recommendation PA166297503", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -28367,10 +28478,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -28378,27 +28489,27 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060132, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060105, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297362", - "name" : "Recommendation PA166297362", - "alternateDrugAvailable" : false, + "id" : "PA166297510", + "name" : "Recommendation PA166297510", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -28410,10 +28521,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: n/a", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -28421,26 +28532,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452059964, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452060112, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297428", - "name" : "Recommendation PA166297428", + "id" : "PA166297515", + "name" : "Recommendation PA166297515", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -28453,10 +28564,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -28464,26 +28575,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060030, - "html" : "

Avoid clomipramine use. If clomipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060117, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297402", - "name" : "Recommendation PA166297402", + "id" : "PA166297528", + "name" : "Recommendation PA166297528", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -28497,9 +28608,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -28507,27 +28618,27 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060004, - "html" : "

Avoid clomipramine use. If clomipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060130, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297397", - "name" : "Recommendation PA166297397", - "alternateDrugAvailable" : false, + "id" : "PA166297529", + "name" : "Recommendation PA166297529", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -28537,12 +28648,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -28550,26 +28661,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452059999, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060131, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297525", - "name" : "Recommendation PA166297525", + "id" : "PA166297530", + "name" : "Recommendation PA166297530", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -28585,7 +28696,7 @@ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -28593,17 +28704,17 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060127, + "id" : 1452060132, "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, @@ -28611,8 +28722,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297494", - "name" : "Recommendation PA166297494", + "id" : "PA166297531", + "name" : "Recommendation PA166297531", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -28625,10 +28736,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -28636,26 +28747,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060096, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452060133, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297512", - "name" : "Recommendation PA166297512", + "id" : "PA166297532", + "name" : "Recommendation PA166297532", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -28668,10 +28779,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -28679,26 +28790,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060114, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060134, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297415", - "name" : "Recommendation PA166297415", + "id" : "PA166297534", + "name" : "Recommendation PA166297534", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -28711,10 +28822,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -28722,27 +28833,27 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060017, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", + "id" : 1452060136, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297384", - "name" : "Recommendation PA166297384", - "alternateDrugAvailable" : false, + "id" : "PA166297535", + "name" : "Recommendation PA166297535", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -28754,10 +28865,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -28765,26 +28876,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452059986, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060137, + "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297481", - "name" : "Recommendation PA166297481", + "id" : "PA166297536", + "name" : "Recommendation PA166297536", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -28797,10 +28908,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -28808,26 +28919,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060083, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452060138, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297521", - "name" : "Recommendation PA166297521", + "id" : "PA166297539", + "name" : "Recommendation PA166297539", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -28840,10 +28951,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -28851,26 +28962,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060123, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060141, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297371", - "name" : "Recommendation PA166297371", + "id" : "PA166297540", + "name" : "Recommendation PA166297540", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -28883,10 +28994,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: n/a", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -28894,27 +29005,27 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452059973, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060142, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297424", - "name" : "Recommendation PA166297424", - "alternateDrugAvailable" : false, + "id" : "PA166297541", + "name" : "Recommendation PA166297541", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -28924,12 +29035,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: n/a", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -28937,27 +29048,27 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060026, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060143, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297547", - "name" : "Recommendation PA166297547", - "alternateDrugAvailable" : false, + "id" : "PA166297542", + "name" : "Recommendation PA166297542", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -28967,12 +29078,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: n/a" + "CYP2C19: n/a", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -28980,26 +29091,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060149, - "html" : "

No recommendation

\n", + "id" : 1452060144, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297534", - "name" : "Recommendation PA166297534", + "id" : "PA166297543", + "name" : "Recommendation PA166297543", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -29012,10 +29123,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -29023,26 +29134,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060136, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060145, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297437", - "name" : "Recommendation PA166297437", + "id" : "PA166297545", + "name" : "Recommendation PA166297545", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -29055,10 +29166,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: n/a", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -29066,26 +29177,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060039, - "html" : "

Avoid clomipramine use. If a clomipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452060147, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297499", - "name" : "Recommendation PA166297499", + "id" : "PA166297546", + "name" : "Recommendation PA166297546", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -29098,10 +29209,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -29109,26 +29220,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060101, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452060148, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297504", - "name" : "Recommendation PA166297504", + "id" : "PA166297548", + "name" : "Recommendation PA166297548", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -29141,10 +29252,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -29152,26 +29263,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060106, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060150, + "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. For tertiary amines, consider a 50% reduction of the recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297451", - "name" : "Recommendation PA166297451", + "id" : "PA166297549", + "name" : "Recommendation PA166297549", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -29184,10 +29295,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -29195,27 +29306,27 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060053, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060151, + "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. If a tertiary amine is warranted, utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297354", - "name" : "Recommendation PA166297354", - "alternateDrugAvailable" : false, + "id" : "PA166297550", + "name" : "Recommendation PA166297550", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -29227,10 +29338,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -29238,26 +29349,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452059956, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060152, + "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. If a tertiary amine is warranted, utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297517", - "name" : "Recommendation PA166297517", + "id" : "PA166297553", + "name" : "Recommendation PA166297553", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -29270,10 +29381,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -29281,56 +29392,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166105007", - "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 - }, - "text" : { - "id" : 1452060119, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166301343", - "name" : "Recommendation Annotation PA166301343", - "alternateDrugAvailable" : false, - "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Likely Intermediate Metabolizer"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA449048", - "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452095662, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "id" : 1452060155, + "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. For tertiary amines, consider a 50% reduction of the recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297486", - "name" : "Recommendation PA166297486", + "id" : "PA166297559", + "name" : "Recommendation PA166297559", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -29343,10 +29424,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -29354,26 +29435,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060088, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452060161, + "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. For tertiary amines, consider a 50% reduction of the recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297389", - "name" : "Recommendation PA166297389", + "id" : "PA166297560", + "name" : "Recommendation PA166297560", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -29386,10 +29467,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -29397,26 +29478,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452059991, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060162, + "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. If a tertiary amine is warranted, utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297407", - "name" : "Recommendation PA166297407", + "id" : "PA166297561", + "name" : "Recommendation PA166297561", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -29430,9 +29511,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -29440,26 +29521,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060009, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060163, + "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. If a tertiary amine is warranted, utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297376", - "name" : "Recommendation PA166297376", + "id" : "PA166297564", + "name" : "Recommendation PA166297564", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -29472,10 +29553,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -29483,26 +29564,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452059978, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060166, + "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. For tertiary amines, consider a 50% reduction of the recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297473", - "name" : "Recommendation PA166297473", + "id" : "PA166297527", + "name" : "Recommendation PA166297527", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -29518,7 +29599,7 @@ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -29526,26 +29607,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060075, + "id" : 1452060129, "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297526", - "name" : "Recommendation PA166297526", + "id" : "PA166297533", + "name" : "Recommendation PA166297533", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -29561,7 +29642,7 @@ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -29569,26 +29650,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060128, + "id" : 1452060135, "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297539", - "name" : "Recommendation PA166297539", + "id" : "PA166297538", + "name" : "Recommendation PA166297538", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -29604,7 +29685,7 @@ "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -29612,26 +29693,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060141, + "id" : 1452060140, "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297460", - "name" : "Recommendation PA166297460", + "id" : "PA166297544", + "name" : "Recommendation PA166297544", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -29644,10 +29725,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", + "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -29655,42 +29736,42 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060062, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", + "id" : 1452060146, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297363", - "name" : "Recommendation PA166297363", - "alternateDrugAvailable" : true, + "id" : "PA166297537", + "name" : "Recommendation PA166297537", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -29698,27 +29779,27 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452059965, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060139, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297429", - "name" : "Recommendation PA166297429", - "alternateDrugAvailable" : true, + "id" : "PA166297554", + "name" : "Recommendation PA166297554", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -29728,12 +29809,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: n/a", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -29741,27 +29822,27 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060031, - "html" : "

Avoid clomipramine use. If clomipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060156, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297508", - "name" : "Recommendation PA166297508", - "alternateDrugAvailable" : true, + "id" : "PA166297552", + "name" : "Recommendation PA166297552", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -29771,12 +29852,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -29784,27 +29865,27 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060110, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060154, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297455", - "name" : "Recommendation PA166297455", - "alternateDrugAvailable" : true, + "id" : "PA166297547", + "name" : "Recommendation PA166297547", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -29814,12 +29895,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -29827,26 +29908,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060057, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060149, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297358", - "name" : "Recommendation PA166297358", + "id" : "PA166297551", + "name" : "Recommendation PA166297551", "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, @@ -29857,12 +29938,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: n/a", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -29870,42 +29951,42 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452059960, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452060153, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297442", - "name" : "Recommendation PA166297442", - "alternateDrugAvailable" : true, + "id" : "PA166297556", + "name" : "Recommendation PA166297556", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -29913,26 +29994,26 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060044, - "html" : "

Avoid clomipramine use. If a clomipramine is warranted, consider a 50% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060158, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297552", - "name" : "Recommendation PA166297552", + "id" : "PA166297563", + "name" : "Recommendation PA166297563", "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, @@ -29948,7 +30029,7 @@ "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -29956,27 +30037,27 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060154, - "html" : "

No recommendation

\n", + "id" : 1452060165, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297477", - "name" : "Recommendation PA166297477", - "alternateDrugAvailable" : true, + "id" : "PA166297555", + "name" : "Recommendation PA166297555", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -29986,12 +30067,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -29999,27 +30080,27 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060079, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060157, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297561", - "name" : "Recommendation PA166297561", - "alternateDrugAvailable" : true, + "id" : "PA166297562", + "name" : "Recommendation PA166297562", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -30029,12 +30110,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: n/a", "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -30042,100 +30123,27 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105007", "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 + "version" : 93 }, "text" : { - "id" : 1452060163, - "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. If a tertiary amine is warranted, utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060164, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166297464", - "name" : "Recommendation PA166297464", - "alternateDrugAvailable" : true, - "classification" : { - "id" : 981565059, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : true, - "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" - ], - "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Normal Metabolizer"}, - "otherPrescribingGuidance" : false, - "population" : "general", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA449048", - "name" : "clomipramine", - "version" : 7 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166105007", - "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 - }, - "text" : { - "id" : 1452060066, - "html" : "

Avoid clomipramine use; If clomipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166301361", - "name" : "Recommendation Annotation PA166301361", - "alternateDrugAvailable" : false, - "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Indeterminate"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA449048", - "name" : "clomipramine", - "version" : 7 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166105007", - "name" : "Annotation of CPIC Guideline for clomipramine and CYP2C19, CYP2D6", - "version" : 45 - }, - "text" : { - "id" : 1452095680, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", - "version" : 0 - }, - "version" : 0 - } - ], - "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166105007" - }, - { - "citations" : [ + "version" : 1 + } + ], + "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166105007" + }, + { + "citations" : [ { "id" : 15127862, "title" : "Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2C19 Genotype and Clopidogrel Therapy: 2022 Update.", @@ -30415,7 +30423,7 @@ "objCls" : "Chemical", "id" : "PA449053", "name" : "clopidogrel", - "version" : 20 + "version" : 58 } ], "relatedGenes" : [ @@ -30424,30 +30432,30 @@ "id" : "PA124", "symbol" : "CYP2C19", "name" : "cytochrome P450 family 2 subfamily C member 19", - "version" : 7210 + "version" : 7266 } ], "source" : "CPIC", "summaryMarkdown" : { "id" : 1447981866, "html" : "

The CPIC Dosing Guideline for clopidogrel recommends an alternative antiplatelet therapy for CYP2C19 poor or intermediate metabolizers (cardiovascular indications: prasugrel or ticagrelor if no contraindication; neurovascular indications: alternative P2Y12 inhibitor if clinically indicated and no contraindication.)

\n", - "version" : 1 + "version" : 3 }, "terms" : [], "textMarkdown" : { "id" : 1451433626, "html" : "

This annotation is based on the CPIC® guideline for clopidogrel and CYP2C19.

\n

January 2022 Update

\n\n

Table 1: Antiplatelet therapy recommendations based on CYP2C19 phenotype when considering clopidogrel for cardiovascular indications

\n

Adapted from Tables 1 and 2 of the 2022 guideline update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
PhenotypeGenotypeExamples of genotypesImplicationsTherapeutic recommendationsClassification of recommendationsa- ACS and/or PCIbClassification of recommendationsa - non-ACS, non-PCI cardiovascular indicationsc
CYP2C19 ultrarapid metabolizerAn individual carrying two increased function alleles*17/*17Increased clopidogrel active metabolite formation; lower on-treatment platelet reactivity; no association with higher bleeding riskIf considering clopidogrel, use at standard dose (75 mg/day)StrongNo recommendation
CYP2C19 rapid metabolizerAn individual carrying one normal function allele and one increased function allele*1/*17Normal or increased clopidogrel active metabolite formation; normal or lower on-treatment platelet reactivity; no association with higher bleeding riskIf considering clopidogrel, use at standard dose (75 mg/day)StrongNo recommendation
CYP2C19 normal metabolizerAn individual carrying two normal function alleles*1/*1Normal clopidogrel active metabolite formation; normal on-treatment platelet reactivityIf considering clopidogrel, use at standard dose (75 mg/day)StrongStrong
CYP2C19 likely intermediate metabolizerdAn individual carrying one normal function allele and one decreased function allele or one increased function allele and one decreased function allele or two decreased function alleles*1/*9, *9/*17, *9/*9Reduced clopidogrel active metabolite formation; increased on-treatment platelet reactivity; increased risk for adverse cardiac and cerebrovascular eventsAvoid standard dose clopidogrel (75 mg) if possible. Use prasugrel or ticagrelor at standard dose if no contraindication.StrongeNo recommendatione
CYP2C19 intermediate metabolizerAn individual carrying one normal function allele and one no function allele or one increased function allele and one no function allele*1/*2, *1/*3, *2/*17, *3/*17Reduced clopidogrel active metabolite formation; increased on-treatment platelet reactivity; increased risk for adverse cardiac and cerebrovascular eventsAvoid standard dose (75 mg) clopidogrel if possible. Use prasugrel or ticagrelor at standard dose if no contraindication.StrongNo recommendation
CYP2C19 likely poor metabolizerdAn individual carrying one decreased function allele and one no function allele*2/*9, *3/*9Significantly reduced clopidogrel active metabolite formation; increased on-treatment platelet reactivity; increased risk for adverse cardiac and cerebrovascular eventsAvoid clopidogrel if possible. Use prasugrel or ticagrelor at standard dose if no contraindication.StrongeModeratee
CYP2C19 poor metabolizerAn individual carrying two no function alleles*2/*2, *3/*3, *2/*3Significantly reduced clopidogrel active metabolite formation; increased on-treatment platelet reactivity; increased risk for adverse cardiac and cerebrovascular eventsAvoid clopidogrel if possible. Use prasugrel or ticagrelor at standard dose if no contraindication.StrongModerate
\n

a Rating scheme described in the Supplemental Material.\nbACS and/or PCI includes patients undergoing PCI for an ACS or non-ACS (elective) indication.\ncNon-ACS, non-PCI cardiovascular indications include peripheral arterial disease and stable coronary artery disease following a recent myocardial infarction outside the setting of PCI.\ndThere are limited data to characterize the function of decreased function alleles.\neThe strength of recommendation for “likely” phenotypes are the same as their respective confirmed phenotypes. “Likely” indicates the uncertainty in the phenotype assignment, but it is reasonable to apply the recommendation for the confirmed phenotype to the corresponding “likely” phenotype.

\n

Table 2: Antiplatelet therapy recommendations based on CYP2C19 phenotype when considering clopidogrel for neurovascular indications

\n

Adapted from Tables 1 and 3 of the 2022 guideline update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
PhenotypeGenotypeExamples of genotypesImplicationsTherapeutic recommendationsClassification of recommendationsaOther Considerations
CYP2C19 ultrarapid metabolizerAn individual carrying two increased function alleles*17/*17Increased clopidogrel active metabolite formation; lower on-treatment platelet reactivityNo recommendationNo recommendation
CYP2C19 rapid metabolizerAn individual carrying one normal function allele and one increased function allele*1/*17Normal or increased clopidogrel active metabolite formation; normal or lower on-treatment platelet reactivityNo recommendationNo recommendation
CYP2C19 normal metabolizerAn individual carrying two normal function alleles*1/*1Normal clopidogrel active metabolite formation; normal on-treatment platelet reactivityIf considering clopidogrel, use at standard dose (75 mg/day)Strong
CYP2C19 likely intermediate metabolizercAn individual carrying one normal function allele and one decreased function allele or one increased function allele and one decreased function allele or two decreased function alleles*1/*9, *9/*17, *9/*9Reduced clopidogrel active metabolite formation; increased on-treatment platelet reactivity; increased risk for adverse cardiac and cerebrovascular eventsConsider an alternative P2Y12 inhibitor at standard dose if clinically indicated and no contraindication.ModeratedAlternative P2Y12 inhibitors not impacted by CYP2C19 genetic variants include ticagrelor and ticlopidine. Prasugrel is contraindicated in patients with a history of stroke or TIA.e
CYP2C19 intermediate metabolizerAn individual carrying one normal function allele and one no function allele or one increased function allele and one no function allele*1/*2, *1/*3, *2/*17, *3/*17Reduced clopidogrel active metabolite formation; increased on-treatment platelet reactivity; increased risk for adverse cardiac and cerebrovascular eventsConsider an alternative P2Y12 inhibitor at standard dose if clinically indicated and no contraindication.ModerateAlternative P2Y12 inhibitors not impacted by CYP2C19 genetic variants include ticagrelor and ticlopidine. Prasugrel is contraindicated in patients with a history of stroke or TIA.e
CYP2C19 likely poor metabolizercAn individual carrying one decreased function allele and one no function allele*2/*9, *3/*9Significantly reduced clopidogrel active metabolite formation; increased on-treatment platelet reactivity; increased risk for adverse cardiac and cerebrovascular eventsAvoid clopidogrel if possible. Consider an alternative P2Y12 inhibitor at standard dose if clinically indicated and no contraindication.ModeratedAlternative P2Y12 inhibitors not impacted by CYP2C19 genetic variants include ticagrelor and ticlopidine. Prasugrel is contraindicated in patients with a history of stroke or TIA.e
CYP2C19 poor metabolizerAn individual carrying two no function alleles*2/*2, *3/*3, *2/*3Significantly reduced clopidogrel active metabolite formation; increased on-treatment platelet reactivity; increased risk for adverse cardiac and cerebrovascular eventsAvoid clopidogrel if possible. Consider an alternative P2Y12 inhibitor at standard dose if clinically indicated and no contraindication.ModerateAlternative P2Y12 inhibitors not impacted by CYP2C19 genetic variants include ticagrelor and ticlopidine. Prasugrel is contraindicated in patients with a history of stroke or TIA.e
\n

aNeurovascular disease includes acute ischemic stroke or transient ischemic attack, secondary prevention of stroke, or prevention of thromboembolic events following neurointerventional procedures such as carotid artery stenting and stent-assisted coiling of intracranial aneurysms.\nbRating scheme described in the Supplemental Material.\ncThere are limited data to characterize the function of decreased function alleles.\ndThe strength of recommendation for “likely” phenotypes are the same as their respective confirmed phenotypes. “Likely” indicates the uncertainty in the phenotype assignment, but it is reasonable to apply the recommendation for the confirmed phenotype to the corresponding “likely” phenotype.\neGiven limited outcomes data for genotype-guided anti-platelet therapy for neurovascular indications, selection of therapy should depend on individual patient treatment goals and risks for adverse events.

\n

September 2013 Update

\n\n

The American Society of Health-System Pharmacists (ASHP) has endorsed the Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450-2C19 (CYP2C19) genotype and clopidogrel therapy.

\n

August 2011

\n\n", - "version" : 2 + "version" : 10 }, "userId" : "whaleyr", - "version" : 47 + "version" : 111 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166297566", - "name" : "Recommendation PA166297566", - "alternateDrugAvailable" : false, + "id" : "PA166297571", + "name" : "Recommendation PA166297571", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, "parents" : [], @@ -30459,9 +30467,9 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2C19: Normal or increased clopidogrel active metabolite formation; normal or lower on-treatment platelet reactivity; no association with higher bleeding risk" + "CYP2C19: Significantly reduced clopidogrel active metabolite formation; increased on-treatment platelet reactivity; increased risk for adverse cardiac and cerebrovascular events" ], - "lookupKey" : {"CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "CVI ACS PCI", "relatedChemicals" : [ @@ -30469,27 +30477,27 @@ "objCls" : "Chemical", "id" : "PA449053", "name" : "clopidogrel", - "version" : 20 + "version" : 58 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104948", "name" : "Annotation of CPIC Guideline for clopidogrel and CYP2C19", - "version" : 47 + "version" : 111 }, "text" : { - "id" : 1452060168, - "html" : "

If considering clopidogrel, use at standard dose (75 mg/day)

\n

Other Considerations

\n

For cardiovascular indications of acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI). ACS and/or PCI includes patients undergoing PCI for an ACS or non-ACS (elective) indication.

\n", - "version" : 0 + "id" : 1452060173, + "html" : "

Avoid clopidogrel if possible. Use prasugrel or ticagrelor at standard dose if no contraindication.

\n

Other Considerations

\n

For cardiovascular indications of acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI). ACS and/or PCI includes patients undergoing PCI for an ACS or non-ACS (elective) indication. The strength of recommendation for "likely" phenotypes are the same as their respective confirmed phenotypes. "Likely" indicates the uncertainty in the phenotype assignment, but it is reasonable to apply the recommendation for the confirmed phenotype to the corresponding "likely" phenotype.

\n", + "version" : 1 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297571", - "name" : "Recommendation PA166297571", - "alternateDrugAvailable" : true, + "id" : "PA166297565", + "name" : "Recommendation PA166297565", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, "parents" : [], @@ -30501,9 +30509,9 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2C19: Significantly reduced clopidogrel active metabolite formation; increased on-treatment platelet reactivity; increased risk for adverse cardiac and cerebrovascular events" + "CYP2C19: Increased clopidogrel active metabolite formation; lower on-treatment platelet reactivity; no association with higher bleeding risk" ], - "lookupKey" : {"CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "CVI ACS PCI", "relatedChemicals" : [ @@ -30511,26 +30519,26 @@ "objCls" : "Chemical", "id" : "PA449053", "name" : "clopidogrel", - "version" : 20 + "version" : 58 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104948", "name" : "Annotation of CPIC Guideline for clopidogrel and CYP2C19", - "version" : 47 + "version" : 111 }, "text" : { - "id" : 1452060173, - "html" : "

Avoid clopidogrel if possible. Use prasugrel or ticagrelor at standard dose if no contraindication.

\n

Other Considerations

\n

For cardiovascular indications of acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI). ACS and/or PCI includes patients undergoing PCI for an ACS or non-ACS (elective) indication. The strength of recommendation for "likely" phenotypes are the same as their respective confirmed phenotypes. "Likely" indicates the uncertainty in the phenotype assignment, but it is reasonable to apply the recommendation for the confirmed phenotype to the corresponding "likely" phenotype.

\n", - "version" : 1 + "id" : 1452060167, + "html" : "

If considering clopidogrel, use at standard dose (75 mg/day)

\n

Other Considerations

\n

For cardiovascular indications of acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI). ACS and/or PCI includes patients undergoing PCI for an ACS or non-ACS (elective) indication.

\n", + "version" : 0 }, "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297584", - "name" : "Recommendation PA166297584", + "id" : "PA166297577", + "name" : "Recommendation PA166297577", "alternateDrugAvailable" : false, "classification" : { "id" : 1448526251, @@ -30543,70 +30551,70 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2C19: Increased clopidogrel active metabolite formation; lower on-treatment platelet reactivity" + "CYP2C19: Reduced clopidogrel active metabolite formation; increased on-treatment platelet reactivity; increased risk for adverse cardiac and cerebrovascular events" ], - "lookupKey" : {"CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, - "population" : "NVI", + "population" : "CVI non-ACS non-PCI", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449053", "name" : "clopidogrel", - "version" : 20 + "version" : 58 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104948", "name" : "Annotation of CPIC Guideline for clopidogrel and CYP2C19", - "version" : 47 + "version" : 111 }, "text" : { - "id" : 1452060186, - "html" : "

No recommendation

\n

Other Considerations

\n

For neurovascular indications. Neurovascular disease includes acute ischemic stroke or transient ischemic attack, secondary prevention of stroke, or prevention of thromboembolic events following neurointerventional procedures such as carotid artery stenting and stent-assisted coiling of intracranial aneurysms.

\n", + "id" : 1452060179, + "html" : "

No recommendation

\n

Other Considerations

\n

For non-acute coronary syndrome (non-ACS) and non-percutaneous coronary intervention (non-PCI) cardiovascular indications. Non-ACS, non-PCI cardiovascular indications include peripheral arterial disease and stable coronary artery disease following a recent myocardial infarction outside the setting of PCI. The strength of recommendation for "likely" phenotypes are the same as their respective confirmed phenotypes. "Likely" indicates the uncertainty in the phenotype assignment, but it is reasonable to apply the recommendation for the confirmed phenotype to the corresponding "likely" phenotype.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297575", - "name" : "Recommendation PA166297575", - "alternateDrugAvailable" : false, + "id" : "PA166297587", + "name" : "Recommendation PA166297587", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2C19: Normal or increased clopidogrel active metabolite formation; normal or lower on-treatment platelet reactivity; no association with higher bleeding risk" + "CYP2C19: Reduced clopidogrel active metabolite formation; increased on-treatment platelet reactivity; increased risk for adverse cardiac and cerebrovascular events" ], - "lookupKey" : {"CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, - "population" : "CVI non-ACS non-PCI", + "population" : "NVI", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449053", "name" : "clopidogrel", - "version" : 20 + "version" : 58 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104948", "name" : "Annotation of CPIC Guideline for clopidogrel and CYP2C19", - "version" : 47 + "version" : 111 }, "text" : { - "id" : 1452060177, - "html" : "

No recommendation

\n

Other Considerations

\n

For non-acute coronary syndrome (non-ACS) and non-percutaneous coronary intervention (non-PCI) cardiovascular indications. Non-ACS, non-PCI cardiovascular indications include peripheral arterial disease and stable coronary artery disease following a recent myocardial infarction outside the setting of PCI.

\n", + "id" : 1452060189, + "html" : "

Consider an alternative P2Y12 inhibitor at standard dose if clinically indicated and no contraindication.

\n

Other Considerations

\n

For neurovascular indications. Neurovascular disease includes acute ischemic stroke or transient ischemic attack, secondary prevention of stroke, or prevention of thromboembolic events following neurointerventional procedures such as carotid artery stenting and stent-assisted coiling of intracranial aneurysms. Alternative P2Y12 inhibitors not impacted by CYP2C19 genetic variants include ticagrelor and ticlopidine. Prasugrel is contraindicated in patients with a history of stroke or TIA. Given limited outcomes data for genotype-guided anti-platelet therapy for neurovascular indications, selection of therapy should depend on individual patient treatment goals and risks for adverse events. The strength of recommendation for "likely" phenotypes are the same as their respective confirmed phenotypes. "Likely" indicates the uncertainty in the phenotype assignment, but it is reasonable to apply the recommendation for the confirmed phenotype to the corresponding "likely" phenotype.

\n", "version" : 0 }, "version" : 0 @@ -30637,14 +30645,14 @@ "objCls" : "Chemical", "id" : "PA449053", "name" : "clopidogrel", - "version" : 20 + "version" : 58 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104948", "name" : "Annotation of CPIC Guideline for clopidogrel and CYP2C19", - "version" : 47 + "version" : 111 }, "text" : { "id" : 1452060190, @@ -30653,6 +30661,132 @@ }, "version" : 0 }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166297589", + "name" : "Recommendation PA166297589", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981501931, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : false, + "implications" : [ + "CYP2C19: Significantly reduced clopidogrel active metabolite formation; increased on-treatment platelet reactivity; increased risk for adverse cardiac and cerebrovascular events" + ], + "lookupKey" : {"CYP2C19": "Likely Poor Metabolizer"}, + "otherPrescribingGuidance" : false, + "population" : "NVI", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA449053", + "name" : "clopidogrel", + "version" : 58 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104948", + "name" : "Annotation of CPIC Guideline for clopidogrel and CYP2C19", + "version" : 111 + }, + "text" : { + "id" : 1452060191, + "html" : "

Avoid clopidogrel if possible. Consider an alternative P2Y12 inhibitor at standard dose if clinically indicated and no contraindication.

\n

Other Considerations

\n

For neurovascular indications. Neurovascular disease includes acute ischemic stroke or transient ischemic attack, secondary prevention of stroke, or prevention of thromboembolic events following neurointerventional procedures such as carotid artery stenting and stent-assisted coiling of intracranial aneurysms. Alternative P2Y12 inhibitors not impacted by CYP2C19 genetic variants include ticagrelor and ticlopidine. Prasugrel is contraindicated in patients with a history of stroke or TIA. Given limited outcomes data for genotype-guided anti-platelet therapy for neurovascular indications, selection of therapy should depend on individual patient treatment goals and risks for adverse events. The strength of recommendation for "likely" phenotypes are the same as their respective confirmed phenotypes. "Likely" indicates the uncertainty in the phenotype assignment, but it is reasonable to apply the recommendation for the confirmed phenotype to the corresponding "likely" phenotype.

\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166297590", + "name" : "Recommendation PA166297590", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981501931, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : false, + "implications" : [ + "CYP2C19: Significantly reduced clopidogrel active metabolite formation; increased on-treatment platelet reactivity; increased risk for adverse cardiac and cerebrovascular events" + ], + "lookupKey" : {"CYP2C19": "Poor Metabolizer"}, + "otherPrescribingGuidance" : false, + "population" : "NVI", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA449053", + "name" : "clopidogrel", + "version" : 58 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104948", + "name" : "Annotation of CPIC Guideline for clopidogrel and CYP2C19", + "version" : 111 + }, + "text" : { + "id" : 1452060192, + "html" : "

Avoid clopidogrel if possible. Consider an alternative P2Y12 inhibitor at standard dose if clinically indicated and no contraindication.

\n

Other Considerations

\n

For neurovascular indications. Neurovascular disease includes acute ischemic stroke or transient ischemic attack, secondary prevention of stroke, or prevention of thromboembolic events following neurointerventional procedures such as carotid artery stenting and stent-assisted coiling of intracranial aneurysms. Alternative P2Y12 inhibitors not impacted by CYP2C19 genetic variants include ticagrelor and ticlopidine. Prasugrel is contraindicated in patients with a history of stroke or TIA. Given limited outcomes data for genotype-guided anti-platelet therapy for neurovascular indications, selection of therapy should depend on individual patient treatment goals and risks for adverse events.

\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166297566", + "name" : "Recommendation PA166297566", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501930, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : false, + "implications" : [ + "CYP2C19: Normal or increased clopidogrel active metabolite formation; normal or lower on-treatment platelet reactivity; no association with higher bleeding risk" + ], + "lookupKey" : {"CYP2C19": "Rapid Metabolizer"}, + "otherPrescribingGuidance" : false, + "population" : "CVI ACS PCI", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA449053", + "name" : "clopidogrel", + "version" : 58 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104948", + "name" : "Annotation of CPIC Guideline for clopidogrel and CYP2C19", + "version" : 111 + }, + "text" : { + "id" : 1452060168, + "html" : "

If considering clopidogrel, use at standard dose (75 mg/day)

\n

Other Considerations

\n

For cardiovascular indications of acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI). ACS and/or PCI includes patients undergoing PCI for an ACS or non-ACS (elective) indication.

\n", + "version" : 0 + }, + "version" : 1 + }, { "objCls" : "Recommendation Annotation", "id" : "PA166297567", @@ -30679,68 +30813,26 @@ "objCls" : "Chemical", "id" : "PA449053", "name" : "clopidogrel", - "version" : 20 + "version" : 58 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104948", "name" : "Annotation of CPIC Guideline for clopidogrel and CYP2C19", - "version" : 47 + "version" : 111 }, "text" : { "id" : 1452060169, "html" : "

If considering clopidogrel, use at standard dose (75 mg/day)

\n

Other Considerations

\n

For cardiovascular indications of acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI). ACS and/or PCI includes patients undergoing PCI for an ACS or non-ACS (elective) indication.

\n", "version" : 0 }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166297589", - "name" : "Recommendation PA166297589", - "alternateDrugAvailable" : true, - "classification" : { - "id" : 981501931, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "CYP2C19: Significantly reduced clopidogrel active metabolite formation; increased on-treatment platelet reactivity; increased risk for adverse cardiac and cerebrovascular events" - ], - "lookupKey" : {"CYP2C19": "Likely Poor Metabolizer"}, - "otherPrescribingGuidance" : false, - "population" : "NVI", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA449053", - "name" : "clopidogrel", - "version" : 20 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166104948", - "name" : "Annotation of CPIC Guideline for clopidogrel and CYP2C19", - "version" : 47 - }, - "text" : { - "id" : 1452060191, - "html" : "

Avoid clopidogrel if possible. Consider an alternative P2Y12 inhibitor at standard dose if clinically indicated and no contraindication.

\n

Other Considerations

\n

For neurovascular indications. Neurovascular disease includes acute ischemic stroke or transient ischemic attack, secondary prevention of stroke, or prevention of thromboembolic events following neurointerventional procedures such as carotid artery stenting and stent-assisted coiling of intracranial aneurysms. Alternative P2Y12 inhibitors not impacted by CYP2C19 genetic variants include ticagrelor and ticlopidine. Prasugrel is contraindicated in patients with a history of stroke or TIA. Given limited outcomes data for genotype-guided anti-platelet therapy for neurovascular indications, selection of therapy should depend on individual patient treatment goals and risks for adverse events. The strength of recommendation for "likely" phenotypes are the same as their respective confirmed phenotypes. "Likely" indicates the uncertainty in the phenotype assignment, but it is reasonable to apply the recommendation for the confirmed phenotype to the corresponding "likely" phenotype.

\n", - "version" : 0 - }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297572", - "name" : "Recommendation PA166297572", + "id" : "PA166297569", + "name" : "Recommendation PA166297569", "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, @@ -30753,9 +30845,9 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2C19: Significantly reduced clopidogrel active metabolite formation; increased on-treatment platelet reactivity; increased risk for adverse cardiac and cerebrovascular events" + "CYP2C19: Reduced clopidogrel active metabolite formation; increased on-treatment platelet reactivity; increased risk for adverse cardiac and cerebrovascular events" ], - "lookupKey" : {"CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "CVI ACS PCI", "relatedChemicals" : [ @@ -30763,110 +30855,68 @@ "objCls" : "Chemical", "id" : "PA449053", "name" : "clopidogrel", - "version" : 20 + "version" : 58 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104948", "name" : "Annotation of CPIC Guideline for clopidogrel and CYP2C19", - "version" : 47 + "version" : 111 }, "text" : { - "id" : 1452060174, - "html" : "

Avoid clopidogrel if possible. Use prasugrel or ticagrelor at standard dose if no contraindication.

\n

Other Considerations

\n

For cardiovascular indications of acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI). ACS and/or PCI includes patients undergoing PCI for an ACS or non-ACS (elective) indication.

\n", - "version" : 1 - }, - "version" : 1 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166297581", - "name" : "Recommendation PA166297581", - "alternateDrugAvailable" : true, - "classification" : { - "id" : 981501931, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", - "valid" : true, + "id" : 1452060171, + "html" : "

Avoid standard dose clopidogrel (75 mg) if possible. Use prasugrel or ticagrelor at standard dose if no contraindication.

\n

Other Considerations

\n

For cardiovascular indications of acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI). ACS and/or PCI includes patients undergoing PCI for an ACS or non-ACS (elective) indication. The strength of recommendation for "likely" phenotypes are the same as their respective confirmed phenotypes. "Likely" indicates the uncertainty in the phenotype assignment, but it is reasonable to apply the recommendation for the confirmed phenotype to the corresponding "likely" phenotype.

\n", "version" : 0 }, - "dosingInformation" : false, - "implications" : [ - "CYP2C19: Significantly reduced clopidogrel active metabolite formation; increased on-treatment platelet reactivity; increased risk for adverse cardiac and cerebrovascular events" - ], - "lookupKey" : {"CYP2C19": "Likely Poor Metabolizer"}, - "otherPrescribingGuidance" : false, - "population" : "CVI non-ACS non-PCI", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA449053", - "name" : "clopidogrel", - "version" : 20 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166104948", - "name" : "Annotation of CPIC Guideline for clopidogrel and CYP2C19", - "version" : 47 - }, - "text" : { - "id" : 1452060183, - "html" : "

Avoid clopidogrel if possible. Use prasugrel or ticagrelor at standard dose if no contraindication.

\n

Other Considerations

\n

For non-acute coronary syndrome (non-ACS) and non-percutaneous coronary intervention (non-PCI) cardiovascular indications. Non-ACS, non-PCI cardiovascular indications include peripheral arterial disease and stable coronary artery disease following a recent myocardial infarction outside the setting of PCI. The strength of recommendation for "likely" phenotypes are the same as their respective confirmed phenotypes. "Likely" indicates the uncertainty in the phenotype assignment, but it is reasonable to apply the recommendation for the confirmed phenotype to the corresponding "likely" phenotype.

\n", - "version" : 1 - }, "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297576", - "name" : "Recommendation PA166297576", + "id" : "PA166297573", + "name" : "Recommendation PA166297573", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2C19: Normal clopidogrel active metabolite formation; normal on-treatment platelet reactivity" + "CYP2C19: n/a" ], - "lookupKey" : {"CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, - "population" : "CVI non-ACS non-PCI", + "population" : "CVI ACS PCI", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449053", "name" : "clopidogrel", - "version" : 20 + "version" : 58 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104948", "name" : "Annotation of CPIC Guideline for clopidogrel and CYP2C19", - "version" : 47 + "version" : 111 }, "text" : { - "id" : 1452060178, - "html" : "

If considering clopidogrel, use at standard dose (75 mg/day)

\n

Other Considerations

\n

For non-acute coronary syndrome (non-ACS) and non-percutaneous coronary intervention (non-PCI) cardiovascular indications. Non-ACS, non-PCI cardiovascular indications include peripheral arterial disease and stable coronary artery disease following a recent myocardial infarction outside the setting of PCI.

\n", + "id" : 1452060175, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297585", - "name" : "Recommendation PA166297585", + "id" : "PA166297574", + "name" : "Recommendation PA166297574", "alternateDrugAvailable" : false, "classification" : { "id" : 1448526251, @@ -30879,36 +30929,36 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2C19: Normal or increased clopidogrel active metabolite formation; normal or lower on-treatment platelet reactivity" + "CYP2C19: Increased clopidogrel active metabolite formation; lower on-treatment platelet reactivity; no association with higher bleeding risk" ], - "lookupKey" : {"CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, - "population" : "NVI", + "population" : "CVI non-ACS non-PCI", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449053", "name" : "clopidogrel", - "version" : 20 + "version" : 58 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104948", "name" : "Annotation of CPIC Guideline for clopidogrel and CYP2C19", - "version" : 47 + "version" : 111 }, "text" : { - "id" : 1452060187, - "html" : "

No recommendation

\n

Other Considerations

\n

For neurovascular indications. Neurovascular disease includes acute ischemic stroke or transient ischemic attack, secondary prevention of stroke, or prevention of thromboembolic events following neurointerventional procedures such as carotid artery stenting and stent-assisted coiling of intracranial aneurysms.

\n", + "id" : 1452060176, + "html" : "

No recommendation

\n

Other Considerations

\n

For non-acute coronary syndrome (non-ACS) and non-percutaneous coronary intervention (non-PCI) cardiovascular indications. Non-ACS, non-PCI cardiovascular indications include peripheral arterial disease and stable coronary artery disease following a recent myocardial infarction outside the setting of PCI.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297577", - "name" : "Recommendation PA166297577", + "id" : "PA166297575", + "name" : "Recommendation PA166297575", "alternateDrugAvailable" : false, "classification" : { "id" : 1448526251, @@ -30921,9 +30971,9 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2C19: Reduced clopidogrel active metabolite formation; increased on-treatment platelet reactivity; increased risk for adverse cardiac and cerebrovascular events" + "CYP2C19: Normal or increased clopidogrel active metabolite formation; normal or lower on-treatment platelet reactivity; no association with higher bleeding risk" ], - "lookupKey" : {"CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "CVI non-ACS non-PCI", "relatedChemicals" : [ @@ -30931,83 +30981,83 @@ "objCls" : "Chemical", "id" : "PA449053", "name" : "clopidogrel", - "version" : 20 + "version" : 58 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104948", "name" : "Annotation of CPIC Guideline for clopidogrel and CYP2C19", - "version" : 47 + "version" : 111 }, "text" : { - "id" : 1452060179, - "html" : "

No recommendation

\n

Other Considerations

\n

For non-acute coronary syndrome (non-ACS) and non-percutaneous coronary intervention (non-PCI) cardiovascular indications. Non-ACS, non-PCI cardiovascular indications include peripheral arterial disease and stable coronary artery disease following a recent myocardial infarction outside the setting of PCI. The strength of recommendation for "likely" phenotypes are the same as their respective confirmed phenotypes. "Likely" indicates the uncertainty in the phenotype assignment, but it is reasonable to apply the recommendation for the confirmed phenotype to the corresponding "likely" phenotype.

\n", + "id" : 1452060177, + "html" : "

No recommendation

\n

Other Considerations

\n

For non-acute coronary syndrome (non-ACS) and non-percutaneous coronary intervention (non-PCI) cardiovascular indications. Non-ACS, non-PCI cardiovascular indications include peripheral arterial disease and stable coronary artery disease following a recent myocardial infarction outside the setting of PCI.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297590", - "name" : "Recommendation PA166297590", - "alternateDrugAvailable" : true, + "id" : "PA166297576", + "name" : "Recommendation PA166297576", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2C19: Significantly reduced clopidogrel active metabolite formation; increased on-treatment platelet reactivity; increased risk for adverse cardiac and cerebrovascular events" + "CYP2C19: Normal clopidogrel active metabolite formation; normal on-treatment platelet reactivity" ], - "lookupKey" : {"CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, - "population" : "NVI", + "population" : "CVI non-ACS non-PCI", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449053", "name" : "clopidogrel", - "version" : 20 + "version" : 58 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104948", "name" : "Annotation of CPIC Guideline for clopidogrel and CYP2C19", - "version" : 47 + "version" : 111 }, "text" : { - "id" : 1452060192, - "html" : "

Avoid clopidogrel if possible. Consider an alternative P2Y12 inhibitor at standard dose if clinically indicated and no contraindication.

\n

Other Considerations

\n

For neurovascular indications. Neurovascular disease includes acute ischemic stroke or transient ischemic attack, secondary prevention of stroke, or prevention of thromboembolic events following neurointerventional procedures such as carotid artery stenting and stent-assisted coiling of intracranial aneurysms. Alternative P2Y12 inhibitors not impacted by CYP2C19 genetic variants include ticagrelor and ticlopidine. Prasugrel is contraindicated in patients with a history of stroke or TIA. Given limited outcomes data for genotype-guided anti-platelet therapy for neurovascular indications, selection of therapy should depend on individual patient treatment goals and risks for adverse events.

\n", + "id" : 1452060178, + "html" : "

If considering clopidogrel, use at standard dose (75 mg/day)

\n

Other Considerations

\n

For non-acute coronary syndrome (non-ACS) and non-percutaneous coronary intervention (non-PCI) cardiovascular indications. Non-ACS, non-PCI cardiovascular indications include peripheral arterial disease and stable coronary artery disease following a recent myocardial infarction outside the setting of PCI.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297582", - "name" : "Recommendation PA166297582", - "alternateDrugAvailable" : true, + "id" : "PA166297578", + "name" : "Recommendation PA166297578", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2C19: Significantly reduced clopidogrel active metabolite formation; increased on-treatment platelet reactivity; increased risk for adverse cardiac and cerebrovascular events" + "CYP2C19: Reduced clopidogrel active metabolite formation; increased on-treatment platelet reactivity; increased risk for adverse cardiac and cerebrovascular events" ], - "lookupKey" : {"CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "CVI non-ACS non-PCI", "relatedChemicals" : [ @@ -31015,26 +31065,26 @@ "objCls" : "Chemical", "id" : "PA449053", "name" : "clopidogrel", - "version" : 20 + "version" : 58 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104948", "name" : "Annotation of CPIC Guideline for clopidogrel and CYP2C19", - "version" : 47 + "version" : 111 }, "text" : { - "id" : 1452060184, - "html" : "

Avoid clopidogrel if possible. Use prasugrel or ticagrelor at standard dose if no contraindication.

\n

Other Considerations

\n

For non-acute coronary syndrome (non-ACS) and non-percutaneous coronary intervention (non-PCI) cardiovascular indications. Non-ACS, non-PCI cardiovascular indications include peripheral arterial disease and stable coronary artery disease following a recent myocardial infarction outside the setting of PCI.

\n", - "version" : 1 + "id" : 1452060180, + "html" : "

No recommendation

\n

Other Considerations

\n

For non-acute coronary syndrome (non-ACS) and non-percutaneous coronary intervention (non-PCI) cardiovascular indications. Non-ACS, non-PCI cardiovascular indications include peripheral arterial disease and stable coronary artery disease following a recent myocardial infarction outside the setting of PCI.

\n", + "version" : 0 }, "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297573", - "name" : "Recommendation PA166297573", + "id" : "PA166297583", + "name" : "Recommendation PA166297583", "alternateDrugAvailable" : false, "classification" : { "id" : 1448526251, @@ -31051,47 +31101,47 @@ ], "lookupKey" : {"CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, - "population" : "CVI ACS PCI", + "population" : "CVI non-ACS non-PCI", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449053", "name" : "clopidogrel", - "version" : 20 + "version" : 58 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104948", "name" : "Annotation of CPIC Guideline for clopidogrel and CYP2C19", - "version" : 47 + "version" : 111 }, "text" : { - "id" : 1452060175, + "id" : 1452060185, "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297586", - "name" : "Recommendation PA166297586", + "id" : "PA166297584", + "name" : "Recommendation PA166297584", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2C19: Normal clopidogrel active metabolite formation; normal on-treatment platelet reactivity" + "CYP2C19: Increased clopidogrel active metabolite formation; lower on-treatment platelet reactivity" ], - "lookupKey" : {"CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "NVI", "relatedChemicals" : [ @@ -31099,68 +31149,68 @@ "objCls" : "Chemical", "id" : "PA449053", "name" : "clopidogrel", - "version" : 20 + "version" : 58 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104948", "name" : "Annotation of CPIC Guideline for clopidogrel and CYP2C19", - "version" : 47 + "version" : 111 }, "text" : { - "id" : 1452060188, - "html" : "

If considering clopidogrel, use at standard dose (75 mg/day)

\n

Other Considerations

\n

For neurovascular indications. Neurovascular disease includes acute ischemic stroke or transient ischemic attack, secondary prevention of stroke, or prevention of thromboembolic events following neurointerventional procedures such as carotid artery stenting and stent-assisted coiling of intracranial aneurysms.

\n", + "id" : 1452060186, + "html" : "

No recommendation

\n

Other Considerations

\n

For neurovascular indications. Neurovascular disease includes acute ischemic stroke or transient ischemic attack, secondary prevention of stroke, or prevention of thromboembolic events following neurointerventional procedures such as carotid artery stenting and stent-assisted coiling of intracranial aneurysms.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297569", - "name" : "Recommendation PA166297569", - "alternateDrugAvailable" : true, + "id" : "PA166297585", + "name" : "Recommendation PA166297585", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2C19: Reduced clopidogrel active metabolite formation; increased on-treatment platelet reactivity; increased risk for adverse cardiac and cerebrovascular events" + "CYP2C19: Normal or increased clopidogrel active metabolite formation; normal or lower on-treatment platelet reactivity" ], - "lookupKey" : {"CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, - "population" : "CVI ACS PCI", + "population" : "NVI", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449053", "name" : "clopidogrel", - "version" : 20 + "version" : 58 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104948", "name" : "Annotation of CPIC Guideline for clopidogrel and CYP2C19", - "version" : 47 + "version" : 111 }, "text" : { - "id" : 1452060171, - "html" : "

Avoid standard dose clopidogrel (75 mg) if possible. Use prasugrel or ticagrelor at standard dose if no contraindication.

\n

Other Considerations

\n

For cardiovascular indications of acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI). ACS and/or PCI includes patients undergoing PCI for an ACS or non-ACS (elective) indication. The strength of recommendation for "likely" phenotypes are the same as their respective confirmed phenotypes. "Likely" indicates the uncertainty in the phenotype assignment, but it is reasonable to apply the recommendation for the confirmed phenotype to the corresponding "likely" phenotype.

\n", + "id" : 1452060187, + "html" : "

No recommendation

\n

Other Considerations

\n

For neurovascular indications. Neurovascular disease includes acute ischemic stroke or transient ischemic attack, secondary prevention of stroke, or prevention of thromboembolic events following neurointerventional procedures such as carotid artery stenting and stent-assisted coiling of intracranial aneurysms.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297565", - "name" : "Recommendation PA166297565", + "id" : "PA166297586", + "name" : "Recommendation PA166297586", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -31173,73 +31223,31 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2C19: Increased clopidogrel active metabolite formation; lower on-treatment platelet reactivity; no association with higher bleeding risk" - ], - "lookupKey" : {"CYP2C19": "Ultrarapid Metabolizer"}, - "otherPrescribingGuidance" : false, - "population" : "CVI ACS PCI", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA449053", - "name" : "clopidogrel", - "version" : 20 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166104948", - "name" : "Annotation of CPIC Guideline for clopidogrel and CYP2C19", - "version" : 47 - }, - "text" : { - "id" : 1452060167, - "html" : "

If considering clopidogrel, use at standard dose (75 mg/day)

\n

Other Considerations

\n

For cardiovascular indications of acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI). ACS and/or PCI includes patients undergoing PCI for an ACS or non-ACS (elective) indication.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166297578", - "name" : "Recommendation PA166297578", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 1448526251, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "CYP2C19: Reduced clopidogrel active metabolite formation; increased on-treatment platelet reactivity; increased risk for adverse cardiac and cerebrovascular events" + "CYP2C19: Normal clopidogrel active metabolite formation; normal on-treatment platelet reactivity" ], - "lookupKey" : {"CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, - "population" : "CVI non-ACS non-PCI", + "population" : "NVI", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449053", "name" : "clopidogrel", - "version" : 20 + "version" : 58 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104948", "name" : "Annotation of CPIC Guideline for clopidogrel and CYP2C19", - "version" : 47 + "version" : 111 }, "text" : { - "id" : 1452060180, - "html" : "

No recommendation

\n

Other Considerations

\n

For non-acute coronary syndrome (non-ACS) and non-percutaneous coronary intervention (non-PCI) cardiovascular indications. Non-ACS, non-PCI cardiovascular indications include peripheral arterial disease and stable coronary artery disease following a recent myocardial infarction outside the setting of PCI.

\n", + "id" : 1452060188, + "html" : "

If considering clopidogrel, use at standard dose (75 mg/day)

\n

Other Considerations

\n

For neurovascular indications. Neurovascular disease includes acute ischemic stroke or transient ischemic attack, secondary prevention of stroke, or prevention of thromboembolic events following neurointerventional procedures such as carotid artery stenting and stent-assisted coiling of intracranial aneurysms.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -31267,41 +31275,41 @@ "objCls" : "Chemical", "id" : "PA449053", "name" : "clopidogrel", - "version" : 20 + "version" : 58 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104948", "name" : "Annotation of CPIC Guideline for clopidogrel and CYP2C19", - "version" : 47 + "version" : 111 }, "text" : { "id" : 1452060193, "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297583", - "name" : "Recommendation PA166297583", - "alternateDrugAvailable" : false, + "id" : "PA166297581", + "name" : "Recommendation PA166297581", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2C19: n/a" + "CYP2C19: Significantly reduced clopidogrel active metabolite formation; increased on-treatment platelet reactivity; increased risk for adverse cardiac and cerebrovascular events" ], - "lookupKey" : {"CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "CVI non-ACS non-PCI", "relatedChemicals" : [ @@ -31309,21 +31317,21 @@ "objCls" : "Chemical", "id" : "PA449053", "name" : "clopidogrel", - "version" : 20 + "version" : 58 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104948", "name" : "Annotation of CPIC Guideline for clopidogrel and CYP2C19", - "version" : 47 + "version" : 111 }, "text" : { - "id" : 1452060185, - "html" : "

No recommendation

\n", - "version" : 0 + "id" : 1452060183, + "html" : "

Avoid clopidogrel if possible. Use prasugrel or ticagrelor at standard dose if no contraindication.

\n

Other Considerations

\n

For non-acute coronary syndrome (non-ACS) and non-percutaneous coronary intervention (non-PCI) cardiovascular indications. Non-ACS, non-PCI cardiovascular indications include peripheral arterial disease and stable coronary artery disease following a recent myocardial infarction outside the setting of PCI. The strength of recommendation for "likely" phenotypes are the same as their respective confirmed phenotypes. "Likely" indicates the uncertainty in the phenotype assignment, but it is reasonable to apply the recommendation for the confirmed phenotype to the corresponding "likely" phenotype.

\n", + "version" : 1 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -31351,14 +31359,14 @@ "objCls" : "Chemical", "id" : "PA449053", "name" : "clopidogrel", - "version" : 20 + "version" : 58 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104948", "name" : "Annotation of CPIC Guideline for clopidogrel and CYP2C19", - "version" : 47 + "version" : 111 }, "text" : { "id" : 1452060172, @@ -31369,65 +31377,65 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297587", - "name" : "Recommendation PA166297587", + "id" : "PA166297572", + "name" : "Recommendation PA166297572", "alternateDrugAvailable" : true, "classification" : { - "id" : 981501931, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2C19: Reduced clopidogrel active metabolite formation; increased on-treatment platelet reactivity; increased risk for adverse cardiac and cerebrovascular events" + "CYP2C19: Significantly reduced clopidogrel active metabolite formation; increased on-treatment platelet reactivity; increased risk for adverse cardiac and cerebrovascular events" ], - "lookupKey" : {"CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, - "population" : "NVI", + "population" : "CVI ACS PCI", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449053", "name" : "clopidogrel", - "version" : 20 + "version" : 58 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104948", "name" : "Annotation of CPIC Guideline for clopidogrel and CYP2C19", - "version" : 47 + "version" : 111 }, "text" : { - "id" : 1452060189, - "html" : "

Consider an alternative P2Y12 inhibitor at standard dose if clinically indicated and no contraindication.

\n

Other Considerations

\n

For neurovascular indications. Neurovascular disease includes acute ischemic stroke or transient ischemic attack, secondary prevention of stroke, or prevention of thromboembolic events following neurointerventional procedures such as carotid artery stenting and stent-assisted coiling of intracranial aneurysms. Alternative P2Y12 inhibitors not impacted by CYP2C19 genetic variants include ticagrelor and ticlopidine. Prasugrel is contraindicated in patients with a history of stroke or TIA. Given limited outcomes data for genotype-guided anti-platelet therapy for neurovascular indications, selection of therapy should depend on individual patient treatment goals and risks for adverse events. The strength of recommendation for "likely" phenotypes are the same as their respective confirmed phenotypes. "Likely" indicates the uncertainty in the phenotype assignment, but it is reasonable to apply the recommendation for the confirmed phenotype to the corresponding "likely" phenotype.

\n", - "version" : 0 + "id" : 1452060174, + "html" : "

Avoid clopidogrel if possible. Use prasugrel or ticagrelor at standard dose if no contraindication.

\n

Other Considerations

\n

For cardiovascular indications of acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI). ACS and/or PCI includes patients undergoing PCI for an ACS or non-ACS (elective) indication.

\n", + "version" : 1 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297574", - "name" : "Recommendation PA166297574", - "alternateDrugAvailable" : false, + "id" : "PA166297582", + "name" : "Recommendation PA166297582", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2C19: Increased clopidogrel active metabolite formation; lower on-treatment platelet reactivity; no association with higher bleeding risk" + "CYP2C19: Significantly reduced clopidogrel active metabolite formation; increased on-treatment platelet reactivity; increased risk for adverse cardiac and cerebrovascular events" ], - "lookupKey" : {"CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "CVI non-ACS non-PCI", "relatedChemicals" : [ @@ -31435,21 +31443,21 @@ "objCls" : "Chemical", "id" : "PA449053", "name" : "clopidogrel", - "version" : 20 + "version" : 58 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104948", "name" : "Annotation of CPIC Guideline for clopidogrel and CYP2C19", - "version" : 47 + "version" : 111 }, "text" : { - "id" : 1452060176, - "html" : "

No recommendation

\n

Other Considerations

\n

For non-acute coronary syndrome (non-ACS) and non-percutaneous coronary intervention (non-PCI) cardiovascular indications. Non-ACS, non-PCI cardiovascular indications include peripheral arterial disease and stable coronary artery disease following a recent myocardial infarction outside the setting of PCI.

\n", - "version" : 0 + "id" : 1452060184, + "html" : "

Avoid clopidogrel if possible. Use prasugrel or ticagrelor at standard dose if no contraindication.

\n

Other Considerations

\n

For non-acute coronary syndrome (non-ACS) and non-percutaneous coronary intervention (non-PCI) cardiovascular indications. Non-ACS, non-PCI cardiovascular indications include peripheral arterial disease and stable coronary artery disease following a recent myocardial infarction outside the setting of PCI.

\n", + "version" : 1 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166104948" @@ -31817,7 +31825,7 @@ "pediatricMarkdown" : { "id" : 1451309601, "html" : "

Excerpts from the guideline:

\n\n", - "version" : 0 + "version" : 2 }, "recommendation" : true, "relatedAlleles" : [], @@ -31826,7 +31834,7 @@ "objCls" : "Chemical", "id" : "PA449088", "name" : "codeine", - "version" : 14 + "version" : 48 } ], "relatedGenes" : [ @@ -31835,14 +31843,14 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "CPIC", "summaryMarkdown" : { "id" : 1447982022, "html" : "

Alternate non-tramadol analgesics are recommended for CYP2D6 ultrarapid and poor metabolizers. A label recommended age- or weight-specific dose of codeine is warranted for CYP2D6 normal and intermediate metabolizers.

\n", - "version" : 1 + "version" : 3 }, "terms" : [], "textMarkdown" : { @@ -31851,47 +31859,77 @@ "version" : 1 }, "userId" : "rachel", - "version" : 66 + "version" : 256 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166297557", - "name" : "Recommendation PA166297557", - "alternateDrugAvailable" : true, + "id" : "PA166297593", + "name" : "Recommendation PA166297593", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Increased formation of morphine leading to higher risk of toxicity" + "CYP2D6: Reduced morphine formation" ], - "lookupKey" : {"CYP2D6": "≥3.75"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"CYP2D6": "0.25"}, + "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449088", "name" : "codeine", - "version" : 14 + "version" : 48 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104996", "name" : "Annotation of CPIC Guideline for codeine and CYP2D6", - "version" : 66 + "version" : 256 }, "text" : { - "id" : 1452060159, - "html" : "

Avoid codeine use because of potential for serious toxicity. If opioid use is warranted, consider a non-tramadol opioid.

\n", + "id" : 1452060195, + "html" : "

Use codeine label recommended age- or weight-specific dosing. If no response and opioid use is warranted, consider a non-tramadol opioid.

\n", + "version" : 0 + }, + "version" : 1 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166301321", + "name" : "Recommendation Annotation PA166301321", + "alternateDrugAvailable" : false, + "dosingInformation" : false, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA449088", + "name" : "codeine", + "version" : 48 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104996", + "name" : "Annotation of CPIC Guideline for codeine and CYP2D6", + "version" : 256 + }, + "text" : { + "id" : 1452095640, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", "version" : 0 }, "version" : 0 @@ -31922,57 +31960,69 @@ "objCls" : "Chemical", "id" : "PA449088", "name" : "codeine", - "version" : 14 + "version" : 48 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104996", "name" : "Annotation of CPIC Guideline for codeine and CYP2D6", - "version" : 66 + "version" : 256 }, "text" : { "id" : 1452060194, "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301321", - "name" : "Recommendation Annotation PA166301321", + "id" : "PA166297594", + "name" : "Recommendation PA166297594", "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501931, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", + "valid" : true, + "version" : 0 + }, "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations"}, - "otherPrescribingGuidance" : false, + "implications" : [ + "CYP2D6: Reduced morphine formation" + ], + "lookupKey" : {"CYP2D6": "0.5"}, + "otherPrescribingGuidance" : true, + "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449088", "name" : "codeine", - "version" : 14 + "version" : 48 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104996", "name" : "Annotation of CPIC Guideline for codeine and CYP2D6", - "version" : 66 + "version" : 256 }, "text" : { - "id" : 1452095640, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
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Use codeine label recommended age- or weight-specific dosing. If no response and opioid use is warranted, consider a non-tramadol opioid.

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Avoid codeine use because of possibility of diminished analgesia. If opioid use is warranted, consider a non-tramadol opioid.

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Use codeine label recommended age- or weight-specific dosing.

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Use codeine label recommended age- or weight-specific dosing. If no response and opioid use is warranted, consider a non-tramadol opioid.

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Avoid codeine use because of potential for serious toxicity. If opioid use is warranted, consider a non-tramadol opioid.

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Use codeine label recommended age- or weight-specific dosing.

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Avoid codeine use because of potential for serious toxicity. If opioid use is warranted, consider a non-tramadol opioid.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297607", - "name" : "Recommendation PA166297607", + "id" : "PA166297557", + "name" : "Recommendation PA166297557", "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, @@ -32154,7 +32204,7 @@ "implications" : [ "CYP2D6: Increased formation of morphine leading to higher risk of toxicity" ], - "lookupKey" : {"CYP2D6": "≥3.0"}, + "lookupKey" : {"CYP2D6": "≥3.75"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -32162,26 +32212,26 @@ "objCls" : "Chemical", "id" : "PA449088", "name" : "codeine", - "version" : 14 + "version" : 48 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104996", "name" : "Annotation of CPIC Guideline for codeine and CYP2D6", - "version" : 66 + "version" : 256 }, "text" : { - "id" : 1452060209, + "id" : 1452060159, "html" : "

Avoid codeine use because of potential for serious toxicity. If opioid use is warranted, consider a non-tramadol opioid.

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Avoid codeine use because of potential for serious toxicity. If opioid use is warranted, consider a non-tramadol opioid.

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Avoid codeine use because of possibility of diminished analgesia. If opioid use is warranted, consider a non-tramadol opioid.

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Use codeine label recommended age- or weight-specific dosing. If no response and opioid use is warranted, consider a non-tramadol opioid.

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Avoid codeine use because of potential for serious toxicity. If opioid use is warranted, consider a non-tramadol opioid.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297603", - "name" : "Recommendation PA166297603", + "id" : "PA166297604", + "name" : "Recommendation PA166297604", "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, @@ -32280,7 +32330,7 @@ "implications" : [ "CYP2D6: Increased formation of morphine leading to higher risk of toxicity" ], - "lookupKey" : {"CYP2D6": "2.5"}, + "lookupKey" : {"CYP2D6": "3.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -32288,17 +32338,17 @@ "objCls" : "Chemical", "id" : "PA449088", "name" : "codeine", - "version" : 14 + "version" : 48 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104996", "name" : "Annotation of CPIC Guideline for codeine and CYP2D6", - "version" : 66 + "version" : 256 }, "text" : { - "id" : 1452060205, + "id" : 1452060206, "html" : "

Avoid codeine use because of potential for serious toxicity. If opioid use is warranted, consider a non-tramadol opioid.

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Use codeine label recommended age- or weight-specific dosing.

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Avoid codeine use because of potential for serious toxicity. If opioid use is warranted, consider a non-tramadol opioid.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297568", - "name" : "Recommendation PA166297568", + "id" : "PA166297607", + "name" : "Recommendation PA166297607", "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, @@ -32364,7 +32414,7 @@ "implications" : [ "CYP2D6: Increased formation of morphine leading to higher risk of toxicity" ], - "lookupKey" : {"CYP2D6": "≥6.0"}, + "lookupKey" : {"CYP2D6": "≥3.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -32372,17 +32422,17 @@ "objCls" : "Chemical", "id" : "PA449088", "name" : "codeine", - "version" : 14 + "version" : 48 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104996", "name" : "Annotation of CPIC Guideline for codeine and CYP2D6", - "version" : 66 + "version" : 256 }, "text" : { - "id" : 1452060170, + "id" : 1452060209, "html" : "

Avoid codeine use because of potential for serious toxicity. If opioid use is warranted, consider a non-tramadol opioid.

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Use codeine label recommended age- or weight-specific dosing.

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Avoid codeine use because of potential for serious toxicity. If opioid use is warranted, consider a non-tramadol opioid.

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Use codeine label recommended age- or weight-specific dosing. If no response and opioid use is warranted, consider a non-tramadol opioid.

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Avoid codeine use because of potential for serious toxicity. If opioid use is warranted, consider a non-tramadol opioid.

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Use codeine label recommended age- or weight-specific dosing.

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Use codeine label recommended age- or weight-specific dosing. If no response and opioid use is warranted, consider a non-tramadol opioid.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297604", - "name" : "Recommendation PA166297604", - "alternateDrugAvailable" : true, + "id" : "PA166297597", + "name" : "Recommendation PA166297597", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, "parents" : [], @@ -32572,9 +32622,9 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Increased formation of morphine leading to higher risk of toxicity" + "CYP2D6: Expected morphine formation" ], - "lookupKey" : {"CYP2D6": "3.0"}, + "lookupKey" : {"CYP2D6": "1.25"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -32582,27 +32632,27 @@ "objCls" : "Chemical", "id" : "PA449088", "name" : "codeine", - "version" : 14 + "version" : 48 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104996", "name" : "Annotation of CPIC Guideline for codeine and CYP2D6", - "version" : 66 + "version" : 256 }, "text" : { - "id" : 1452060206, - "html" : "

Avoid codeine use because of potential for serious toxicity. If opioid use is warranted, consider a non-tramadol opioid.

\n", + "id" : 1452060199, + "html" : "

Use codeine label recommended age- or weight-specific dosing.

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Avoid codeine use because of potential for serious toxicity. If opioid use is warranted, consider a non-tramadol opioid.

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Use codeine label recommended age- or weight-specific dosing.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297601", - "name" : "Recommendation PA166297601", + "id" : "PA166297599", + "name" : "Recommendation PA166297599", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -32658,7 +32708,7 @@ "implications" : [ "CYP2D6: Expected morphine formation" ], - "lookupKey" : {"CYP2D6": "2.25"}, + "lookupKey" : {"CYP2D6": "1.75"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -32666,69 +32716,27 @@ "objCls" : "Chemical", "id" : "PA449088", "name" : "codeine", - "version" : 14 + "version" : 48 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104996", "name" : "Annotation of CPIC Guideline for codeine and CYP2D6", - "version" : 66 + "version" : 256 }, "text" : { - "id" : 1452060203, + "id" : 1452060201, "html" : "

Use codeine label recommended age- or weight-specific dosing.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297596", - "name" : "Recommendation PA166297596", + "id" : "PA166297600", + "name" : "Recommendation PA166297600", "alternateDrugAvailable" : false, - "classification" : { - "id" : 981501931, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "CYP2D6: Reduced morphine formation" - ], - "lookupKey" : {"CYP2D6": "1.0"}, - "otherPrescribingGuidance" : true, - "population" : "general", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA449088", - "name" : "codeine", - "version" : 14 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166104996", - "name" : "Annotation of CPIC Guideline for codeine and CYP2D6", - "version" : 66 - }, - "text" : { - "id" : 1452060198, - "html" : "

Use codeine label recommended age- or weight-specific dosing. If no response and opioid use is warranted, consider a non-tramadol opioid.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166297610", - "name" : "Recommendation PA166297610", - "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, "parents" : [], @@ -32740,9 +32748,9 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Increased formation of morphine leading to higher risk of toxicity" + "CYP2D6: Expected morphine formation" ], - "lookupKey" : {"CYP2D6": "≥4.0"}, + "lookupKey" : {"CYP2D6": "2.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -32750,21 +32758,21 @@ "objCls" : "Chemical", "id" : "PA449088", "name" : "codeine", - "version" : 14 + "version" : 48 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104996", "name" : "Annotation of CPIC Guideline for codeine and CYP2D6", - "version" : 66 + "version" : 256 }, "text" : { - "id" : 1452060212, - "html" : "

Avoid codeine use because of potential for serious toxicity. If opioid use is warranted, consider a non-tramadol opioid.

\n", + "id" : 1452060202, + "html" : "

Use codeine label recommended age- or weight-specific dosing.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -32792,21 +32800,21 @@ "objCls" : "Chemical", "id" : "PA449088", "name" : "codeine", - "version" : 14 + "version" : 48 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104996", "name" : "Annotation of CPIC Guideline for codeine and CYP2D6", - "version" : 66 + "version" : 256 }, "text" : { "id" : 1452060207, "html" : "

Avoid codeine use because of potential for serious toxicity. If opioid use is warranted, consider a non-tramadol opioid.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166104996" @@ -33042,37 +33050,37 @@ "objCls" : "Chemical", "id" : "PA449211", "name" : "dapsone", - "version" : 6 + "version" : 24 }, { "objCls" : "Chemical", "id" : "PA450457", "name" : "methylene blue", - "version" : 8 + "version" : 14 }, { "objCls" : "Chemical", "id" : "PA165963961", "name" : "pegloticase", - "version" : 6 + "version" : 11 }, { "objCls" : "Chemical", "id" : "PA10176", "name" : "rasburicase", - "version" : 7 + "version" : 20 }, { "objCls" : "Chemical", "id" : "PA166115580", "name" : "tafenoquine", - "version" : 6 + "version" : 8 }, { "objCls" : "Chemical", "id" : "PA166268821", "name" : "toluidine blue", - "version" : 3 + "version" : 2 } ], "relatedGenes" : [ @@ -33081,44 +33089,44 @@ "id" : "PA28469", "symbol" : "G6PD", "name" : "glucose-6-phosphate dehydrogenase", - "version" : 135 + "version" : 1326 } ], "source" : "CPIC", "summaryMarkdown" : { "id" : 1447982051, "html" : "

High risk drugs should be avoided in G6PD deficient patients with or without chronic non-spherocytic hemolytic anemia (CNSHA). In patients with a G6PD variable or indeterminate phenotype an enzyme activity test should be carried out before initiating drug therapy.

\n

The G6PD gene is located on the X chromosome. Therefore, some patients will only have one copy, whereas others will have two copies. See full guideline for disclaimers, further details and supporting evidence.

\n", - "version" : 1 + "version" : 3 }, "terms" : [], "textMarkdown" : { "id" : 1451433652, "html" : "

This annotation is based on the Expanded CPIC® Guideline for Medication Use in the Context of G6PD Genotype. The CPIC authors evaluated the available evidence for the use of various drugs in patients carrying G6PD variants.

\n

September 2022

\n\n\n

Adapted from Tables 1, 2 and 3 of the guideline

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Predicted PhenotypeGenotypeaExample genotypesbImplicationsTherapeutic RecommendationsClassification of recommendationscConsiderations
NormalA person with one X chromosome carrying a non-deficient (class IV) allele
OR
A person carrying two non-deficient (class IV) alleles		B, Sao Boria, IV
 
B/B, B/Sao Boria, B/A, IV/IV		Low risk of acute hemolytic anemiaNo reason to avoid high risk drugs based on G6PD statusStrongTafenoquine’s safety has been established for a G6PD enzyme activity ≥70% of normal.
DeficientA person with one X chromosome carrying a deficient (class II-III) allele
OR
A person carrying two deficient (class II-III) alleles OR one class I allele and one class II or III allele		A-, Orissa, Kalyan-Kerala, Mediterranean, Canton, Chatham, II, III
 
A-/A-, A-/Orissa, Orissa/ Kalyan-Kerala, Mediterranean/ Mediterranean, Chatham /Mediterranean, Canton/ Viangchan, II/II, II/III, III/III, I/II, I/III		High risk of acute hemolytic anemiaAvoid use of high risk drugsMethylene blue and toluidine bluef: Moderate.
 
All other high risk drugs: Strong
Deficient with CNSHAA person with one X chromosome carrying a deficient (class I) allele
OR
A person carrying two deficient (class I) allelesd		Bangkok, Villeurbanne, I
 
Bangkok/Bangkok, Bangkok/Villeurbanne, I/I		High risk of acute exacerbation of chronic hemolysisAvoid use of high risk drugsStrongAlthough there are no published data in individuals with the G6PD Deficient with CNSHA phenotype, there is a strong rationale to avoid these drugs based on evidence in G6PD Deficient individuals.
VariableeA person carrying one non-deficient (class IV) allele and one deficient (class I-III) alleleB /Bangkok, B/Mediterranean, B/A-, IV/I, IV/II, IV/IIIVariable risk of acute hemolytic anemiaNo reason to avoid low-to-no risk drugs based on G6PD status at standard dosesModerateDue to X-linked mosaicism, individuals with more than one X chromosome (e.g., females, individuals with Klinefelter syndrome) and heterozygous for one non-deficient (class IV) and one deficient (class I–III) allele may display a normal or a deficient phenotype; an enzyme activity test is needed to assign G6PD phenotype in such cases.
 
Tafenoquine’s safety has been established for a G6PD enzyme activity ≥70% of normal.
IndeterminateA person carrying at least one allele with uncertain functionDagua
 
B/Dagua		Unknown risk of acute hemolytic anemiaTo ascertain G6PD status, enzyme activity must be measured. Drug use should be guided per the recommendations based on the activity-based phenotype.Moderate
\n

CNSHA: chronic non-spherocytic hemolytic anemia
\na WHO classifications from [Article:22293322], other details from [Article:4963040]. Class I alleles are extremely rare; the distinction between Class II and III alleles is not clear. Almost all patients will carry class II, III, or IV alleles.
\nb Due to the large number of G6PD alleles, other genotypes may be possible besides those given as examples here; see the G6PD Allele Definition Table for a more comprehensive list of alleles and G6PD Allele Functionality Table for their assigned function (WHO class). Note that some labs use the designation “B allele” to indicate an allele carrying no known class I-III variants. The G6PD Frequency Table can be referenced for the frequency of G6PD alleles across major biogeographical groups.
\nc Rating scheme described in the Strength of Recommendations section in the guideline supplement.
\nd Such genotypes have never been seen and are presumably exceedingly rare.
\ne Due to X-linked mosaicism, persons heterozygous (generally females) for one non-deficient (class IV) and one deficient (class I-III alleles) allele may display a normal or a deficient phenotype. It is therefore difficult to predict the phenotype of these individuals (see Supplement, G6PD Heterozygotes).\nf Strength of evidence for toluidine blue recommendation is based on extrapolation from methylene blue data.

\n

September 2018 Update

\n

The CPIC authors recommend that the G6PD A variant be categorized as IV/normal function (previously II-IV/Deficient-Normal function) based on new evidence supporting function [Article:27040960] and [Article:30206300]. This change has been incorporated into the G6PD allele definition table.

\n

August 2014

\n

Accepted article preview online May 2014, advance online publication 11 June 2014

\n\n\n

Adapted from Table 1 and Table 2 of the 2014 guideline manuscript.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Phenotype (Genotype) aExamples of diplotypes bImplications for phenotypic measuresDosing recommendations for rasburicaseClassification of recommendations c
Normal d. A male carrying a non-deficient (class IV) allele or a female carrying two non-deficient (class IV) alleles.Male: B, Sao Boria. Female: B/B, B/ Sao Boria.Low or reduced risk of hemolytic anemia.No reason to withhold rasburicase based on G6PD status d.Strong
Deficient or Deficient with CNSHA. A male carrying a class I, II or III allele, a female carrying two deficient class I-III alleles.Male: A-, Orissa, Kalyan-Kerala, Mediterranean, Canton, Chatham, Bangkok, Villeurbanne. Female: A-/A-, A-/ Orissa, Orissa/ Kalyan-Kerala, Mediterranean/ Mediterranean, Chatham/Mediterranean, Canton/ Viangchan, Bangkok/ Bangkok, Bangkok/ Villeurbanne.At risk of acute hemolytic anemia.Rasburicase is contraindicated; alternatives include allopurinol e.Strong
Variable d,f. A female carrying one non-deficient (class IV) and one deficient (class I-III variants) allele.B/A-, B/Mediterranean, B/Bangkok.Unknown risk of hemolytic anemia.To ascertain that G6PD status is normal, enzyme activity must be measured; alternatives include allopurinol e.Moderate
\n

a "Class" refers to the WHO classifications from [Article:22293322], other details from [Article:4963040]. Class I variants are extremely rare; the distinction between class II and III variants is not clear; and the "class V" very high activity variant has only been reported in a single case [Article:4963040]. Therefore, almost all patients will carry class II, III, or IV alleles. It should be noted that the class of a variant may have been assigned only by the clinical manifestations of a patient in which the variant was subsequently identified.

\n

(*) Luzzatto, L. & Poggi, V. Glucose-6-Phosphate Dehydrogenase Deficiency In: Nathan and Oski's Hematology of Infancy and Childhood, 7th Edition (ed. Meloni, D., Anderson, A. Authors of the book: Orkin, S.H., Fisher, D.E., Look, A.T., Lux IV, S.E., Ginsburg, D., Nathan, D.G. ) (Saunders, Elsevier., 2009).

\n

b Due to the large number of G6PD variants, many other diplotypes may be possible besides those given as examples here; see Supplemental Table S1 for a more comprehensive list of variant alleles with their assigned WHO class.

\n

c Rating scheme described in Supplement (See Strength of Recommendations material).

\n

d A negative or inconclusive genetic test cannot be assumed to indicate normal G6PD phenotype; an enzyme activity test is needed to assign G6PD phenotype in such cases.

\n

e Allopurinol is associated with severe cutaneous reactions in the rare carriers of the HLA-B*58:01 allele [Article:23232549].

\n

f Due to X-linked mosaicism, females heterozygous for one non-deficient (class IV) and one deficient (class I-III variants) allele may display a normal or a deficient phenotype. It is therefore difficult to predict the phenotype of these individuals (Supplement, G6PD heterozygotes).

\n

Figure 1: Workflow for interpreting G6PD genotype and for assessing need for an enzyme activity test.

\n

Figure 1 from the guideline manuscript.

\n

\"CPIC

\n

*It should be noted that the class of a variant may have been assigned only by the clinical manifestations of a patient in which the variant was subsequently identified [Article:22293322].

\n", - "version" : 3 + "version" : 8 }, "userId" : "whaleyr", - "version" : 47 + "version" : 142 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166298576", - "name" : "Recommendation PA166298576", - "alternateDrugAvailable" : false, + "id" : "PA166298509", + "name" : "Recommendation PA166298509", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "G6PD: Low risk of acute hemolytic anemia" + "G6PD: High risk of acute hemolytic anemia" ], - "lookupKey" : {"G6PD": "Normal"}, + "lookupKey" : {"G6PD": "Deficient"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -33126,27 +33134,27 @@ "objCls" : "Chemical", "id" : "PA166268821", "name" : "toluidine blue", - "version" : 3 + "version" : 2 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166119846", "name" : "Annotation of CPIC Guideline for dapsone, methylene blue, pegloticase, rasburicase, tafenoquine, toluidine blue and G6PD", - "version" : 47 + "version" : 142 }, "text" : { - "id" : 1452061178, - "html" : "

No reason to avoid based on G6PD status

\n

Other Considerations

\n

Toluidine blue classification strength is based on extrapolation from methylene blue data

\n", + "id" : 1452061111, + "html" : "

Avoid use

\n

Other Considerations

\n

Toluidine blue classification strength is based on extrapolation from methylene blue data

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297619", - "name" : "Recommendation PA166297619", - "alternateDrugAvailable" : false, + "id" : "PA166298516", + "name" : "Recommendation PA166298516", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, "parents" : [], @@ -33158,36 +33166,36 @@ }, "dosingInformation" : false, "implications" : [ - "G6PD: Low risk of acute hemolytic anemia" + "G6PD: High risk of acute hemolytic anemia" ], - "lookupKey" : {"G6PD": "Normal"}, + "lookupKey" : {"G6PD": "Deficient"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA10176", - "name" : "rasburicase", - "version" : 7 + "id" : "PA166115580", + "name" : "tafenoquine", + "version" : 8 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166119846", "name" : "Annotation of CPIC Guideline for dapsone, methylene blue, pegloticase, rasburicase, tafenoquine, toluidine blue and G6PD", - "version" : 47 + "version" : 142 }, "text" : { - "id" : 1452060221, - "html" : "

No reason to avoid based on G6PD status

\n", + "id" : 1452061118, + "html" : "

Avoid use

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297579", - "name" : "Recommendation PA166297579", + "id" : "PA166298517", + "name" : "Recommendation PA166298517", "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, @@ -33200,78 +33208,78 @@ }, "dosingInformation" : false, "implications" : [ - "G6PD: High risk of acute hemolytic anemia" + "G6PD: High risk of acute exacerbation of chronic hemolysis" ], - "lookupKey" : {"G6PD": "Deficient"}, + "lookupKey" : {"G6PD": "Deficient with CNSHA"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA449211", - "name" : "dapsone", - "version" : 6 + "id" : "PA166115580", + "name" : "tafenoquine", + "version" : 8 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166119846", "name" : "Annotation of CPIC Guideline for dapsone, methylene blue, pegloticase, rasburicase, tafenoquine, toluidine blue and G6PD", - "version" : 47 + "version" : 142 }, "text" : { - "id" : 1452060181, - "html" : "

Avoid use

\n", + "id" : 1452061119, + "html" : "

Avoid use

\n

Other Considerations

\n

Although there are not published data in individuals with the G6PD Deficient with CNSHA phenotype, there is a strong rationale to avoid these drugs based on evidence in G6PD Deficient individuals.

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To ascertain G6PD status, enzyme activity must be measured. Drug use should be guided per the recommendations based on the activity-based phenotype.

\n", + "id" : 1452061136, + "html" : "

Avoid use

\n

Other Considerations

\n

Although there are not published data in individuals with the G6PD Deficient with CNSHA phenotype, there is a strong rationale to avoid these drugs based on evidence in G6PD Deficient individuals. Toluidine blue classification strength is based on extrapolation from methylene blue data

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297611", - "name" : "Recommendation PA166297611", + "id" : "PA166298515", + "name" : "Recommendation PA166298515", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -33292,92 +33300,92 @@ "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA449211", - "name" : "dapsone", - "version" : 6 + "id" : "PA166115580", + "name" : "tafenoquine", + "version" : 8 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166119846", "name" : "Annotation of CPIC Guideline for dapsone, methylene blue, pegloticase, rasburicase, tafenoquine, toluidine blue and G6PD", - "version" : 47 + "version" : 142 }, "text" : { - "id" : 1452060213, - "html" : "

No reason to avoid based on G6PD status

\n", + "id" : 1452061117, + "html" : "

No reason to avoid based on G6PD status

\n

Other Considerations

\n

Tafenoquine’s safety has been established for a G6PD enzyme activity ≥70% of normal. (Inclusion criteria for clinical trials involving tafenoquine included G6PD activity ≥70%.)

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297615", - "name" : "Recommendation PA166297615", - "alternateDrugAvailable" : true, + "id" : "PA166298518", + "name" : "Recommendation PA166298518", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "G6PD: High risk of acute hemolytic anemia" + "G6PD: Variable risk of acute hemolytic anemia" ], - "lookupKey" : {"G6PD": "Deficient"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"G6PD": "Variable"}, + "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA165963961", - "name" : "pegloticase", - "version" : 6 + "id" : "PA166115580", + "name" : "tafenoquine", + "version" : 8 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166119846", "name" : "Annotation of CPIC Guideline for dapsone, methylene blue, pegloticase, rasburicase, tafenoquine, toluidine blue and G6PD", - "version" : 47 + "version" : 142 }, "text" : { - "id" : 1452060217, - "html" : "

Avoid use

\n", + "id" : 1452061120, + "html" : "

To ascertain G6PD status, enzyme activity must be measured. Drug use should be guided per the recommendations based on the activity-based phenotype.

\n

Other Considerations

\n

Due to X-linked mosaicism, individuals with more than one X chromosome (e.g., females, individuals with Klinefelter syndrome) and heterozygous for one non-deficient (class IV) and one deficient (class I–III) allele may display a normal or a deficient phenotype; an enzyme activity test is needed to assign G6PD phenotype in such cases. Tafenoquine’s safety has been established for a G6PD enzyme activity ≥70% of normal. (Inclusion criteria for clinical trials involving tafenoquine included G6PD activity ≥70%.)

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298241", - "name" : "Recommendation PA166298241", - "alternateDrugAvailable" : true, + "id" : "PA166298519", + "name" : "Recommendation PA166298519", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "G6PD: High risk of acute exacerbation of chronic hemolysis" + "G6PD: Unknown risk of acute hemolytic anemia" ], - "lookupKey" : {"G6PD": "Deficient with CNSHA"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"G6PD": "Indeterminate"}, + "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA450457", - "name" : "methylene blue", + "id" : "PA166115580", + "name" : "tafenoquine", "version" : 8 } ], @@ -33385,62 +33393,104 @@ "objCls" : "Guideline Annotation", "id" : "PA166119846", "name" : "Annotation of CPIC Guideline for dapsone, methylene blue, pegloticase, rasburicase, tafenoquine, toluidine blue and G6PD", - "version" : 47 + "version" : 142 }, "text" : { - "id" : 1452060843, - "html" : "

Avoid use

\n

Other Considerations

\n

Although there are not published data in individuals with the G6PD Deficient with CNSHA phenotype, there is a strong rationale to avoid these drugs based on evidence in G6PD Deficient individuals.

\n", + "id" : 1452061121, + "html" : "

To ascertain G6PD status, enzyme activity must be measured. Drug use should be guided per the recommendations based on the activity-based phenotype.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297620", - "name" : "Recommendation PA166297620", - "alternateDrugAvailable" : true, + "id" : "PA166298543", + "name" : "Recommendation PA166298543", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "G6PD: High risk of acute hemolytic anemia" + "G6PD: Unknown risk of acute hemolytic anemia" ], - "lookupKey" : {"G6PD": "Deficient"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"G6PD": "Indeterminate"}, + "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA10176", - "name" : "rasburicase", - "version" : 7 + "id" : "PA166268821", + "name" : "toluidine blue", + "version" : 2 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166119846", "name" : "Annotation of CPIC Guideline for dapsone, methylene blue, pegloticase, rasburicase, tafenoquine, toluidine blue and G6PD", - "version" : 47 + "version" : 142 }, "text" : { - "id" : 1452060222, - "html" : "

Avoid use

\n", + "id" : 1452061145, + "html" : "

To ascertain G6PD status, enzyme activity must be measured. Drug use should be guided per the recommendations based on the activity-based phenotype.

\n

Other Considerations

\n

Toluidine blue classification strength is based on extrapolation from methylene blue data

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297580", - "name" : "Recommendation PA166297580", - "alternateDrugAvailable" : true, + "id" : "PA166298569", + "name" : "Recommendation PA166298569", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501931, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : false, + "implications" : [ + "G6PD: Variable risk of acute hemolytic anemia" + ], + "lookupKey" : {"G6PD": "Variable"}, + "otherPrescribingGuidance" : true, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA166268821", + "name" : "toluidine blue", + "version" : 2 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166119846", + "name" : "Annotation of CPIC Guideline for dapsone, methylene blue, pegloticase, rasburicase, tafenoquine, toluidine blue and G6PD", + "version" : 142 + }, + "text" : { + "id" : 1452061171, + "html" : "

To ascertain G6PD status, enzyme activity must be measured. Drug use should be guided per the recommendations based on the activity-based phenotype.

\n

Other Considerations

\n

Due to X-linked mosaicism, individuals with more than one X chromosome (e.g., females, individuals with Klinefelter syndrome) and heterozygous for one non-deficient (class IV) and one deficient (class I–III) allele may display a normal or a deficient phenotype; an enzyme activity test is needed to assign G6PD phenotype in such cases. Toluidine blue classification strength is based on extrapolation from methylene blue data

\n", + "version" : 0 + }, + "version" : 1 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166298576", + "name" : "Recommendation PA166298576", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, "parents" : [], @@ -33452,36 +33502,36 @@ }, "dosingInformation" : false, "implications" : [ - "G6PD: High risk of acute eacerbation of chronic hemolysis" + "G6PD: Low risk of acute hemolytic anemia" ], - "lookupKey" : {"G6PD": "Deficient with CNSHA"}, + "lookupKey" : {"G6PD": "Normal"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA449211", - "name" : "dapsone", - "version" : 6 + "id" : "PA166268821", + "name" : "toluidine blue", + "version" : 2 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166119846", "name" : "Annotation of CPIC Guideline for dapsone, methylene blue, pegloticase, rasburicase, tafenoquine, toluidine blue and G6PD", - "version" : 47 + "version" : 142 }, "text" : { - "id" : 1452060182, - "html" : "

Avoid use

\n

Other Considerations

\n

Although there are not published data in individuals with the G6PD Deficient with CNSHA phenotype, there is a strong rationale to avoid these drugs based on evidence in G6PD Deficient individuals.

\n", - "version" : 0 + "id" : 1452061178, + "html" : "

No reason to avoid based on G6PD status

\n

Other Considerations

\n

Toluidine blue classification strength is based on extrapolation from methylene blue data

\n", + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298242", - "name" : "Recommendation PA166298242", + "id" : "PA166297622", + "name" : "Recommendation PA166297622", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -33502,28 +33552,28 @@ "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA450457", - "name" : "methylene blue", - "version" : 8 + "id" : "PA10176", + "name" : "rasburicase", + "version" : 20 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166119846", "name" : "Annotation of CPIC Guideline for dapsone, methylene blue, pegloticase, rasburicase, tafenoquine, toluidine blue and G6PD", - "version" : 47 + "version" : 142 }, "text" : { - "id" : 1452060844, + "id" : 1452060224, "html" : "

To ascertain G6PD status, enzyme activity must be measured. Drug use should be guided per the recommendations based on the activity-based phenotype.

\n

Other Considerations

\n

Due to X-linked mosaicism, individuals with more than one X chromosome (e.g., females, individuals with Klinefelter syndrome) and heterozygous for one non-deficient (class IV) and one deficient (class I–III) allele may display a normal or a deficient phenotype; an enzyme activity test is needed to assign G6PD phenotype in such cases.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298515", - "name" : "Recommendation PA166298515", + "id" : "PA166297619", + "name" : "Recommendation PA166297619", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -33544,70 +33594,70 @@ "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA166115580", - "name" : "tafenoquine", - "version" : 6 + "id" : "PA10176", + "name" : "rasburicase", + "version" : 20 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166119846", "name" : "Annotation of CPIC Guideline for dapsone, methylene blue, pegloticase, rasburicase, tafenoquine, toluidine blue and G6PD", - "version" : 47 + "version" : 142 }, "text" : { - "id" : 1452061117, - "html" : "

No reason to avoid based on G6PD status

\n

Other Considerations

\n

Tafenoquine’s safety has been established for a G6PD enzyme activity ≥70% of normal. (Inclusion criteria for clinical trials involving tafenoquine included G6PD activity ≥70%.)

\n", + "id" : 1452060221, + "html" : "

No reason to avoid based on G6PD status

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297612", - "name" : "Recommendation PA166297612", - "alternateDrugAvailable" : false, + "id" : "PA166297579", + "name" : "Recommendation PA166297579", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501931, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "G6PD: Variable risk of acute hemolytic anemia" + "G6PD: High risk of acute hemolytic anemia" ], - "lookupKey" : {"G6PD": "Variable"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"G6PD": "Deficient"}, + "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449211", "name" : "dapsone", - "version" : 6 + "version" : 24 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166119846", "name" : "Annotation of CPIC Guideline for dapsone, methylene blue, pegloticase, rasburicase, tafenoquine, toluidine blue and G6PD", - "version" : 47 + "version" : 142 }, "text" : { - "id" : 1452060214, - "html" : "

To ascertain G6PD status, enzyme activity must be measured. Drug use should be guided per the recommendations based on the activity-based phenotype.

\n

Other Considerations

\n

Due to X-linked mosaicism, individuals with more than one X chromosome (e.g., females, individuals with Klinefelter syndrome) and heterozygous for one non-deficient (class IV) and one deficient (class I–III) allele may display a normal or a deficient phenotype; an enzyme activity test is needed to assign G6PD phenotype in such cases.

\n", + "id" : 1452060181, + "html" : "

Avoid use

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297616", - "name" : "Recommendation PA166297616", + "id" : "PA166297580", + "name" : "Recommendation PA166297580", "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, @@ -33625,32 +33675,74 @@ "lookupKey" : {"G6PD": "Deficient with CNSHA"}, "otherPrescribingGuidance" : false, "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA449211", + "name" : "dapsone", + "version" : 24 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166119846", + "name" : "Annotation of CPIC Guideline for dapsone, methylene blue, pegloticase, rasburicase, tafenoquine, toluidine blue and G6PD", + "version" : 142 + }, + "text" : { + "id" : 1452060182, + "html" : "

Avoid use

\n

Other Considerations

\n

Although there are not published data in individuals with the G6PD Deficient with CNSHA phenotype, there is a strong rationale to avoid these drugs based on evidence in G6PD Deficient individuals.

\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166297615", + "name" : "Recommendation PA166297615", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981501930, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : false, + "implications" : [ + "G6PD: High risk of acute hemolytic anemia" + ], + "lookupKey" : {"G6PD": "Deficient"}, + "otherPrescribingGuidance" : false, + "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA165963961", "name" : "pegloticase", - "version" : 6 + "version" : 11 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166119846", "name" : "Annotation of CPIC Guideline for dapsone, methylene blue, pegloticase, rasburicase, tafenoquine, toluidine blue and G6PD", - "version" : 47 + "version" : 142 }, "text" : { - "id" : 1452060218, - "html" : "

Avoid use

\n

Other Considerations

\n

Although there are not published data in individuals with the G6PD Deficient with CNSHA phenotype, there is a strong rationale to avoid these drugs based on evidence in G6PD Deficient individuals.

\n", + "id" : 1452060217, + "html" : "

Avoid use

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298239", - "name" : "Recommendation PA166298239", - "alternateDrugAvailable" : false, + "id" : "PA166297616", + "name" : "Recommendation PA166297616", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, "parents" : [], @@ -33662,70 +33754,70 @@ }, "dosingInformation" : false, "implications" : [ - "G6PD: Low risk of acute hemolytic anemia" + "G6PD: High risk of acute eacerbation of chronic hemolysis" ], - "lookupKey" : {"G6PD": "Normal"}, + "lookupKey" : {"G6PD": "Deficient with CNSHA"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA450457", - "name" : "methylene blue", - "version" : 8 + "id" : "PA165963961", + "name" : "pegloticase", + "version" : 11 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166119846", "name" : "Annotation of CPIC Guideline for dapsone, methylene blue, pegloticase, rasburicase, tafenoquine, toluidine blue and G6PD", - "version" : 47 + "version" : 142 }, "text" : { - "id" : 1452060841, - "html" : "

No reason to avoid based on G6PD status

\n", + "id" : 1452060218, + "html" : "

Avoid use

\n

Other Considerations

\n

Although there are not published data in individuals with the G6PD Deficient with CNSHA phenotype, there is a strong rationale to avoid these drugs based on evidence in G6PD Deficient individuals.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298569", - "name" : "Recommendation PA166298569", - "alternateDrugAvailable" : false, + "id" : "PA166297620", + "name" : "Recommendation PA166297620", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501931, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "G6PD: Variable risk of acute hemolytic anemia" + "G6PD: High risk of acute hemolytic anemia" ], - "lookupKey" : {"G6PD": "Variable"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"G6PD": "Deficient"}, + "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA166268821", - "name" : "toluidine blue", - "version" : 3 + "id" : "PA10176", + "name" : "rasburicase", + "version" : 20 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166119846", "name" : "Annotation of CPIC Guideline for dapsone, methylene blue, pegloticase, rasburicase, tafenoquine, toluidine blue and G6PD", - "version" : 47 + "version" : 142 }, "text" : { - "id" : 1452061171, - "html" : "

To ascertain G6PD status, enzyme activity must be measured. Drug use should be guided per the recommendations based on the activity-based phenotype.

\n

Other Considerations

\n

Due to X-linked mosaicism, individuals with more than one X chromosome (e.g., females, individuals with Klinefelter syndrome) and heterozygous for one non-deficient (class IV) and one deficient (class I–III) allele may display a normal or a deficient phenotype; an enzyme activity test is needed to assign G6PD phenotype in such cases. Toluidine blue classification strength is based on extrapolation from methylene blue data

\n", + "id" : 1452060222, + "html" : "

Avoid use

\n", "version" : 0 }, "version" : 0 @@ -33756,14 +33848,14 @@ "objCls" : "Chemical", "id" : "PA10176", "name" : "rasburicase", - "version" : 7 + "version" : 20 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166119846", "name" : "Annotation of CPIC Guideline for dapsone, methylene blue, pegloticase, rasburicase, tafenoquine, toluidine blue and G6PD", - "version" : 47 + "version" : 142 }, "text" : { "id" : 1452060223, @@ -33774,8 +33866,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298543", - "name" : "Recommendation PA166298543", + "id" : "PA166297623", + "name" : "Recommendation PA166297623", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -33796,70 +33888,70 @@ "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA166268821", - "name" : "toluidine blue", - "version" : 3 + "id" : "PA10176", + "name" : "rasburicase", + "version" : 20 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166119846", "name" : "Annotation of CPIC Guideline for dapsone, methylene blue, pegloticase, rasburicase, tafenoquine, toluidine blue and G6PD", - "version" : 47 + "version" : 142 }, "text" : { - "id" : 1452061145, - "html" : "

To ascertain G6PD status, enzyme activity must be measured. Drug use should be guided per the recommendations based on the activity-based phenotype.

\n

Other Considerations

\n

Toluidine blue classification strength is based on extrapolation from methylene blue data

\n", + "id" : 1452060225, + "html" : "

To ascertain G6PD status, enzyme activity must be measured. Drug use should be guided per the recommendations based on the activity-based phenotype.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297613", - "name" : "Recommendation PA166297613", + "id" : "PA166297611", + "name" : "Recommendation PA166297611", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "G6PD: Unknown risk of acute hemolytic anemia" + "G6PD: Low risk of acute hemolytic anemia" ], - "lookupKey" : {"G6PD": "Indeterminate"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"G6PD": "Normal"}, + "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449211", "name" : "dapsone", - "version" : 6 + "version" : 24 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166119846", "name" : "Annotation of CPIC Guideline for dapsone, methylene blue, pegloticase, rasburicase, tafenoquine, toluidine blue and G6PD", - "version" : 47 + "version" : 142 }, "text" : { - "id" : 1452060215, - "html" : "

To ascertain G6PD status, enzyme activity must be measured. Drug use should be guided per the recommendations based on the activity-based phenotype.

\n", + "id" : 1452060213, + "html" : "

No reason to avoid based on G6PD status

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298243", - "name" : "Recommendation PA166298243", + "id" : "PA166297612", + "name" : "Recommendation PA166297612", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -33872,78 +33964,36 @@ }, "dosingInformation" : false, "implications" : [ - "G6PD: Unknown risk of acute hemolytic anemia" + "G6PD: Variable risk of acute hemolytic anemia" ], - "lookupKey" : {"G6PD": "Indeterminate"}, + "lookupKey" : {"G6PD": "Variable"}, "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA450457", - "name" : "methylene blue", - "version" : 8 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166119846", - "name" : "Annotation of CPIC Guideline for dapsone, methylene blue, pegloticase, rasburicase, tafenoquine, toluidine blue and G6PD", - "version" : 47 - }, - "text" : { - "id" : 1452060845, - "html" : "

To ascertain G6PD status, enzyme activity must be measured. Drug use should be guided per the recommendations based on the activity-based phenotype.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166298509", - "name" : "Recommendation PA166298509", - "alternateDrugAvailable" : true, - "classification" : { - "id" : 981501931, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "G6PD: High risk of acute hemolytic anemia" - ], - "lookupKey" : {"G6PD": "Deficient"}, - "otherPrescribingGuidance" : false, - "population" : "general", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA166268821", - "name" : "toluidine blue", - "version" : 3 + "id" : "PA449211", + "name" : "dapsone", + "version" : 24 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166119846", "name" : "Annotation of CPIC Guideline for dapsone, methylene blue, pegloticase, rasburicase, tafenoquine, toluidine blue and G6PD", - "version" : 47 + "version" : 142 }, "text" : { - "id" : 1452061111, - "html" : "

Avoid use

\n

Other Considerations

\n

Toluidine blue classification strength is based on extrapolation from methylene blue data

\n", + "id" : 1452060214, + "html" : "

To ascertain G6PD status, enzyme activity must be measured. Drug use should be guided per the recommendations based on the activity-based phenotype.

\n

Other Considerations

\n

Due to X-linked mosaicism, individuals with more than one X chromosome (e.g., females, individuals with Klinefelter syndrome) and heterozygous for one non-deficient (class IV) and one deficient (class I–III) allele may display a normal or a deficient phenotype; an enzyme activity test is needed to assign G6PD phenotype in such cases.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297622", - "name" : "Recommendation PA166297622", + "id" : "PA166297613", + "name" : "Recommendation PA166297613", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -33956,37 +34006,37 @@ }, "dosingInformation" : false, "implications" : [ - "G6PD: Variable risk of acute hemolytic anemia" + "G6PD: Unknown risk of acute hemolytic anemia" ], - "lookupKey" : {"G6PD": "Variable"}, + "lookupKey" : {"G6PD": "Indeterminate"}, "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA10176", - "name" : "rasburicase", - "version" : 7 + "id" : "PA449211", + "name" : "dapsone", + "version" : 24 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166119846", "name" : "Annotation of CPIC Guideline for dapsone, methylene blue, pegloticase, rasburicase, tafenoquine, toluidine blue and G6PD", - "version" : 47 + "version" : 142 }, "text" : { - "id" : 1452060224, - "html" : "

To ascertain G6PD status, enzyme activity must be measured. Drug use should be guided per the recommendations based on the activity-based phenotype.

\n

Other Considerations

\n

Due to X-linked mosaicism, individuals with more than one X chromosome (e.g., females, individuals with Klinefelter syndrome) and heterozygous for one non-deficient (class IV) and one deficient (class I–III) allele may display a normal or a deficient phenotype; an enzyme activity test is needed to assign G6PD phenotype in such cases.

\n", + "id" : 1452060215, + "html" : "

To ascertain G6PD status, enzyme activity must be measured. Drug use should be guided per the recommendations based on the activity-based phenotype.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298516", - "name" : "Recommendation PA166298516", - "alternateDrugAvailable" : true, + "id" : "PA166297614", + "name" : "Recommendation PA166297614", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, "parents" : [], @@ -33998,31 +34048,31 @@ }, "dosingInformation" : false, "implications" : [ - "G6PD: High risk of acute hemolytic anemia" + "G6PD: Low risk of acute hemolytic anemia" ], - "lookupKey" : {"G6PD": "Deficient"}, + "lookupKey" : {"G6PD": "Normal"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA166115580", - "name" : "tafenoquine", - "version" : 6 + "id" : "PA165963961", + "name" : "pegloticase", + "version" : 11 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166119846", "name" : "Annotation of CPIC Guideline for dapsone, methylene blue, pegloticase, rasburicase, tafenoquine, toluidine blue and G6PD", - "version" : 47 + "version" : 142 }, "text" : { - "id" : 1452061118, - "html" : "

Avoid use

\n", + "id" : 1452060216, + "html" : "

No reason to avoid based on G6PD status

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -34050,69 +34100,69 @@ "objCls" : "Chemical", "id" : "PA165963961", "name" : "pegloticase", - "version" : 6 + "version" : 11 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166119846", "name" : "Annotation of CPIC Guideline for dapsone, methylene blue, pegloticase, rasburicase, tafenoquine, toluidine blue and G6PD", - "version" : 47 + "version" : 142 }, "text" : { "id" : 1452060219, "html" : "

To ascertain G6PD status, enzyme activity must be measured. Drug use should be guided per the recommendations based on the activity-based phenotype.

\n

Other Considerations

\n

Due to X-linked mosaicism, individuals with more than one X chromosome (e.g., females, individuals with Klinefelter syndrome) and heterozygous for one non-deficient (class IV) and one deficient (class I–III) allele may display a normal or a deficient phenotype; an enzyme activity test is needed to assign G6PD phenotype in such cases.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298534", - "name" : "Recommendation PA166298534", - "alternateDrugAvailable" : true, + "id" : "PA166297618", + "name" : "Recommendation PA166297618", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "G6PD: High risk of acute exacerbation of chronic hemolysis" + "G6PD: Unknown risk of acute hemolytic anemia" ], - "lookupKey" : {"G6PD": "Deficient with CNSHA"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"G6PD": "Indeterminate"}, + "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA166268821", - "name" : "toluidine blue", - "version" : 3 + "id" : "PA165963961", + "name" : "pegloticase", + "version" : 11 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166119846", "name" : "Annotation of CPIC Guideline for dapsone, methylene blue, pegloticase, rasburicase, tafenoquine, toluidine blue and G6PD", - "version" : 47 + "version" : 142 }, "text" : { - "id" : 1452061136, - "html" : "

Avoid use

\n

Other Considerations

\n

Although there are not published data in individuals with the G6PD Deficient with CNSHA phenotype, there is a strong rationale to avoid these drugs based on evidence in G6PD Deficient individuals. Toluidine blue classification strength is based on extrapolation from methylene blue data

\n", + "id" : 1452060220, + "html" : "

To ascertain G6PD status, enzyme activity must be measured. Drug use should be guided per the recommendations based on the activity-based phenotype.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298518", - "name" : "Recommendation PA166298518", - "alternateDrugAvailable" : false, + "id" : "PA166298240", + "name" : "Recommendation PA166298240", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501931, "parents" : [], @@ -34124,37 +34174,37 @@ }, "dosingInformation" : false, "implications" : [ - "G6PD: Variable risk of acute hemolytic anemia" + "G6PD: High risk of acute hemolytic anemia" ], - "lookupKey" : {"G6PD": "Variable"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"G6PD": "Deficient"}, + "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA166115580", - "name" : "tafenoquine", - "version" : 6 + "id" : "PA450457", + "name" : "methylene blue", + "version" : 14 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166119846", "name" : "Annotation of CPIC Guideline for dapsone, methylene blue, pegloticase, rasburicase, tafenoquine, toluidine blue and G6PD", - "version" : 47 + "version" : 142 }, "text" : { - "id" : 1452061120, - "html" : "

To ascertain G6PD status, enzyme activity must be measured. Drug use should be guided per the recommendations based on the activity-based phenotype.

\n

Other Considerations

\n

Due to X-linked mosaicism, individuals with more than one X chromosome (e.g., females, individuals with Klinefelter syndrome) and heterozygous for one non-deficient (class IV) and one deficient (class I–III) allele may display a normal or a deficient phenotype; an enzyme activity test is needed to assign G6PD phenotype in such cases. Tafenoquine’s safety has been established for a G6PD enzyme activity ≥70% of normal. (Inclusion criteria for clinical trials involving tafenoquine included G6PD activity ≥70%.)

\n", + "id" : 1452060842, + "html" : "

Avoid use

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297614", - "name" : "Recommendation PA166297614", - "alternateDrugAvailable" : false, + "id" : "PA166298241", + "name" : "Recommendation PA166298241", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, "parents" : [], @@ -34166,36 +34216,36 @@ }, "dosingInformation" : false, "implications" : [ - "G6PD: Low risk of acute hemolytic anemia" + "G6PD: High risk of acute exacerbation of chronic hemolysis" ], - "lookupKey" : {"G6PD": "Normal"}, + "lookupKey" : {"G6PD": "Deficient with CNSHA"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA165963961", - "name" : "pegloticase", - "version" : 6 + "id" : "PA450457", + "name" : "methylene blue", + "version" : 14 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166119846", "name" : "Annotation of CPIC Guideline for dapsone, methylene blue, pegloticase, rasburicase, tafenoquine, toluidine blue and G6PD", - "version" : 47 + "version" : 142 }, "text" : { - "id" : 1452060216, - "html" : "

No reason to avoid based on G6PD status

\n", + "id" : 1452060843, + "html" : "

Avoid use

\n

Other Considerations

\n

Although there are not published data in individuals with the G6PD Deficient with CNSHA phenotype, there is a strong rationale to avoid these drugs based on evidence in G6PD Deficient individuals.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297623", - "name" : "Recommendation PA166297623", + "id" : "PA166298242", + "name" : "Recommendation PA166298242", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -34208,78 +34258,36 @@ }, "dosingInformation" : false, "implications" : [ - "G6PD: Unknown risk of acute hemolytic anemia" + "G6PD: Variable risk of acute hemolytic anemia" ], - "lookupKey" : {"G6PD": "Indeterminate"}, + "lookupKey" : {"G6PD": "Variable"}, "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA10176", - "name" : "rasburicase", - "version" : 7 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166119846", - "name" : "Annotation of CPIC Guideline for dapsone, methylene blue, pegloticase, rasburicase, tafenoquine, toluidine blue and G6PD", - "version" : 47 - }, - "text" : { - "id" : 1452060225, - "html" : "

To ascertain G6PD status, enzyme activity must be measured. Drug use should be guided per the recommendations based on the activity-based phenotype.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166298517", - "name" : "Recommendation PA166298517", - "alternateDrugAvailable" : true, - "classification" : { - "id" : 981501930, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "G6PD: High risk of acute exacerbation of chronic hemolysis" - ], - "lookupKey" : {"G6PD": "Deficient with CNSHA"}, - "otherPrescribingGuidance" : false, - "population" : "general", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA166115580", - "name" : "tafenoquine", - "version" : 6 + "id" : "PA450457", + "name" : "methylene blue", + "version" : 14 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166119846", "name" : "Annotation of CPIC Guideline for dapsone, methylene blue, pegloticase, rasburicase, tafenoquine, toluidine blue and G6PD", - "version" : 47 + "version" : 142 }, "text" : { - "id" : 1452061119, - "html" : "

Avoid use

\n

Other Considerations

\n

Although there are not published data in individuals with the G6PD Deficient with CNSHA phenotype, there is a strong rationale to avoid these drugs based on evidence in G6PD Deficient individuals.

\n", + "id" : 1452060844, + "html" : "

To ascertain G6PD status, enzyme activity must be measured. Drug use should be guided per the recommendations based on the activity-based phenotype.

\n

Other Considerations

\n

Due to X-linked mosaicism, individuals with more than one X chromosome (e.g., females, individuals with Klinefelter syndrome) and heterozygous for one non-deficient (class IV) and one deficient (class I–III) allele may display a normal or a deficient phenotype; an enzyme activity test is needed to assign G6PD phenotype in such cases.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297618", - "name" : "Recommendation PA166297618", + "id" : "PA166298243", + "name" : "Recommendation PA166298243", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -34300,43 +34308,43 @@ "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA165963961", - "name" : "pegloticase", - "version" : 6 + "id" : "PA450457", + "name" : "methylene blue", + "version" : 14 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166119846", "name" : "Annotation of CPIC Guideline for dapsone, methylene blue, pegloticase, rasburicase, tafenoquine, toluidine blue and G6PD", - "version" : 47 + "version" : 142 }, "text" : { - "id" : 1452060220, + "id" : 1452060845, "html" : "

To ascertain G6PD status, enzyme activity must be measured. Drug use should be guided per the recommendations based on the activity-based phenotype.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298240", - "name" : "Recommendation PA166298240", - "alternateDrugAvailable" : true, + "id" : "PA166298239", + "name" : "Recommendation PA166298239", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "G6PD: High risk of acute hemolytic anemia" + "G6PD: Low risk of acute hemolytic anemia" ], - "lookupKey" : {"G6PD": "Deficient"}, + "lookupKey" : {"G6PD": "Normal"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -34344,21 +34352,21 @@ "objCls" : "Chemical", "id" : "PA450457", "name" : "methylene blue", - "version" : 8 + "version" : 14 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166119846", "name" : "Annotation of CPIC Guideline for dapsone, methylene blue, pegloticase, rasburicase, tafenoquine, toluidine blue and G6PD", - "version" : 47 + "version" : 142 }, "text" : { - "id" : 1452060842, - "html" : "

Avoid use

\n", - "version" : 0 + "id" : 1452060841, + "html" : "

No reason to avoid based on G6PD status

\n", + "version" : 1 }, - "version" : 0 + "version" : 2 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166119846" @@ -34496,56 +34504,56 @@ "id" : "PA166155524", "symbol" : "rs111888148", "name" : "rs111888148", - "version" : 5 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166155526", "symbol" : "rs112563513", "name" : "rs112563513", - "version" : 5 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166155528", "symbol" : "rs118192116", "name" : "rs118192116", - "version" : 5 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166155529", "symbol" : "rs118192122", "name" : "rs118192122", - "version" : 5 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166155531", "symbol" : "rs118192124", "name" : "rs118192124", - "version" : 5 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166155532", "symbol" : "rs118192161", "name" : "rs118192161", - "version" : 5 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166155533", "symbol" : "rs118192162", "name" : "rs118192162", - "version" : 5 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166155534", "symbol" : "rs118192163", "name" : "rs118192163", - "version" : 5 + "version" : 3 }, { "objCls" : "Variant", @@ -34566,35 +34574,35 @@ "id" : "PA166155536", "symbol" : "rs118192170", "name" : "rs118192170", - "version" : 4 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166155537", "symbol" : "rs118192172", "name" : "rs118192172", - "version" : 5 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166155538", "symbol" : "rs118192175", "name" : "rs118192175", - "version" : 5 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166155539", "symbol" : "rs118192176", "name" : "rs118192176", - "version" : 5 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166155540", "symbol" : "rs118192177", "name" : "rs118192177", - "version" : 5 + "version" : 3 }, { "objCls" : "Variant", @@ -34608,21 +34616,21 @@ "id" : "PA166155543", "symbol" : "rs121918592", "name" : "rs121918592", - "version" : 5 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166155544", "symbol" : "rs121918593", "name" : "rs121918593", - "version" : 5 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166155545", "symbol" : "rs121918594", "name" : "rs121918594", - "version" : 5 + "version" : 3 }, { "objCls" : "Variant", @@ -34643,7 +34651,7 @@ "id" : "PA166180325", "symbol" : "rs144336148", "name" : "rs144336148", - "version" : 5 + "version" : 3 }, { "objCls" : "Variant", @@ -34657,28 +34665,28 @@ "id" : "PA166155375", "symbol" : "rs1801086", "name" : "rs1801086", - "version" : 6 + "version" : 4 }, { "objCls" : "Variant", "id" : "PA166155564", "symbol" : "rs193922747", "name" : "rs193922747", - "version" : 5 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166180322", "symbol" : "rs193922748", "name" : "rs193922748", - "version" : 5 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166155565", "symbol" : "rs193922753", "name" : "rs193922753", - "version" : 5 + "version" : 3 }, { "objCls" : "Variant", @@ -34692,112 +34700,112 @@ "id" : "PA166176176", "symbol" : "rs193922764", "name" : "rs193922764", - "version" : 5 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166180324", "symbol" : "rs193922768", "name" : "rs193922768", - "version" : 5 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166155567", "symbol" : "rs193922770", "name" : "rs193922770", - "version" : 5 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166155568", "symbol" : "rs193922772", "name" : "rs193922772", - "version" : 5 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166155569", "symbol" : "rs193922802", "name" : "rs193922802", - "version" : 5 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166155570", "symbol" : "rs193922803", "name" : "rs193922803", - "version" : 6 + "version" : 4 }, { "objCls" : "Variant", "id" : "PA166155571", "symbol" : "rs193922807", "name" : "rs193922807", - "version" : 4 + "version" : 2 }, { "objCls" : "Variant", "id" : "PA166155572", "symbol" : "rs193922809", "name" : "rs193922809", - "version" : 5 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166155573", "symbol" : "rs193922816", "name" : "rs193922816", - "version" : 5 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166155574", "symbol" : "rs193922818", "name" : "rs193922818", - "version" : 5 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166163667", "symbol" : "rs193922832", "name" : "rs193922832", - "version" : 5 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166163663", "symbol" : "rs193922843", "name" : "rs193922843", - "version" : 4 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166155575", "symbol" : "rs193922876", "name" : "rs193922876", - "version" : 4 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166155576", "symbol" : "rs193922878", "name" : "rs193922878", - "version" : 4 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166155481", "symbol" : "rs28933396", "name" : "rs28933396", - "version" : 5 + "version" : 3 }, { "objCls" : "Variant", "id" : "PA166155482", "symbol" : "rs28933397", "name" : "rs28933397", - "version" : 5 + "version" : 3 }, { "objCls" : "Variant", @@ -34811,7 +34819,7 @@ "id" : "PA166153940", "symbol" : "rs772226819", "name" : "rs772226819", - "version" : 5 + "version" : 3 } ], "relatedChemicals" : [ @@ -34819,43 +34827,43 @@ "objCls" : "Chemical", "id" : "PA164749136", "name" : "desflurane", - "version" : 8 + "version" : 32 }, { "objCls" : "Chemical", "id" : "PA449461", "name" : "enflurane", - "version" : 11 + "version" : 41 }, { "objCls" : "Chemical", "id" : "PA449845", "name" : "halothane", - "version" : 18 + "version" : 66 }, { "objCls" : "Chemical", "id" : "PA450106", "name" : "isoflurane", - "version" : 7 + "version" : 33 }, { "objCls" : "Chemical", "id" : "PA450434", "name" : "methoxyflurane", - "version" : 8 + "version" : 34 }, { "objCls" : "Chemical", "id" : "PA451341", "name" : "sevoflurane", - "version" : 9 + "version" : 34 }, { "objCls" : "Chemical", "id" : "PA451522", "name" : "succinylcholine", - "version" : 7 + "version" : 26 } ], "relatedGenes" : [ @@ -34864,14 +34872,14 @@ "id" : "PA85", "symbol" : "CACNA1S", "name" : "calcium voltage-gated channel subunit alpha1 S", - "version" : 19 + "version" : 59 }, { "objCls" : "Gene", "id" : "PA34896", "symbol" : "RYR1", "name" : "ryanodine receptor 1", - "version" : 131 + "version" : 7467 } ], "source" : "CPIC", @@ -34884,59 +34892,17 @@ "textMarkdown" : { "id" : 1452116501, "html" : "

This annotation is based on the CPIC® guideline for potent volatile anesthetic agents and succinylcholine and RYR1 and CACNA1S.

\n

December 2023 update

\n

Subsequent to the publication of the CPIC guideline for RYR1 and malignant hyperthermia [Article:30499100], the ClinGen variant curation expert panel (VCEP) developed and published recommendations for RYR1 pathogenicity classifications in malignant hyperthermia susceptibility [Article:35849058]. CPIC has added an additional 291 variants and updated the allele definition, frequency, and functionality tables accordingly (additional details can be found in the notes tab of the RYR1 allele functionality table, see Gene-specific Information Tables for RYR1). Additionally, CPIC has created RYR1 and CACNA1S diplotype to phenotype tables. See the notes tab in the supporting files and the PharmGKB blogpost for mappings from pathogenicity terms to CPIC terms, and details of diplotypes in the case of >2 RYR1 variants found.

\n

July 2023 update

\n

As part of the Malignant Hyperthermia Susceptibility VCEP two-year variant review, c.1589G>A (R530H) is now classified as Likely Pathogenic and c.14582G>A (R4861H) is now classified as VUS. Based on this classification, the assignment for the variant c.1589G>A has been changed from "uncertain function" to “malignant hyperthermia-associated” and for the variant c.14582G>A from “malignant hyperthermia-associated” to “uncertain function” in the RYR1 allele functionality table. Additional variants beyond these 44 have been identified by the VCEP and the current CPIC authors are reviewing these variants for inclusion in the CPIC tables.

\n

November 2021 update

\n

Subsequent to the publication of the CPIC guideline for RYR1 and malignant hyperthermia [Article:30499100], the ClinGen variant curation expert panel (VCEP) developed and published recommendations for RYR1 pathogenicity classifications in malignant hyperthermia susceptibility. These revised ACMG/AMP criteria were applied to the 44 variants originally included in the CPIC recommendations and 29 variants were classified as pathogenic, 13 as likely pathogenic, and 2 as variants of uncertain significance [Article:33767344]. Based on this classification, the assignment for the variants c.1589G>A p.(Arg530His) and c.1598G>A p.(Arg533His) has been changed from “malignant hyperthermia-associated” to “uncertain function” in the RYR1 allele functionality table. Additional variants beyond these 44 have been identified by the VCEP and the current CPIC authors are reviewing these variants for inclusion in the CPIC tables.

\n

September 2019 update

\n

The published version of this article included a typographical error in Table 1 and in the supplemental tables: RYR1 c.488G>A should instead be listed as RYR1 c.488G>T. The Table 1 in guideline, RYR1 allele definition table, RYR1 allele functionality table, and RYR1 frequency table have been updated accordingly.

\n

November 2018

\n

Advance online publication November 2018

\n\n

Table 1: Recommendations for inhaled anesthetics or succinylcholine in the context of RYR1 or CACNA1S genotypes.

\n

Adapted from Tables 1 and 2 of the 2018 guideline manuscript.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
RYR1 or CACNA1S phenotypeGenotypeExample VariantsImplications for phenotypic measuresDosing recommendations for inhaled anesthetics or succinylcholineClassification of recommendationsa
Malignant Hyperthermia susceptibleAn individual heterozygousb for a RYR1 or CACNA1S malignant hyperthermia causative variant as designated by the EMHG c,d,eRYR1 c.103T>C; p.(Cys35Arg), RYR1 c.130C>T; p.(Arg44Cys), RYR1 c.487C>T; p.(Arg163Cys), RYR1 c.488G>T; p.(Arg163Leu), RYR1 c.742G>A/C; p.(Gly248Arg), RYR1 c.982C>T; p.(Arg328Trp), RYR1 c.1021G>C ; p.(Gly341Arg), RYR1 c.1021G>A; p.(Gly341Arg), RYR1 c.1201C>T; p.(Arg401Cys), RYR1 c.1209C>G; p.(Ile403Met), RYR1 c.1565A>C; p.(Try522Ser), RYR1 c.1597C>T; p.(Arg533Cys), RYR1 c.1654C>T; p.(Arg552Trp), RYR1 c.1840C>T; p.(Arg614Cys), RYR1 c.1841G>T; p.(Arg614Leu), RYR1 c.6487C>T; p.(Arg2163Cys), RYR1 c.6488G>A; p.(Arg2163His), RYR1 c.6502G>A; p.(Val2168Met), RYR1 c.6617C>G; p.(Thr2206Arg), RYR1 c.6617C>T; p.(Thr2206Met), RYR1 c.7007G>A; p.(Arg2336His), RYR1 c.7039_7041delGAG/RYR1 c.7042_7044delGAG; p.(Glu2348del), RYR1 c.7048G>A; p.(Ala2350Thr), RYR1 c.7063C>T; p.(Arg2355Trp), RYR1 c.7124G>C; p.(Gly2375Ala), RYR1 c.7282G>A; p.(Ala2428Thr), RYR1 c.7300G>A; p.(Gly2434Arg), RYR1 c.7304G>A; p.(Arg2435His), RYR1 c.7354C>T; p.(Arg2452Trp), RYR1 c.7360C>T; p.(Arg2454Cys), RYR1 c.7361G>A; p.(Arg2454His), RYR1 c.7372C>T; p.(Arg2458Cys), RYR1 c.7373G>A; p.(Arg2458His), RYR1 c.7522C>G; p.(Arg2508Gly), RYR1 c.7522C>T; p.(Arg2508Cys), RYR1 c.7523G>A; p.(Arg2508His), RYR1 c.9310G>A; p.(Glu3104Lys), RYR1 c.11969G>T; p.(Gly3990Val), RYR1 c.14387A>G; p.(Try4796Cys), RYR1 c.14477C>T; p.(Thr4826Ile), RYR1 c.14497C>T; p.(His4833Tyr), RYR1 c.14512C>G; p.(Leu4838Val), RYR1 c.14545G>A; p.(Val4849Ile), RYR1 c.14582G>A; p.(Arg4861His), RYR1 c.14693T>C; p.(Ile4898Thr), CACNA1S c.520C>T; p.(Arg174Trp), CACNA1S c3257G>A; p. (Arg1086His)Individuals are at increased risk of developing malignant hyperthermia if administered halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine fHalogenated volatile anesthetics or depolarizing muscle relaxants succinylcholine are relatively contraindicated in persons with MHS. They should not be used, except in extraordinary circumstances where the benefits outweigh the risks. In general, alternative anesthetics are widely available and effective in patients with MHS.Strong
Uncertain susceptibilityAn individual negative for a RYR1 or CACNA1S malignant hyperthermia causative variant as designated by the European Malignant Hyperthermia Group (EMHG) c,d,eThese results do not eliminate the chance that this patient is susceptible to Malignant Hyperthermia. The genetic cause of about half of all MH survivors, with MH susceptibility confirmed by contracture test, remains unknown [Article:28902675].Clinical findings, family history, further genetic testing and other laboratory data should guide use of halogenated volatile anesthetics or depolarizing muscle relaxants.Strong
\n

a Rating scheme described in Supplement.
\nb Individuals who have biallelic (homozygous or compound heterozygous) pathogenic variants in RYR1 generally will have autosomal recessive myopathies and should be managed according to the standard of care for those disorders. While some may indeed have susceptibility to anesthetic agents, the recommendations described here cannot adequately address such patients and they should be managed by a physician who is knowledgeable regarding those disorders.
\nc European Malignant Hyperthermia Group https://www.emhg.org/diagnostic-mutations (accessed September 8, 2018)
\nd A negative or inconclusive genetic test cannot be assumed to indicate normal RYR1-related phenotype and should be interpreted in context of clinical findings, family history and other laboratory data.
\ne It is recognized that clinical laboratories and treating physicians can make a determination that a variant not evaluated by EMHG is pathogenic.
\nf A list of unsafe halogenated volatile anesthetics or depolarizing muscle relaxants and alternative anesthetics can be found at http://www.mhaus.org/healthcare-professionals/be-prepared/safe-and-unsafe-anesthetics.

\n", - "version" : 2 + "version" : 6 }, "userId" : "whaleyr", - "version" : 2 + "version" : 13 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166323362", - "name" : "Recommendation Annotation PA166323362", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 981501930, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "RYR1: These results do not eliminate the chance that this patient is susceptible to malignant hyperthermia (MH). The genetic cause of about half of all MH survivors, with MH susceptibility confirmed by contracture test, remains unknown (PMID 28902675)." - ], - "lookupKey" : {"RYR1": "Uncertain Susceptibility", "CACNA1S": "No Result"}, - "otherPrescribingGuidance" : true, - "population" : "general", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA164749136", - "name" : "desflurane", - "version" : 8 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166303941", - "name" : "Annotation of CPIC Guideline for desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, succinylcholine and CACNA1S, RYR1", - "version" : 2 - }, - "text" : { - "id" : 1452326461, - "html" : "

No CACNA1S genotype is available. Based on RYR1 status, clinical findings, family history, further genetic testing and other laboratory data should guide use of halogenated volatile anesthetics or depolarizing muscle relaxants.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166323401", - "name" : "Recommendation Annotation PA166323401", - "alternateDrugAvailable" : false, + "id" : "PA166323301", + "name" : "Recommendation Annotation PA166323301", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, "parents" : [], @@ -34948,9 +34914,9 @@ }, "dosingInformation" : false, "implications" : [ - "CACNA1S: These results do not eliminate the chance that this patient is susceptible to malignant hyperthermia (MH). The genetic cause of about half of all MH survivors, with MH susceptibility confirmed by contracture test, remains unknown (PMID 28902675)." + "Individuals are at increased risk of developing malignant hyperthermia if administered halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine" ], - "lookupKey" : {"RYR1": "No Result", "CACNA1S": "Uncertain Susceptibility"}, + "lookupKey" : {"RYR1": "Malignant Hyperthermia Susceptibility", "CACNA1S": "Malignant Hyperthermia Susceptibility"}, "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ @@ -34958,27 +34924,27 @@ "objCls" : "Chemical", "id" : "PA164749136", "name" : "desflurane", - "version" : 8 + "version" : 32 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166303941", "name" : "Annotation of CPIC Guideline for desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, succinylcholine and CACNA1S, RYR1", - "version" : 2 + "version" : 13 }, "text" : { - "id" : 1452326500, - "html" : "

No RYR1 genotype is available. Based on CACNA1S status, clinical findings, family history, further genetic testing and other laboratory data should guide use of halogenated volatile anesthetics or depolarizing muscle relaxants.

\n", + "id" : 1452326400, + "html" : "

Halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine are relatively contraindicated in persons with malignant hyperthermia susceptibility (MHS). They should not be used, except in extraordinary circumstances where the benefits outweigh the risks. In general, alternative anesthetics are widely available and effective in patients with MHS.

\n

A list of unsafe halogenated volatile anesthetics or depolarizing muscle relaxants and alternative anesthetics can be found at http://www.mhaus.org/healthcare-professionals/be-prepared/safe-and-unsafe-anesthetics. Individuals who have biallelic (homozygous or compound heterozygous) pathogenic variants in RYR1 or CACNA1S generally will have autosomal recessive myopathies and should be managed according to the standard of care for those disorders. Although some may, indeed, have susceptibility to anesthetic agents, the recommendations described here cannot adequately address such patients, and they should be managed by a physician who is knowledgeable regarding those disorders.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166323421", - "name" : "Recommendation Annotation PA166323421", - "alternateDrugAvailable" : false, + "id" : "PA166323321", + "name" : "Recommendation Annotation PA166323321", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, "parents" : [], @@ -34990,9 +34956,9 @@ }, "dosingInformation" : false, "implications" : [ - "These results do not eliminate the chance that this patient is susceptible to malignant hyperthermia (MH). The genetic cause of about half of all MH survivors, with MH susceptibility confirmed by contracture test, remains unknown (PMID 28902675)." + "CACNA1S: Individuals are at increased risk of developing malignant hyperthermia if administered halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine" ], - "lookupKey" : {"RYR1": "Uncertain Susceptibility", "CACNA1S": "Uncertain Susceptibility"}, + "lookupKey" : {"RYR1": "No Result", "CACNA1S": "Malignant Hyperthermia Susceptibility"}, "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ @@ -35000,26 +34966,26 @@ "objCls" : "Chemical", "id" : "PA164749136", "name" : "desflurane", - "version" : 8 + "version" : 32 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166303941", "name" : "Annotation of CPIC Guideline for desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, succinylcholine and CACNA1S, RYR1", - "version" : 2 + "version" : 13 }, "text" : { - "id" : 1452326520, - "html" : "

Clinical findings, family history, further genetic testing and other laboratory data should guide use of halogenated volatile anesthetics or depolarizing muscle relaxants.

\n", + "id" : 1452326420, + "html" : "

Based on CACNA1S status, halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine are relatively contraindicated in persons with malignant hyperthermia susceptibility (MHS). They should not be used, except in extraordinary circumstances where the benefits outweigh the risks. In general, alternative anesthetics are widely available and effective in patients with MHS.

\n

A list of unsafe halogenated volatile anesthetics or depolarizing muscle relaxants and alternative anesthetics can be found at http://www.mhaus.org/healthcare-professionals/be-prepared/safe-and-unsafe-anesthetics. Individuals who have biallelic (homozygous or compound heterozygous) pathogenic variants in CACNA1S generally will have autosomal recessive myopathies and should be managed according to the standard of care for those disorders. Although some may, indeed, have susceptibility to anesthetic agents, the recommendations described here cannot adequately address such patients, and they should be managed by a physician who is knowledgeable regarding those disorders.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166323321", - "name" : "Recommendation Annotation PA166323321", + "id" : "PA166323341", + "name" : "Recommendation Annotation PA166323341", "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, @@ -35032,9 +34998,9 @@ }, "dosingInformation" : false, "implications" : [ - "CACNA1S: Individuals are at increased risk of developing malignant hyperthermia if administered halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine" + "RYR1: These results do not eliminate the chance that this patient is susceptible to malignant hyperthermia (MH). The genetic cause of about half of all MH survivors, with MH susceptibility confirmed by contracture test, remains unknown (PMID 28902675). CACNA1S: Individuals are at increased risk of developing malignant hyperthermia if administered halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine" ], - "lookupKey" : {"RYR1": "No Result", "CACNA1S": "Malignant Hyperthermia Susceptibility"}, + "lookupKey" : {"RYR1": "Uncertain Susceptibility", "CACNA1S": "Malignant Hyperthermia Susceptibility"}, "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ @@ -35042,27 +35008,27 @@ "objCls" : "Chemical", "id" : "PA164749136", "name" : "desflurane", - "version" : 8 + "version" : 32 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166303941", "name" : "Annotation of CPIC Guideline for desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, succinylcholine and CACNA1S, RYR1", - "version" : 2 + "version" : 13 }, "text" : { - "id" : 1452326420, - "html" : "

Based on CACNA1S status, halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine are relatively contraindicated in persons with malignant hyperthermia susceptibility (MHS). They should not be used, except in extraordinary circumstances where the benefits outweigh the risks. In general, alternative anesthetics are widely available and effective in patients with MHS.

\n

A list of unsafe halogenated volatile anesthetics or depolarizing muscle relaxants and alternative anesthetics can be found at http://www.mhaus.org/healthcare-professionals/be-prepared/safe-and-unsafe-anesthetics. Individuals who have biallelic (homozygous or compound heterozygous) pathogenic variants in CACNA1S generally will have autosomal recessive myopathies and should be managed according to the standard of care for those disorders. Although some may, indeed, have susceptibility to anesthetic agents, the recommendations described here cannot adequately address such patients, and they should be managed by a physician who is knowledgeable regarding those disorders.

\n", + "id" : 1452326440, + "html" : "

Halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine are relatively contraindicated in persons with malignant hyperthermia susceptibility (MHS). They should not be used, except in extraordinary circumstances where the benefits outweigh the risks. In general, alternative anesthetics are widely available and effective in patients with MHS.

\n

A list of unsafe halogenated volatile anesthetics or depolarizing muscle relaxants and alternative anesthetics can be found at http://www.mhaus.org/healthcare-professionals/be-prepared/safe-and-unsafe-anesthetics. Individuals who have biallelic (homozygous or compound heterozygous) pathogenic variants in CACNA1S generally will have autosomal recessive myopathies and should be managed according to the standard of care for those disorders. Although some may, indeed, have susceptibility to anesthetic agents, the recommendations described here cannot adequately address such patients, and they should be managed by a physician who is knowledgeable regarding those disorders.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166323301", - "name" : "Recommendation Annotation PA166323301", - "alternateDrugAvailable" : true, + "id" : "PA166323362", + "name" : "Recommendation Annotation PA166323362", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, "parents" : [], @@ -35074,9 +35040,9 @@ }, "dosingInformation" : false, "implications" : [ - "Individuals are at increased risk of developing malignant hyperthermia if administered halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine" + "RYR1: These results do not eliminate the chance that this patient is susceptible to malignant hyperthermia (MH). The genetic cause of about half of all MH survivors, with MH susceptibility confirmed by contracture test, remains unknown (PMID 28902675)." ], - "lookupKey" : {"RYR1": "Malignant Hyperthermia Susceptibility", "CACNA1S": "Malignant Hyperthermia Susceptibility"}, + "lookupKey" : {"RYR1": "Uncertain Susceptibility", "CACNA1S": "No Result"}, "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ @@ -35084,18 +35050,18 @@ "objCls" : "Chemical", "id" : "PA164749136", "name" : "desflurane", - "version" : 8 + "version" : 32 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166303941", "name" : "Annotation of CPIC Guideline for desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, succinylcholine and CACNA1S, RYR1", - "version" : 2 + "version" : 13 }, "text" : { - "id" : 1452326400, - "html" : "

Halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine are relatively contraindicated in persons with malignant hyperthermia susceptibility (MHS). They should not be used, except in extraordinary circumstances where the benefits outweigh the risks. In general, alternative anesthetics are widely available and effective in patients with MHS.

\n

A list of unsafe halogenated volatile anesthetics or depolarizing muscle relaxants and alternative anesthetics can be found at http://www.mhaus.org/healthcare-professionals/be-prepared/safe-and-unsafe-anesthetics. Individuals who have biallelic (homozygous or compound heterozygous) pathogenic variants in RYR1 or CACNA1S generally will have autosomal recessive myopathies and should be managed according to the standard of care for those disorders. Although some may, indeed, have susceptibility to anesthetic agents, the recommendations described here cannot adequately address such patients, and they should be managed by a physician who is knowledgeable regarding those disorders.

\n", + "id" : 1452326461, + "html" : "

No CACNA1S genotype is available. Based on RYR1 status, clinical findings, family history, further genetic testing and other laboratory data should guide use of halogenated volatile anesthetics or depolarizing muscle relaxants.

\n", "version" : 0 }, "version" : 0 @@ -35126,21 +35092,21 @@ "objCls" : "Chemical", "id" : "PA164749136", "name" : "desflurane", - "version" : 8 + "version" : 32 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166303941", "name" : "Annotation of CPIC Guideline for desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, succinylcholine and CACNA1S, RYR1", - "version" : 2 + "version" : 13 }, "text" : { "id" : 1452326460, "html" : "

Based on RYR1 status, halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine are relatively contraindicated in persons with malignant hyperthermia susceptibility (MHS). They should not be used, except in extraordinary circumstances where the benefits outweigh the risks. In general, alternative anesthetics are widely available and effective in patients with MHS.

\n

A list of unsafe halogenated volatile anesthetics or depolarizing muscle relaxants and alternative anesthetics can be found at http://www.mhaus.org/healthcare-professionals/be-prepared/safe-and-unsafe-anesthetics. Individuals who have biallelic (homozygous or compound heterozygous) pathogenic variants in RYR1 generally will have autosomal recessive myopathies and should be managed according to the standard of care for those disorders. Although some may, indeed, have susceptibility to anesthetic agents, the recommendations described here cannot adequately address such patients, and they should be managed by a physician who is knowledgeable regarding those disorders.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -35168,68 +35134,26 @@ "objCls" : "Chemical", "id" : "PA164749136", "name" : "desflurane", - "version" : 8 + "version" : 32 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166303941", "name" : "Annotation of CPIC Guideline for desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, succinylcholine and CACNA1S, RYR1", - "version" : 2 + "version" : 13 }, "text" : { "id" : 1452326480, "html" : "

Halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine are relatively contraindicated in persons with malignant hyperthermia susceptibility (MHS). They should not be used, except in extraordinary circumstances where the benefits outweigh the risks. In general, alternative anesthetics are widely available and effective in patients with MHS.

\n

A list of unsafe halogenated volatile anesthetics or depolarizing muscle relaxants and alternative anesthetics can be found at http://www.mhaus.org/healthcare-professionals/be-prepared/safe-and-unsafe-anesthetics. Individuals who have biallelic (homozygous or compound heterozygous) pathogenic variants in RYR1 generally will have autosomal recessive myopathies and should be managed according to the standard of care for those disorders. Although some may, indeed, have susceptibility to anesthetic agents, the recommendations described here cannot adequately address such patients, and they should be managed by a physician who is knowledgeable regarding those disorders.

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Halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine are relatively contraindicated in persons with malignant hyperthermia susceptibility (MHS). They should not be used, except in extraordinary circumstances where the benefits outweigh the risks. In general, alternative anesthetics are widely available and effective in patients with MHS.

\n

A list of unsafe halogenated volatile anesthetics or depolarizing muscle relaxants and alternative anesthetics can be found at http://www.mhaus.org/healthcare-professionals/be-prepared/safe-and-unsafe-anesthetics. Individuals who have biallelic (homozygous or compound heterozygous) pathogenic variants in CACNA1S generally will have autosomal recessive myopathies and should be managed according to the standard of care for those disorders. Although some may, indeed, have susceptibility to anesthetic agents, the recommendations described here cannot adequately address such patients, and they should be managed by a physician who is knowledgeable regarding those disorders.

\n", - "version" : 0 - }, "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166323447", - "name" : "Recommendation Annotation PA166323447", + "id" : "PA166323401", + "name" : "Recommendation Annotation PA166323401", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -35250,19 +35174,19 @@ "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA449461", - "name" : "enflurane", - "version" : 11 + "id" : "PA164749136", + "name" : "desflurane", + "version" : 32 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166303941", "name" : "Annotation of CPIC Guideline for desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, succinylcholine and CACNA1S, RYR1", - "version" : 2 + "version" : 13 }, "text" : { - "id" : 1452326546, + "id" : 1452326500, "html" : "

No RYR1 genotype is available. Based on CACNA1S status, clinical findings, family history, further genetic testing and other laboratory data should guide use of halogenated volatile anesthetics or depolarizing muscle relaxants.

\n", "version" : 0 }, @@ -35270,8 +35194,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166323448", - "name" : "Recommendation Annotation PA166323448", + "id" : "PA166323421", + "name" : "Recommendation Annotation PA166323421", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -35292,19 +35216,19 @@ "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA449461", - "name" : "enflurane", - "version" : 11 + "id" : "PA164749136", + "name" : "desflurane", + "version" : 32 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166303941", "name" : "Annotation of CPIC Guideline for desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, succinylcholine and CACNA1S, RYR1", - "version" : 2 + "version" : 13 }, "text" : { - "id" : 1452326547, + "id" : 1452326520, "html" : "

Clinical findings, family history, further genetic testing and other laboratory data should guide use of halogenated volatile anesthetics or depolarizing muscle relaxants.

\n", "version" : 0 }, @@ -35336,14 +35260,14 @@ "objCls" : "Chemical", "id" : "PA449461", "name" : "enflurane", - "version" : 11 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166303941", "name" : "Annotation of CPIC Guideline for desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, succinylcholine and CACNA1S, RYR1", - "version" : 2 + "version" : 13 }, "text" : { "id" : 1452326540, @@ -35378,14 +35302,14 @@ "objCls" : "Chemical", "id" : "PA449461", "name" : "enflurane", - "version" : 11 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166303941", "name" : "Annotation of CPIC Guideline for desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, succinylcholine and CACNA1S, RYR1", - "version" : 2 + "version" : 13 }, "text" : { "id" : 1452326541, @@ -35420,14 +35344,14 @@ "objCls" : "Chemical", "id" : "PA449461", "name" : "enflurane", - "version" : 11 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166303941", "name" : "Annotation of CPIC Guideline for desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, succinylcholine and CACNA1S, RYR1", - "version" : 2 + "version" : 13 }, "text" : { "id" : 1452326542, @@ -35462,14 +35386,14 @@ "objCls" : "Chemical", "id" : "PA449461", "name" : "enflurane", - "version" : 11 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166303941", "name" : "Annotation of CPIC Guideline for desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, succinylcholine and CACNA1S, RYR1", - "version" : 2 + "version" : 13 }, "text" : { "id" : 1452326543, @@ -35504,14 +35428,14 @@ "objCls" : "Chemical", "id" : "PA449461", "name" : "enflurane", - "version" : 11 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166303941", "name" : "Annotation of CPIC Guideline for desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, succinylcholine and CACNA1S, RYR1", - "version" : 2 + "version" : 13 }, "text" : { "id" : 1452326544, @@ -35546,14 +35470,14 @@ "objCls" : "Chemical", "id" : "PA449461", "name" : "enflurane", - "version" : 11 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166303941", "name" : "Annotation of CPIC Guideline for desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, succinylcholine and CACNA1S, RYR1", - "version" : 2 + "version" : 13 }, "text" : { "id" : 1452326545, @@ -35562,6 +35486,132 @@ }, "version" : 0 }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166323447", + "name" : "Recommendation Annotation PA166323447", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501930, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : false, + "implications" : [ + "CACNA1S: These results do not eliminate the chance that this patient is susceptible to malignant hyperthermia (MH). The genetic cause of about half of all MH survivors, with MH susceptibility confirmed by contracture test, remains unknown (PMID 28902675)." + ], + "lookupKey" : {"RYR1": "No Result", "CACNA1S": "Uncertain Susceptibility"}, + "otherPrescribingGuidance" : true, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA449461", + "name" : "enflurane", + "version" : 41 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166303941", + "name" : "Annotation of CPIC Guideline for desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, succinylcholine and CACNA1S, RYR1", + "version" : 13 + }, + "text" : { + "id" : 1452326546, + "html" : "

No RYR1 genotype is available. Based on CACNA1S status, clinical findings, family history, further genetic testing and other laboratory data should guide use of halogenated volatile anesthetics or depolarizing muscle relaxants.

\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166323448", + "name" : "Recommendation Annotation PA166323448", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501930, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : false, + "implications" : [ + "These results do not eliminate the chance that this patient is susceptible to malignant hyperthermia (MH). The genetic cause of about half of all MH survivors, with MH susceptibility confirmed by contracture test, remains unknown (PMID 28902675)." + ], + "lookupKey" : {"RYR1": "Uncertain Susceptibility", "CACNA1S": "Uncertain Susceptibility"}, + "otherPrescribingGuidance" : true, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA449461", + "name" : "enflurane", + "version" : 41 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166303941", + "name" : "Annotation of CPIC Guideline for desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, succinylcholine and CACNA1S, RYR1", + "version" : 13 + }, + "text" : { + "id" : 1452326547, + "html" : "

Clinical findings, family history, further genetic testing and other laboratory data should guide use of halogenated volatile anesthetics or depolarizing muscle relaxants.

\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166323449", + "name" : "Recommendation Annotation PA166323449", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981501930, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : false, + "implications" : [ + "Individuals are at increased risk of developing malignant hyperthermia if administered halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine" + ], + "lookupKey" : {"RYR1": "Malignant Hyperthermia Susceptibility", "CACNA1S": "Malignant Hyperthermia Susceptibility"}, + "otherPrescribingGuidance" : true, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA449845", + "name" : "halothane", + "version" : 66 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166303941", + "name" : "Annotation of CPIC Guideline for desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, succinylcholine and CACNA1S, RYR1", + "version" : 13 + }, + "text" : { + "id" : 1452326548, + "html" : "

Halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine are relatively contraindicated in persons with malignant hyperthermia susceptibility (MHS). They should not be used, except in extraordinary circumstances where the benefits outweigh the risks. In general, alternative anesthetics are widely available and effective in patients with MHS.

\n

A list of unsafe halogenated volatile anesthetics or depolarizing muscle relaxants and alternative anesthetics can be found at http://www.mhaus.org/healthcare-professionals/be-prepared/safe-and-unsafe-anesthetics. Individuals who have biallelic (homozygous or compound heterozygous) pathogenic variants in RYR1 or CACNA1S generally will have autosomal recessive myopathies and should be managed according to the standard of care for those disorders. Although some may, indeed, have susceptibility to anesthetic agents, the recommendations described here cannot adequately address such patients, and they should be managed by a physician who is knowledgeable regarding those disorders.

\n", + "version" : 0 + }, + "version" : 0 + }, { "objCls" : "Recommendation Annotation", "id" : "PA166323450", @@ -35588,14 +35638,14 @@ "objCls" : "Chemical", "id" : "PA449845", "name" : "halothane", - "version" : 18 + "version" : 66 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166303941", "name" : "Annotation of CPIC Guideline for desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, succinylcholine and CACNA1S, RYR1", - "version" : 2 + "version" : 13 }, "text" : { "id" : 1452326549, @@ -35606,8 +35656,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166323461", - "name" : "Recommendation Annotation PA166323461", + "id" : "PA166323451", + "name" : "Recommendation Annotation PA166323451", "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, @@ -35620,9 +35670,9 @@ }, "dosingInformation" : false, "implications" : [ - "RYR1: Individuals are at increased risk of developing malignant hyperthermia if administered halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine" + "CACNA1S: Individuals are at increased risk of developing malignant hyperthermia if administered halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine, RYR1: These results do not eliminate the chance that this patient is susceptible to malignant hyperthermia (MH). The genetic cause of about half of all MH survivors, with MH susceptibility confirmed by contracture test, remains unknown (PMID 28902675)." ], - "lookupKey" : {"RYR1": "Malignant Hyperthermia Susceptibility", "CACNA1S": "No Result"}, + "lookupKey" : {"RYR1": "Uncertain Susceptibility", "CACNA1S": "Malignant Hyperthermia Susceptibility"}, "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ @@ -35630,27 +35680,27 @@ "objCls" : "Chemical", "id" : "PA449845", "name" : "halothane", - "version" : 18 + "version" : 66 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166303941", "name" : "Annotation of CPIC Guideline for desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, succinylcholine and CACNA1S, RYR1", - "version" : 2 + "version" : 13 }, "text" : { - "id" : 1452326560, - "html" : "

Based on RYR1 status, halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine are relatively contraindicated in persons with malignant hyperthermia susceptibility (MHS). They should not be used, except in extraordinary circumstances where the benefits outweigh the risks. In general, alternative anesthetics are widely available and effective in patients with MHS.

\n

A list of unsafe halogenated volatile anesthetics or depolarizing muscle relaxants and alternative anesthetics can be found at http://www.mhaus.org/healthcare-professionals/be-prepared/safe-and-unsafe-anesthetics. Individuals who have biallelic (homozygous or compound heterozygous) pathogenic variants in RYR1 generally will have autosomal recessive myopathies and should be managed according to the standard of care for those disorders. Although some may, indeed, have susceptibility to anesthetic agents, the recommendations described here cannot adequately address such patients, and they should be managed by a physician who is knowledgeable regarding those disorders.

\n", + "id" : 1452326550, + "html" : "

Halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine are relatively contraindicated in persons with malignant hyperthermia susceptibility (MHS). They should not be used, except in extraordinary circumstances where the benefits outweigh the risks. In general, alternative anesthetics are widely available and effective in patients with MHS.

\n

A list of unsafe halogenated volatile anesthetics or depolarizing muscle relaxants and alternative anesthetics can be found at http://www.mhaus.org/healthcare-professionals/be-prepared/safe-and-unsafe-anesthetics. Individuals who have biallelic (homozygous or compound heterozygous) pathogenic variants in CACNA1S generally will have autosomal recessive myopathies and should be managed according to the standard of care for those disorders. Although some may, indeed, have susceptibility to anesthetic agents, the recommendations described here cannot adequately address such patients, and they should be managed by a physician who is knowledgeable regarding those disorders.

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No CACNA1S genotype is available. Based on RYR1 status, clinical findings, family history, further genetic testing and other laboratory data should guide use of halogenated volatile anesthetics or depolarizing muscle relaxants.

\n", + "id" : 1452326560, + "html" : "

Based on RYR1 status, halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine are relatively contraindicated in persons with malignant hyperthermia susceptibility (MHS). They should not be used, except in extraordinary circumstances where the benefits outweigh the risks. In general, alternative anesthetics are widely available and effective in patients with MHS.

\n

A list of unsafe halogenated volatile anesthetics or depolarizing muscle relaxants and alternative anesthetics can be found at http://www.mhaus.org/healthcare-professionals/be-prepared/safe-and-unsafe-anesthetics. Individuals who have biallelic (homozygous or compound heterozygous) pathogenic variants in RYR1 generally will have autosomal recessive myopathies and should be managed according to the standard of care for those disorders. Although some may, indeed, have susceptibility to anesthetic agents, the recommendations described here cannot adequately address such patients, and they should be managed by a physician who is knowledgeable regarding those disorders.

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Halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine are relatively contraindicated in persons with malignant hyperthermia susceptibility (MHS). They should not be used, except in extraordinary circumstances where the benefits outweigh the risks. In general, alternative anesthetics are widely available and effective in patients with MHS.

\n

A list of unsafe halogenated volatile anesthetics or depolarizing muscle relaxants and alternative anesthetics can be found at http://www.mhaus.org/healthcare-professionals/be-prepared/safe-and-unsafe-anesthetics. Individuals who have biallelic (homozygous or compound heterozygous) pathogenic variants in CACNA1S generally will have autosomal recessive myopathies and should be managed according to the standard of care for those disorders. Although some may, indeed, have susceptibility to anesthetic agents, the recommendations described here cannot adequately address such patients, and they should be managed by a physician who is knowledgeable regarding those disorders.

\n", + "id" : 1452326561, + "html" : "

No CACNA1S genotype is available. Based on RYR1 status, clinical findings, family history, further genetic testing and other laboratory data should guide use of halogenated volatile anesthetics or depolarizing muscle relaxants.

\n", "version" : 0 }, "version" : 0 @@ -35756,14 +35806,14 @@ "objCls" : "Chemical", "id" : "PA449845", "name" : "halothane", - "version" : 18 + "version" : 66 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166303941", "name" : "Annotation of CPIC Guideline for desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, succinylcholine and CACNA1S, RYR1", - "version" : 2 + "version" : 13 }, "text" : { "id" : 1452326562, @@ -35774,9 +35824,9 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166323449", - "name" : "Recommendation Annotation PA166323449", - "alternateDrugAvailable" : true, + "id" : "PA166323481", + "name" : "Recommendation Annotation PA166323481", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, "parents" : [], @@ -35788,9 +35838,9 @@ }, "dosingInformation" : false, "implications" : [ - "Individuals are at increased risk of developing malignant hyperthermia if administered halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine" + "CACNA1S: These results do not eliminate the chance that this patient is susceptible to malignant hyperthermia (MH). The genetic cause of about half of all MH survivors, with MH susceptibility confirmed by contracture test, remains unknown (PMID 28902675)." ], - "lookupKey" : {"RYR1": "Malignant Hyperthermia Susceptibility", "CACNA1S": "Malignant Hyperthermia Susceptibility"}, + "lookupKey" : {"RYR1": "No Result", "CACNA1S": "Uncertain Susceptibility"}, "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ @@ -35798,18 +35848,18 @@ "objCls" : "Chemical", "id" : "PA449845", "name" : "halothane", - "version" : 18 + "version" : 66 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166303941", "name" : "Annotation of CPIC Guideline for desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, succinylcholine and CACNA1S, RYR1", - "version" : 2 + "version" : 13 }, "text" : { - "id" : 1452326548, - "html" : "

Halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine are relatively contraindicated in persons with malignant hyperthermia susceptibility (MHS). They should not be used, except in extraordinary circumstances where the benefits outweigh the risks. In general, alternative anesthetics are widely available and effective in patients with MHS.

\n

A list of unsafe halogenated volatile anesthetics or depolarizing muscle relaxants and alternative anesthetics can be found at http://www.mhaus.org/healthcare-professionals/be-prepared/safe-and-unsafe-anesthetics. Individuals who have biallelic (homozygous or compound heterozygous) pathogenic variants in RYR1 or CACNA1S generally will have autosomal recessive myopathies and should be managed according to the standard of care for those disorders. Although some may, indeed, have susceptibility to anesthetic agents, the recommendations described here cannot adequately address such patients, and they should be managed by a physician who is knowledgeable regarding those disorders.

\n", + "id" : 1452326580, + "html" : "

No RYR1 genotype is available. Based on CACNA1S status, clinical findings, family history, further genetic testing and other laboratory data should guide use of halogenated volatile anesthetics or depolarizing muscle relaxants.

\n", "version" : 0 }, "version" : 0 @@ -35840,14 +35890,14 @@ "objCls" : "Chemical", "id" : "PA449845", "name" : "halothane", - "version" : 18 + "version" : 66 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166303941", "name" : "Annotation of CPIC Guideline for desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, succinylcholine and CACNA1S, RYR1", - "version" : 2 + "version" : 13 }, "text" : { "id" : 1452326581, @@ -35858,9 +35908,9 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166323481", - "name" : "Recommendation Annotation PA166323481", - "alternateDrugAvailable" : false, + "id" : "PA166323501", + "name" : "Recommendation Annotation PA166323501", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, "parents" : [], @@ -35872,28 +35922,70 @@ }, "dosingInformation" : false, "implications" : [ - "CACNA1S: These results do not eliminate the chance that this patient is susceptible to malignant hyperthermia (MH). The genetic cause of about half of all MH survivors, with MH susceptibility confirmed by contracture test, remains unknown (PMID 28902675)." + "Individuals are at increased risk of developing malignant hyperthermia if administered halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine" ], - "lookupKey" : {"RYR1": "No Result", "CACNA1S": "Uncertain Susceptibility"}, + "lookupKey" : {"RYR1": "Malignant Hyperthermia Susceptibility", "CACNA1S": "Malignant Hyperthermia Susceptibility"}, "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA449845", - "name" : "halothane", - "version" : 18 + "id" : "PA450106", + "name" : "isoflurane", + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166303941", "name" : "Annotation of CPIC Guideline for desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, succinylcholine and CACNA1S, RYR1", - "version" : 2 + "version" : 13 }, "text" : { - "id" : 1452326580, - "html" : "

No RYR1 genotype is available. Based on CACNA1S status, clinical findings, family history, further genetic testing and other laboratory data should guide use of halogenated volatile anesthetics or depolarizing muscle relaxants.

\n", + "id" : 1452326620, + "html" : "

Halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine are relatively contraindicated in persons with malignant hyperthermia susceptibility (MHS). They should not be used, except in extraordinary circumstances where the benefits outweigh the risks. In general, alternative anesthetics are widely available and effective in patients with MHS.

\n

A list of unsafe halogenated volatile anesthetics or depolarizing muscle relaxants and alternative anesthetics can be found at http://www.mhaus.org/healthcare-professionals/be-prepared/safe-and-unsafe-anesthetics. Individuals who have biallelic (homozygous or compound heterozygous) pathogenic variants in RYR1 or CACNA1S generally will have autosomal recessive myopathies and should be managed according to the standard of care for those disorders. Although some may, indeed, have susceptibility to anesthetic agents, the recommendations described here cannot adequately address such patients, and they should be managed by a physician who is knowledgeable regarding those disorders.

\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166323521", + "name" : "Recommendation Annotation PA166323521", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981501930, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : false, + "implications" : [ + "CACNA1S: Individuals are at increased risk of developing malignant hyperthermia if administered halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine" + ], + "lookupKey" : {"RYR1": "No Result", "CACNA1S": "Malignant Hyperthermia Susceptibility"}, + "otherPrescribingGuidance" : true, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA450106", + "name" : "isoflurane", + "version" : 33 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166303941", + "name" : "Annotation of CPIC Guideline for desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, succinylcholine and CACNA1S, RYR1", + "version" : 13 + }, + "text" : { + "id" : 1452326640, + "html" : "

Based on CACNA1S status, halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine are relatively contraindicated in persons with malignant hyperthermia susceptibility (MHS). They should not be used, except in extraordinary circumstances where the benefits outweigh the risks. In general, alternative anesthetics are widely available and effective in patients with MHS.

\n

A list of unsafe halogenated volatile anesthetics or depolarizing muscle relaxants and alternative anesthetics can be found at http://www.mhaus.org/healthcare-professionals/be-prepared/safe-and-unsafe-anesthetics. Individuals who have biallelic (homozygous or compound heterozygous) pathogenic variants in CACNA1S generally will have autosomal recessive myopathies and should be managed according to the standard of care for those disorders. Although some may, indeed, have susceptibility to anesthetic agents, the recommendations described here cannot adequately address such patients, and they should be managed by a physician who is knowledgeable regarding those disorders.

\n", "version" : 0 }, "version" : 0 @@ -35924,14 +36016,14 @@ "objCls" : "Chemical", "id" : "PA450106", "name" : "isoflurane", - "version" : 7 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166303941", "name" : "Annotation of CPIC Guideline for desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, succinylcholine and CACNA1S, RYR1", - "version" : 2 + "version" : 13 }, "text" : { "id" : 1452326641, @@ -35966,14 +36058,14 @@ "objCls" : "Chemical", "id" : "PA450106", "name" : "isoflurane", - "version" : 7 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166303941", "name" : "Annotation of CPIC Guideline for desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, succinylcholine and CACNA1S, RYR1", - "version" : 2 + "version" : 13 }, "text" : { "id" : 1452326642, @@ -35984,9 +36076,9 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166323501", - "name" : "Recommendation Annotation PA166323501", - "alternateDrugAvailable" : true, + "id" : "PA166323524", + "name" : "Recommendation Annotation PA166323524", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, "parents" : [], @@ -35998,9 +36090,9 @@ }, "dosingInformation" : false, "implications" : [ - "Individuals are at increased risk of developing malignant hyperthermia if administered halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine" + "RYR1: These results do not eliminate the chance that this patient is susceptible to malignant hyperthermia (MH). The genetic cause of about half of all MH survivors, with MH susceptibility confirmed by contracture test, remains unknown (PMID 28902675)." ], - "lookupKey" : {"RYR1": "Malignant Hyperthermia Susceptibility", "CACNA1S": "Malignant Hyperthermia Susceptibility"}, + "lookupKey" : {"RYR1": "Uncertain Susceptibility", "CACNA1S": "No Result"}, "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ @@ -36008,26 +36100,26 @@ "objCls" : "Chemical", "id" : "PA450106", "name" : "isoflurane", - "version" : 7 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166303941", "name" : "Annotation of CPIC Guideline for desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, succinylcholine and CACNA1S, RYR1", - "version" : 2 + "version" : 13 }, "text" : { - "id" : 1452326620, - "html" : "

Halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine are relatively contraindicated in persons with malignant hyperthermia susceptibility (MHS). They should not be used, except in extraordinary circumstances where the benefits outweigh the risks. In general, alternative anesthetics are widely available and effective in patients with MHS.

\n

A list of unsafe halogenated volatile anesthetics or depolarizing muscle relaxants and alternative anesthetics can be found at http://www.mhaus.org/healthcare-professionals/be-prepared/safe-and-unsafe-anesthetics. Individuals who have biallelic (homozygous or compound heterozygous) pathogenic variants in RYR1 or CACNA1S generally will have autosomal recessive myopathies and should be managed according to the standard of care for those disorders. Although some may, indeed, have susceptibility to anesthetic agents, the recommendations described here cannot adequately address such patients, and they should be managed by a physician who is knowledgeable regarding those disorders.

\n", + "id" : 1452326643, + "html" : "

No CACNA1S genotype is available. Based on RYR1 status, clinical findings, family history, further genetic testing and other laboratory data should guide use of halogenated volatile anesthetics or depolarizing muscle relaxants.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166323521", - "name" : "Recommendation Annotation PA166323521", + "id" : "PA166323525", + "name" : "Recommendation Annotation PA166323525", "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, @@ -36040,51 +36132,9 @@ }, "dosingInformation" : false, "implications" : [ - "CACNA1S: Individuals are at increased risk of developing malignant hyperthermia if administered halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine" - ], - "lookupKey" : {"RYR1": "No Result", "CACNA1S": "Malignant Hyperthermia Susceptibility"}, - "otherPrescribingGuidance" : true, - "population" : "general", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA450106", - "name" : "isoflurane", - "version" : 7 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166303941", - "name" : "Annotation of CPIC Guideline for desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, succinylcholine and CACNA1S, RYR1", - "version" : 2 - }, - "text" : { - "id" : 1452326640, - "html" : "

Based on CACNA1S status, halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine are relatively contraindicated in persons with malignant hyperthermia susceptibility (MHS). They should not be used, except in extraordinary circumstances where the benefits outweigh the risks. In general, alternative anesthetics are widely available and effective in patients with MHS.

\n

A list of unsafe halogenated volatile anesthetics or depolarizing muscle relaxants and alternative anesthetics can be found at http://www.mhaus.org/healthcare-professionals/be-prepared/safe-and-unsafe-anesthetics. Individuals who have biallelic (homozygous or compound heterozygous) pathogenic variants in CACNA1S generally will have autosomal recessive myopathies and should be managed according to the standard of care for those disorders. Although some may, indeed, have susceptibility to anesthetic agents, the recommendations described here cannot adequately address such patients, and they should be managed by a physician who is knowledgeable regarding those disorders.

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Clinical findings, family history, further genetic testing and other laboratory data should guide use of halogenated volatile anesthetics or depolarizing muscle relaxants.

\n", + "id" : 1452326644, + "html" : "

Halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine are relatively contraindicated in persons with malignant hyperthermia susceptibility (MHS). They should not be used, except in extraordinary circumstances where the benefits outweigh the risks. In general, alternative anesthetics are widely available and effective in patients with MHS.

\n

A list of unsafe halogenated volatile anesthetics or depolarizing muscle relaxants and alternative anesthetics can be found at http://www.mhaus.org/healthcare-professionals/be-prepared/safe-and-unsafe-anesthetics. Individuals who have biallelic (homozygous or compound heterozygous) pathogenic variants in RYR1 generally will have autosomal recessive myopathies and should be managed according to the standard of care for those disorders. Although some may, indeed, have susceptibility to anesthetic agents, the recommendations described here cannot adequately address such patients, and they should be managed by a physician who is knowledgeable regarding those disorders.

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No CACNA1S genotype is available. Based on RYR1 status, clinical findings, family history, further genetic testing and other laboratory data should guide use of halogenated volatile anesthetics or depolarizing muscle relaxants.

\n", + "id" : 1452326646, + "html" : "

Clinical findings, family history, further genetic testing and other laboratory data should guide use of halogenated volatile anesthetics or depolarizing muscle relaxants.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166323525", - "name" : "Recommendation Annotation PA166323525", + "id" : "PA166323533", + "name" : "Recommendation Annotation PA166323533", "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, @@ -36213,73 +36263,31 @@ "lookupKey" : {"RYR1": "Malignant Hyperthermia Susceptibility", "CACNA1S": "Uncertain Susceptibility"}, "otherPrescribingGuidance" : true, "population" : "general", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA450106", - "name" : "isoflurane", - "version" : 7 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166303941", - "name" : "Annotation of CPIC Guideline for desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, succinylcholine and CACNA1S, RYR1", - "version" : 2 - }, - "text" : { - "id" : 1452326644, - "html" : "

Halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine are relatively contraindicated in persons with malignant hyperthermia susceptibility (MHS). They should not be used, except in extraordinary circumstances where the benefits outweigh the risks. In general, alternative anesthetics are widely available and effective in patients with MHS.

\n

A list of unsafe halogenated volatile anesthetics or depolarizing muscle relaxants and alternative anesthetics can be found at http://www.mhaus.org/healthcare-professionals/be-prepared/safe-and-unsafe-anesthetics. Individuals who have biallelic (homozygous or compound heterozygous) pathogenic variants in RYR1 generally will have autosomal recessive myopathies and should be managed according to the standard of care for those disorders. Although some may, indeed, have susceptibility to anesthetic agents, the recommendations described here cannot adequately address such patients, and they should be managed by a physician who is knowledgeable regarding those disorders.

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No RYR1 genotype is available. Based on CACNA1S status, clinical findings, family history, further genetic testing and other laboratory data should guide use of halogenated volatile anesthetics or depolarizing muscle relaxants.

\n", + "id" : 1452326652, + "html" : "

Halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine are relatively contraindicated in persons with malignant hyperthermia susceptibility (MHS). They should not be used, except in extraordinary circumstances where the benefits outweigh the risks. In general, alternative anesthetics are widely available and effective in patients with MHS.

\n

A list of unsafe halogenated volatile anesthetics or depolarizing muscle relaxants and alternative anesthetics can be found at http://www.mhaus.org/healthcare-professionals/be-prepared/safe-and-unsafe-anesthetics. Individuals who have biallelic (homozygous or compound heterozygous) pathogenic variants in RYR1 generally will have autosomal recessive myopathies and should be managed according to the standard of care for those disorders. Although some may, indeed, have susceptibility to anesthetic agents, the recommendations described here cannot adequately address such patients, and they should be managed by a physician who is knowledgeable regarding those disorders.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166323533", - "name" : "Recommendation Annotation PA166323533", + "id" : "PA166323528", + "name" : "Recommendation Annotation PA166323528", "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, @@ -36292,9 +36300,9 @@ }, "dosingInformation" : false, "implications" : [ - "RYR1: Individuals are at increased risk of developing malignant hyperthermia if administered halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine, CACNA1S: These results do not eliminate the chance that this patient is susceptible to malignant hyperthermia (MH). The genetic cause of about half of all MH survivors, with MH susceptibility confirmed by contracture test, remains unknown (PMID 28902675)." + "Individuals are at increased risk of developing malignant hyperthermia if administered halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine" ], - "lookupKey" : {"RYR1": "Malignant Hyperthermia Susceptibility", "CACNA1S": "Uncertain Susceptibility"}, + "lookupKey" : {"RYR1": "Malignant Hyperthermia Susceptibility", "CACNA1S": "Malignant Hyperthermia Susceptibility"}, "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ @@ -36302,27 +36310,27 @@ "objCls" : "Chemical", "id" : "PA450434", "name" : "methoxyflurane", - "version" : 8 + "version" : 34 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166303941", "name" : "Annotation of CPIC Guideline for desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, succinylcholine and CACNA1S, RYR1", - "version" : 2 + "version" : 13 }, "text" : { - "id" : 1452326652, - "html" : "

Halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine are relatively contraindicated in persons with malignant hyperthermia susceptibility (MHS). They should not be used, except in extraordinary circumstances where the benefits outweigh the risks. In general, alternative anesthetics are widely available and effective in patients with MHS.

\n

A list of unsafe halogenated volatile anesthetics or depolarizing muscle relaxants and alternative anesthetics can be found at http://www.mhaus.org/healthcare-professionals/be-prepared/safe-and-unsafe-anesthetics. Individuals who have biallelic (homozygous or compound heterozygous) pathogenic variants in RYR1 generally will have autosomal recessive myopathies and should be managed according to the standard of care for those disorders. Although some may, indeed, have susceptibility to anesthetic agents, the recommendations described here cannot adequately address such patients, and they should be managed by a physician who is knowledgeable regarding those disorders.

\n", + "id" : 1452326647, + "html" : "

Halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine are relatively contraindicated in persons with malignant hyperthermia susceptibility (MHS). They should not be used, except in extraordinary circumstances where the benefits outweigh the risks. In general, alternative anesthetics are widely available and effective in patients with MHS.

\n

A list of unsafe halogenated volatile anesthetics or depolarizing muscle relaxants and alternative anesthetics can be found at http://www.mhaus.org/healthcare-professionals/be-prepared/safe-and-unsafe-anesthetics. Individuals who have biallelic (homozygous or compound heterozygous) pathogenic variants in RYR1 or CACNA1S generally will have autosomal recessive myopathies and should be managed according to the standard of care for those disorders. Although some may, indeed, have susceptibility to anesthetic agents, the recommendations described here cannot adequately address such patients, and they should be managed by a physician who is knowledgeable regarding those disorders.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166323532", - "name" : "Recommendation Annotation PA166323532", - "alternateDrugAvailable" : false, + "id" : "PA166323529", + "name" : "Recommendation Annotation PA166323529", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, "parents" : [], @@ -36334,9 +36342,9 @@ }, "dosingInformation" : false, "implications" : [ - "RYR1: These results do not eliminate the chance that this patient is susceptible to malignant hyperthermia (MH). The genetic cause of about half of all MH survivors, with MH susceptibility confirmed by contracture test, remains unknown (PMID 28902675)." + "CACNA1S: Individuals are at increased risk of developing malignant hyperthermia if administered halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine" ], - "lookupKey" : {"RYR1": "Uncertain Susceptibility", "CACNA1S": "No Result"}, + "lookupKey" : {"RYR1": "No Result", "CACNA1S": "Malignant Hyperthermia Susceptibility"}, "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ @@ -36344,26 +36352,26 @@ "objCls" : "Chemical", "id" : "PA450434", "name" : "methoxyflurane", - "version" : 8 + "version" : 34 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166303941", "name" : "Annotation of CPIC Guideline for desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, succinylcholine and CACNA1S, RYR1", - "version" : 2 + "version" : 13 }, "text" : { - "id" : 1452326651, - "html" : "

No CACNA1S genotype is available. Based on RYR1 status, clinical findings, family history, further genetic testing and other laboratory data should guide use of halogenated volatile anesthetics or depolarizing muscle relaxants.

\n", + "id" : 1452326648, + "html" : "

Based on CACNA1S status, halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine are relatively contraindicated in persons with malignant hyperthermia susceptibility (MHS). They should not be used, except in extraordinary circumstances where the benefits outweigh the risks. In general, alternative anesthetics are widely available and effective in patients with MHS.

\n

A list of unsafe halogenated volatile anesthetics or depolarizing muscle relaxants and alternative anesthetics can be found at http://www.mhaus.org/healthcare-professionals/be-prepared/safe-and-unsafe-anesthetics. Individuals who have biallelic (homozygous or compound heterozygous) pathogenic variants in CACNA1S generally will have autosomal recessive myopathies and should be managed according to the standard of care for those disorders. Although some may, indeed, have susceptibility to anesthetic agents, the recommendations described here cannot adequately address such patients, and they should be managed by a physician who is knowledgeable regarding those disorders.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166323529", - "name" : "Recommendation Annotation PA166323529", + "id" : "PA166323530", + "name" : "Recommendation Annotation PA166323530", "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, @@ -36376,9 +36384,9 @@ }, "dosingInformation" : false, "implications" : [ - "CACNA1S: Individuals are at increased risk of developing malignant hyperthermia if administered halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine" + "CACNA1S: Individuals are at increased risk of developing malignant hyperthermia if administered halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine, RYR1: These results do not eliminate the chance that this patient is susceptible to malignant hyperthermia (MH). The genetic cause of about half of all MH survivors, with MH susceptibility confirmed by contracture test, remains unknown (PMID 28902675)." ], - "lookupKey" : {"RYR1": "No Result", "CACNA1S": "Malignant Hyperthermia Susceptibility"}, + "lookupKey" : {"RYR1": "Uncertain Susceptibility", "CACNA1S": "Malignant Hyperthermia Susceptibility"}, "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ @@ -36386,27 +36394,27 @@ "objCls" : "Chemical", "id" : "PA450434", "name" : "methoxyflurane", - "version" : 8 + "version" : 34 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166303941", "name" : "Annotation of CPIC Guideline for desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, succinylcholine and CACNA1S, RYR1", - "version" : 2 + "version" : 13 }, "text" : { - "id" : 1452326648, - "html" : "

Based on CACNA1S status, halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine are relatively contraindicated in persons with malignant hyperthermia susceptibility (MHS). They should not be used, except in extraordinary circumstances where the benefits outweigh the risks. In general, alternative anesthetics are widely available and effective in patients with MHS.

\n

A list of unsafe halogenated volatile anesthetics or depolarizing muscle relaxants and alternative anesthetics can be found at http://www.mhaus.org/healthcare-professionals/be-prepared/safe-and-unsafe-anesthetics. Individuals who have biallelic (homozygous or compound heterozygous) pathogenic variants in CACNA1S generally will have autosomal recessive myopathies and should be managed according to the standard of care for those disorders. Although some may, indeed, have susceptibility to anesthetic agents, the recommendations described here cannot adequately address such patients, and they should be managed by a physician who is knowledgeable regarding those disorders.

\n", + "id" : 1452326649, + "html" : "

Halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine are relatively contraindicated in persons with malignant hyperthermia susceptibility (MHS). They should not be used, except in extraordinary circumstances where the benefits outweigh the risks. In general, alternative anesthetics are widely available and effective in patients with MHS.

\n

A list of unsafe halogenated volatile anesthetics or depolarizing muscle relaxants and alternative anesthetics can be found at http://www.mhaus.org/healthcare-professionals/be-prepared/safe-and-unsafe-anesthetics. Individuals who have biallelic (homozygous or compound heterozygous) pathogenic variants in CACNA1S generally will have autosomal recessive myopathies and should be managed according to the standard of care for those disorders. Although some may, indeed, have susceptibility to anesthetic agents, the recommendations described here cannot adequately address such patients, and they should be managed by a physician who is knowledgeable regarding those disorders.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166323531", - "name" : "Recommendation Annotation PA166323531", - "alternateDrugAvailable" : true, + "id" : "PA166323532", + "name" : "Recommendation Annotation PA166323532", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, "parents" : [], @@ -36418,9 +36426,9 @@ }, "dosingInformation" : false, "implications" : [ - "RYR1: Individuals are at increased risk of developing malignant hyperthermia if administered halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine" + "RYR1: These results do not eliminate the chance that this patient is susceptible to malignant hyperthermia (MH). The genetic cause of about half of all MH survivors, with MH susceptibility confirmed by contracture test, remains unknown (PMID 28902675)." ], - "lookupKey" : {"RYR1": "Malignant Hyperthermia Susceptibility", "CACNA1S": "No Result"}, + "lookupKey" : {"RYR1": "Uncertain Susceptibility", "CACNA1S": "No Result"}, "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ @@ -36428,27 +36436,27 @@ "objCls" : "Chemical", "id" : "PA450434", "name" : "methoxyflurane", - "version" : 8 + "version" : 34 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166303941", "name" : "Annotation of CPIC Guideline for desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, succinylcholine and CACNA1S, RYR1", - "version" : 2 + "version" : 13 }, "text" : { - "id" : 1452326650, - "html" : "

Based on RYR1 status, halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine are relatively contraindicated in persons with malignant hyperthermia susceptibility (MHS). They should not be used, except in extraordinary circumstances where the benefits outweigh the risks. In general, alternative anesthetics are widely available and effective in patients with MHS.

\n

A list of unsafe halogenated volatile anesthetics or depolarizing muscle relaxants and alternative anesthetics can be found at http://www.mhaus.org/healthcare-professionals/be-prepared/safe-and-unsafe-anesthetics. Individuals who have biallelic (homozygous or compound heterozygous) pathogenic variants in RYR1 generally will have autosomal recessive myopathies and should be managed according to the standard of care for those disorders. Although some may, indeed, have susceptibility to anesthetic agents, the recommendations described here cannot adequately address such patients, and they should be managed by a physician who is knowledgeable regarding those disorders.

\n", + "id" : 1452326651, + "html" : "

No CACNA1S genotype is available. Based on RYR1 status, clinical findings, family history, further genetic testing and other laboratory data should guide use of halogenated volatile anesthetics or depolarizing muscle relaxants.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166323528", - "name" : "Recommendation Annotation PA166323528", - "alternateDrugAvailable" : true, + "id" : "PA166323534", + "name" : "Recommendation Annotation PA166323534", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, "parents" : [], @@ -36460,9 +36468,9 @@ }, "dosingInformation" : false, "implications" : [ - "Individuals are at increased risk of developing malignant hyperthermia if administered halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine" + "CACNA1S: These results do not eliminate the chance that this patient is susceptible to malignant hyperthermia (MH). The genetic cause of about half of all MH survivors, with MH susceptibility confirmed by contracture test, remains unknown (PMID 28902675)." ], - "lookupKey" : {"RYR1": "Malignant Hyperthermia Susceptibility", "CACNA1S": "Malignant Hyperthermia Susceptibility"}, + "lookupKey" : {"RYR1": "No Result", "CACNA1S": "Uncertain Susceptibility"}, "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ @@ -36470,27 +36478,27 @@ "objCls" : "Chemical", "id" : "PA450434", "name" : "methoxyflurane", - "version" : 8 + "version" : 34 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166303941", "name" : "Annotation of CPIC Guideline for desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, succinylcholine and CACNA1S, RYR1", - "version" : 2 + "version" : 13 }, "text" : { - "id" : 1452326647, - "html" : "

Halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine are relatively contraindicated in persons with malignant hyperthermia susceptibility (MHS). They should not be used, except in extraordinary circumstances where the benefits outweigh the risks. In general, alternative anesthetics are widely available and effective in patients with MHS.

\n

A list of unsafe halogenated volatile anesthetics or depolarizing muscle relaxants and alternative anesthetics can be found at http://www.mhaus.org/healthcare-professionals/be-prepared/safe-and-unsafe-anesthetics. Individuals who have biallelic (homozygous or compound heterozygous) pathogenic variants in RYR1 or CACNA1S generally will have autosomal recessive myopathies and should be managed according to the standard of care for those disorders. Although some may, indeed, have susceptibility to anesthetic agents, the recommendations described here cannot adequately address such patients, and they should be managed by a physician who is knowledgeable regarding those disorders.

\n", + "id" : 1452326653, + "html" : "

No RYR1 genotype is available. Based on CACNA1S status, clinical findings, family history, further genetic testing and other laboratory data should guide use of halogenated volatile anesthetics or depolarizing muscle relaxants.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166323530", - "name" : "Recommendation Annotation PA166323530", - "alternateDrugAvailable" : true, + "id" : "PA166323535", + "name" : "Recommendation Annotation PA166323535", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, "parents" : [], @@ -36502,9 +36510,9 @@ }, "dosingInformation" : false, "implications" : [ - "CACNA1S: Individuals are at increased risk of developing malignant hyperthermia if administered halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine, RYR1: These results do not eliminate the chance that this patient is susceptible to malignant hyperthermia (MH). The genetic cause of about half of all MH survivors, with MH susceptibility confirmed by contracture test, remains unknown (PMID 28902675)." + "These results do not eliminate the chance that this patient is susceptible to malignant hyperthermia (MH). The genetic cause of about half of all MH survivors, with MH susceptibility confirmed by contracture test, remains unknown (PMID 28902675)." ], - "lookupKey" : {"RYR1": "Uncertain Susceptibility", "CACNA1S": "Malignant Hyperthermia Susceptibility"}, + "lookupKey" : {"RYR1": "Uncertain Susceptibility", "CACNA1S": "Uncertain Susceptibility"}, "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ @@ -36512,27 +36520,27 @@ "objCls" : "Chemical", "id" : "PA450434", "name" : "methoxyflurane", - "version" : 8 + "version" : 34 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166303941", "name" : "Annotation of CPIC Guideline for desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, succinylcholine and CACNA1S, RYR1", - "version" : 2 + "version" : 13 }, "text" : { - "id" : 1452326649, - "html" : "

Halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine are relatively contraindicated in persons with malignant hyperthermia susceptibility (MHS). They should not be used, except in extraordinary circumstances where the benefits outweigh the risks. In general, alternative anesthetics are widely available and effective in patients with MHS.

\n

A list of unsafe halogenated volatile anesthetics or depolarizing muscle relaxants and alternative anesthetics can be found at http://www.mhaus.org/healthcare-professionals/be-prepared/safe-and-unsafe-anesthetics. Individuals who have biallelic (homozygous or compound heterozygous) pathogenic variants in CACNA1S generally will have autosomal recessive myopathies and should be managed according to the standard of care for those disorders. Although some may, indeed, have susceptibility to anesthetic agents, the recommendations described here cannot adequately address such patients, and they should be managed by a physician who is knowledgeable regarding those disorders.

\n", + "id" : 1452326654, + "html" : "

Clinical findings, family history, further genetic testing and other laboratory data should guide use of halogenated volatile anesthetics or depolarizing muscle relaxants.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166323535", - "name" : "Recommendation Annotation PA166323535", - "alternateDrugAvailable" : false, + "id" : "PA166323536", + "name" : "Recommendation Annotation PA166323536", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, "parents" : [], @@ -36544,36 +36552,36 @@ }, "dosingInformation" : false, "implications" : [ - "These results do not eliminate the chance that this patient is susceptible to malignant hyperthermia (MH). The genetic cause of about half of all MH survivors, with MH susceptibility confirmed by contracture test, remains unknown (PMID 28902675)." + "Individuals are at increased risk of developing malignant hyperthermia if administered halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine" ], - "lookupKey" : {"RYR1": "Uncertain Susceptibility", "CACNA1S": "Uncertain Susceptibility"}, + "lookupKey" : {"RYR1": "Malignant Hyperthermia Susceptibility", "CACNA1S": "Malignant Hyperthermia Susceptibility"}, "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA450434", - "name" : "methoxyflurane", - "version" : 8 + "id" : "PA451341", + "name" : "sevoflurane", + "version" : 34 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166303941", "name" : "Annotation of CPIC Guideline for desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, succinylcholine and CACNA1S, RYR1", - "version" : 2 + "version" : 13 }, "text" : { - "id" : 1452326654, - "html" : "

Clinical findings, family history, further genetic testing and other laboratory data should guide use of halogenated volatile anesthetics or depolarizing muscle relaxants.

\n", + "id" : 1452326655, + "html" : "

Halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine are relatively contraindicated in persons with malignant hyperthermia susceptibility (MHS). They should not be used, except in extraordinary circumstances where the benefits outweigh the risks. In general, alternative anesthetics are widely available and effective in patients with MHS.

\n

A list of unsafe halogenated volatile anesthetics or depolarizing muscle relaxants and alternative anesthetics can be found at http://www.mhaus.org/healthcare-professionals/be-prepared/safe-and-unsafe-anesthetics. Individuals who have biallelic (homozygous or compound heterozygous) pathogenic variants in RYR1 or CACNA1S generally will have autosomal recessive myopathies and should be managed according to the standard of care for those disorders. Although some may, indeed, have susceptibility to anesthetic agents, the recommendations described here cannot adequately address such patients, and they should be managed by a physician who is knowledgeable regarding those disorders.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166323539", - "name" : "Recommendation Annotation PA166323539", + "id" : "PA166323537", + "name" : "Recommendation Annotation PA166323537", "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, @@ -36586,9 +36594,9 @@ }, "dosingInformation" : false, "implications" : [ - "RYR1: Individuals are at increased risk of developing malignant hyperthermia if administered halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine" + "CACNA1S: Individuals are at increased risk of developing malignant hyperthermia if administered halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine" ], - "lookupKey" : {"RYR1": "Malignant Hyperthermia Susceptibility", "CACNA1S": "No Result"}, + "lookupKey" : {"RYR1": "No Result", "CACNA1S": "Malignant Hyperthermia Susceptibility"}, "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ @@ -36596,18 +36604,18 @@ "objCls" : "Chemical", "id" : "PA451341", "name" : "sevoflurane", - "version" : 9 + "version" : 34 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166303941", "name" : "Annotation of CPIC Guideline for desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, succinylcholine and CACNA1S, RYR1", - "version" : 2 + "version" : 13 }, "text" : { - "id" : 1452326658, - "html" : "

Based on RYR1 status, halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine are relatively contraindicated in persons with malignant hyperthermia susceptibility (MHS). They should not be used, except in extraordinary circumstances where the benefits outweigh the risks. In general, alternative anesthetics are widely available and effective in patients with MHS.

\n

A list of unsafe halogenated volatile anesthetics or depolarizing muscle relaxants and alternative anesthetics can be found at http://www.mhaus.org/healthcare-professionals/be-prepared/safe-and-unsafe-anesthetics. Individuals who have biallelic (homozygous or compound heterozygous) pathogenic variants in RYR1 generally will have autosomal recessive myopathies and should be managed according to the standard of care for those disorders. Although some may, indeed, have susceptibility to anesthetic agents, the recommendations described here cannot adequately address such patients, and they should be managed by a physician who is knowledgeable regarding those disorders.

\n", + "id" : 1452326656, + "html" : "

Based on CACNA1S status, halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine are relatively contraindicated in persons with malignant hyperthermia susceptibility (MHS). They should not be used, except in extraordinary circumstances where the benefits outweigh the risks. In general, alternative anesthetics are widely available and effective in patients with MHS.

\n

A list of unsafe halogenated volatile anesthetics or depolarizing muscle relaxants and alternative anesthetics can be found at http://www.mhaus.org/healthcare-professionals/be-prepared/safe-and-unsafe-anesthetics. Individuals who have biallelic (homozygous or compound heterozygous) pathogenic variants in CACNA1S generally will have autosomal recessive myopathies and should be managed according to the standard of care for those disorders. Although some may, indeed, have susceptibility to anesthetic agents, the recommendations described here cannot adequately address such patients, and they should be managed by a physician who is knowledgeable regarding those disorders.

\n", "version" : 0 }, "version" : 0 @@ -36638,14 +36646,14 @@ "objCls" : "Chemical", "id" : "PA451341", "name" : "sevoflurane", - "version" : 9 + "version" : 34 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166303941", "name" : "Annotation of CPIC Guideline for desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, succinylcholine and CACNA1S, RYR1", - "version" : 2 + "version" : 13 }, "text" : { "id" : 1452326657, @@ -36656,8 +36664,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166323541", - "name" : "Recommendation Annotation PA166323541", + "id" : "PA166323539", + "name" : "Recommendation Annotation PA166323539", "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, @@ -36670,9 +36678,9 @@ }, "dosingInformation" : false, "implications" : [ - "RYR1: Individuals are at increased risk of developing malignant hyperthermia if administered halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine, CACNA1S: These results do not eliminate the chance that this patient is susceptible to malignant hyperthermia (MH). The genetic cause of about half of all MH survivors, with MH susceptibility confirmed by contracture test, remains unknown (PMID 28902675)." + "RYR1: Individuals are at increased risk of developing malignant hyperthermia if administered halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine" ], - "lookupKey" : {"RYR1": "Malignant Hyperthermia Susceptibility", "CACNA1S": "Uncertain Susceptibility"}, + "lookupKey" : {"RYR1": "Malignant Hyperthermia Susceptibility", "CACNA1S": "No Result"}, "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ @@ -36680,26 +36688,26 @@ "objCls" : "Chemical", "id" : "PA451341", "name" : "sevoflurane", - "version" : 9 + "version" : 34 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166303941", "name" : "Annotation of CPIC Guideline for desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, succinylcholine and CACNA1S, RYR1", - "version" : 2 + "version" : 13 }, "text" : { - "id" : 1452326660, - "html" : "

Halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine are relatively contraindicated in persons with malignant hyperthermia susceptibility (MHS). They should not be used, except in extraordinary circumstances where the benefits outweigh the risks. In general, alternative anesthetics are widely available and effective in patients with MHS.

\n

A list of unsafe halogenated volatile anesthetics or depolarizing muscle relaxants and alternative anesthetics can be found at http://www.mhaus.org/healthcare-professionals/be-prepared/safe-and-unsafe-anesthetics. Individuals who have biallelic (homozygous or compound heterozygous) pathogenic variants in RYR1 generally will have autosomal recessive myopathies and should be managed according to the standard of care for those disorders. Although some may, indeed, have susceptibility to anesthetic agents, the recommendations described here cannot adequately address such patients, and they should be managed by a physician who is knowledgeable regarding those disorders.

\n", + "id" : 1452326658, + "html" : "

Based on RYR1 status, halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine are relatively contraindicated in persons with malignant hyperthermia susceptibility (MHS). They should not be used, except in extraordinary circumstances where the benefits outweigh the risks. In general, alternative anesthetics are widely available and effective in patients with MHS.

\n

A list of unsafe halogenated volatile anesthetics or depolarizing muscle relaxants and alternative anesthetics can be found at http://www.mhaus.org/healthcare-professionals/be-prepared/safe-and-unsafe-anesthetics. Individuals who have biallelic (homozygous or compound heterozygous) pathogenic variants in RYR1 generally will have autosomal recessive myopathies and should be managed according to the standard of care for those disorders. Although some may, indeed, have susceptibility to anesthetic agents, the recommendations described here cannot adequately address such patients, and they should be managed by a physician who is knowledgeable regarding those disorders.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166323562", - "name" : "Recommendation Annotation PA166323562", + "id" : "PA166323540", + "name" : "Recommendation Annotation PA166323540", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -36712,9 +36720,9 @@ }, "dosingInformation" : false, "implications" : [ - "These results do not eliminate the chance that this patient is susceptible to malignant hyperthermia (MH). The genetic cause of about half of all MH survivors, with MH susceptibility confirmed by contracture test, remains unknown (PMID 28902675)." + "RYR1: These results do not eliminate the chance that this patient is susceptible to malignant hyperthermia (MH). The genetic cause of about half of all MH survivors, with MH susceptibility confirmed by contracture test, remains unknown (PMID 28902675)." ], - "lookupKey" : {"RYR1": "Uncertain Susceptibility", "CACNA1S": "Uncertain Susceptibility"}, + "lookupKey" : {"RYR1": "Uncertain Susceptibility", "CACNA1S": "No Result"}, "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ @@ -36722,27 +36730,27 @@ "objCls" : "Chemical", "id" : "PA451341", "name" : "sevoflurane", - "version" : 9 + "version" : 34 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166303941", "name" : "Annotation of CPIC Guideline for desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, succinylcholine and CACNA1S, RYR1", - "version" : 2 + "version" : 13 }, "text" : { - "id" : 1452326681, - "html" : "

Clinical findings, family history, further genetic testing and other laboratory data should guide use of halogenated volatile anesthetics or depolarizing muscle relaxants.

\n", + "id" : 1452326659, + "html" : "

No CACNA1S genotype is available. Based on RYR1 status, clinical findings, family history, further genetic testing and other laboratory data should guide use of halogenated volatile anesthetics or depolarizing muscle relaxants.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166323540", - "name" : "Recommendation Annotation PA166323540", - "alternateDrugAvailable" : false, + "id" : "PA166323541", + "name" : "Recommendation Annotation PA166323541", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, "parents" : [], @@ -36754,9 +36762,9 @@ }, "dosingInformation" : false, "implications" : [ - "RYR1: These results do not eliminate the chance that this patient is susceptible to malignant hyperthermia (MH). The genetic cause of about half of all MH survivors, with MH susceptibility confirmed by contracture test, remains unknown (PMID 28902675)." + "RYR1: Individuals are at increased risk of developing malignant hyperthermia if administered halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine, CACNA1S: These results do not eliminate the chance that this patient is susceptible to malignant hyperthermia (MH). The genetic cause of about half of all MH survivors, with MH susceptibility confirmed by contracture test, remains unknown (PMID 28902675)." ], - "lookupKey" : {"RYR1": "Uncertain Susceptibility", "CACNA1S": "No Result"}, + "lookupKey" : {"RYR1": "Malignant Hyperthermia Susceptibility", "CACNA1S": "Uncertain Susceptibility"}, "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ @@ -36764,27 +36772,27 @@ "objCls" : "Chemical", "id" : "PA451341", "name" : "sevoflurane", - "version" : 9 + "version" : 34 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166303941", "name" : "Annotation of CPIC Guideline for desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, succinylcholine and CACNA1S, RYR1", - "version" : 2 + "version" : 13 }, "text" : { - "id" : 1452326659, - "html" : "

No CACNA1S genotype is available. Based on RYR1 status, clinical findings, family history, further genetic testing and other laboratory data should guide use of halogenated volatile anesthetics or depolarizing muscle relaxants.

\n", + "id" : 1452326660, + "html" : "

Halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine are relatively contraindicated in persons with malignant hyperthermia susceptibility (MHS). They should not be used, except in extraordinary circumstances where the benefits outweigh the risks. In general, alternative anesthetics are widely available and effective in patients with MHS.

\n

A list of unsafe halogenated volatile anesthetics or depolarizing muscle relaxants and alternative anesthetics can be found at http://www.mhaus.org/healthcare-professionals/be-prepared/safe-and-unsafe-anesthetics. Individuals who have biallelic (homozygous or compound heterozygous) pathogenic variants in RYR1 generally will have autosomal recessive myopathies and should be managed according to the standard of care for those disorders. Although some may, indeed, have susceptibility to anesthetic agents, the recommendations described here cannot adequately address such patients, and they should be managed by a physician who is knowledgeable regarding those disorders.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166323537", - "name" : "Recommendation Annotation PA166323537", - "alternateDrugAvailable" : true, + "id" : "PA166323561", + "name" : "Recommendation Annotation PA166323561", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, "parents" : [], @@ -36796,9 +36804,9 @@ }, "dosingInformation" : false, "implications" : [ - "CACNA1S: Individuals are at increased risk of developing malignant hyperthermia if administered halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine" + "CACNA1S: These results do not eliminate the chance that this patient is susceptible to malignant hyperthermia (MH). The genetic cause of about half of all MH survivors, with MH susceptibility confirmed by contracture test, remains unknown (PMID 28902675)." ], - "lookupKey" : {"RYR1": "No Result", "CACNA1S": "Malignant Hyperthermia Susceptibility"}, + "lookupKey" : {"RYR1": "No Result", "CACNA1S": "Uncertain Susceptibility"}, "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ @@ -36806,26 +36814,26 @@ "objCls" : "Chemical", "id" : "PA451341", "name" : "sevoflurane", - "version" : 9 + "version" : 34 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166303941", "name" : "Annotation of CPIC Guideline for desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, succinylcholine and CACNA1S, RYR1", - "version" : 2 + "version" : 13 }, "text" : { - "id" : 1452326656, - "html" : "

Based on CACNA1S status, halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine are relatively contraindicated in persons with malignant hyperthermia susceptibility (MHS). They should not be used, except in extraordinary circumstances where the benefits outweigh the risks. In general, alternative anesthetics are widely available and effective in patients with MHS.

\n

A list of unsafe halogenated volatile anesthetics or depolarizing muscle relaxants and alternative anesthetics can be found at http://www.mhaus.org/healthcare-professionals/be-prepared/safe-and-unsafe-anesthetics. Individuals who have biallelic (homozygous or compound heterozygous) pathogenic variants in CACNA1S generally will have autosomal recessive myopathies and should be managed according to the standard of care for those disorders. Although some may, indeed, have susceptibility to anesthetic agents, the recommendations described here cannot adequately address such patients, and they should be managed by a physician who is knowledgeable regarding those disorders.

\n", + "id" : 1452326680, + "html" : "

No RYR1 genotype is available. Based on CACNA1S status, clinical findings, family history, further genetic testing and other laboratory data should guide use of halogenated volatile anesthetics or depolarizing muscle relaxants.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166323561", - "name" : "Recommendation Annotation PA166323561", + "id" : "PA166323562", + "name" : "Recommendation Annotation PA166323562", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -36838,9 +36846,9 @@ }, "dosingInformation" : false, "implications" : [ - "CACNA1S: These results do not eliminate the chance that this patient is susceptible to malignant hyperthermia (MH). The genetic cause of about half of all MH survivors, with MH susceptibility confirmed by contracture test, remains unknown (PMID 28902675)." + "These results do not eliminate the chance that this patient is susceptible to malignant hyperthermia (MH). The genetic cause of about half of all MH survivors, with MH susceptibility confirmed by contracture test, remains unknown (PMID 28902675)." ], - "lookupKey" : {"RYR1": "No Result", "CACNA1S": "Uncertain Susceptibility"}, + "lookupKey" : {"RYR1": "Uncertain Susceptibility", "CACNA1S": "Uncertain Susceptibility"}, "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ @@ -36848,26 +36856,26 @@ "objCls" : "Chemical", "id" : "PA451341", "name" : "sevoflurane", - "version" : 9 + "version" : 34 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166303941", "name" : "Annotation of CPIC Guideline for desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, succinylcholine and CACNA1S, RYR1", - "version" : 2 + "version" : 13 }, "text" : { - "id" : 1452326680, - "html" : "

No RYR1 genotype is available. Based on CACNA1S status, clinical findings, family history, further genetic testing and other laboratory data should guide use of halogenated volatile anesthetics or depolarizing muscle relaxants.

\n", + "id" : 1452326681, + "html" : "

Clinical findings, family history, further genetic testing and other laboratory data should guide use of halogenated volatile anesthetics or depolarizing muscle relaxants.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166323536", - "name" : "Recommendation Annotation PA166323536", + "id" : "PA166323563", + "name" : "Recommendation Annotation PA166323563", "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, @@ -36888,19 +36896,19 @@ "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA451341", - "name" : "sevoflurane", - "version" : 9 + "id" : "PA451522", + "name" : "succinylcholine", + "version" : 26 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166303941", "name" : "Annotation of CPIC Guideline for desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, succinylcholine and CACNA1S, RYR1", - "version" : 2 + "version" : 13 }, "text" : { - "id" : 1452326655, + "id" : 1452326682, "html" : "

Halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine are relatively contraindicated in persons with malignant hyperthermia susceptibility (MHS). They should not be used, except in extraordinary circumstances where the benefits outweigh the risks. In general, alternative anesthetics are widely available and effective in patients with MHS.

\n

A list of unsafe halogenated volatile anesthetics or depolarizing muscle relaxants and alternative anesthetics can be found at http://www.mhaus.org/healthcare-professionals/be-prepared/safe-and-unsafe-anesthetics. Individuals who have biallelic (homozygous or compound heterozygous) pathogenic variants in RYR1 or CACNA1S generally will have autosomal recessive myopathies and should be managed according to the standard of care for those disorders. Although some may, indeed, have susceptibility to anesthetic agents, the recommendations described here cannot adequately address such patients, and they should be managed by a physician who is knowledgeable regarding those disorders.

\n", "version" : 0 }, @@ -36908,8 +36916,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166323582", - "name" : "Recommendation Annotation PA166323582", + "id" : "PA166323564", + "name" : "Recommendation Annotation PA166323564", "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, @@ -36922,9 +36930,9 @@ }, "dosingInformation" : false, "implications" : [ - "RYR1: Individuals are at increased risk of developing malignant hyperthermia if administered halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine" + "CACNA1S: Individuals are at increased risk of developing malignant hyperthermia if administered halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine" ], - "lookupKey" : {"RYR1": "Malignant Hyperthermia Susceptibility", "CACNA1S": "No Result"}, + "lookupKey" : {"RYR1": "No Result", "CACNA1S": "Malignant Hyperthermia Susceptibility"}, "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ @@ -36932,27 +36940,27 @@ "objCls" : "Chemical", "id" : "PA451522", "name" : "succinylcholine", - "version" : 7 + "version" : 26 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166303941", "name" : "Annotation of CPIC Guideline for desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, succinylcholine and CACNA1S, RYR1", - "version" : 2 + "version" : 13 }, "text" : { - "id" : 1452326701, - "html" : "

Based on RYR1 status, halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine are relatively contraindicated in persons with malignant hyperthermia susceptibility (MHS). They should not be used, except in extraordinary circumstances where the benefits outweigh the risks. In general, alternative anesthetics are widely available and effective in patients with MHS.

\n

Based on RYR1 status, halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine are relatively contraindicated in persons with malignant hyperthermia susceptibility (MHS). They should not be used, except in extraordinary circumstances where the benefits outweigh the risks. In general, alternative anesthetics are widely available and effective in patients with MHS.

\n", + "id" : 1452326683, + "html" : "

Based on CACNA1S status, halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine are relatively contraindicated in persons with malignant hyperthermia susceptibility (MHS). They should not be used, except in extraordinary circumstances where the benefits outweigh the risks. In general, alternative anesthetics are widely available and effective in patients with MHS.

\n

A list of unsafe halogenated volatile anesthetics or depolarizing muscle relaxants and alternative anesthetics can be found at http://www.mhaus.org/healthcare-professionals/be-prepared/safe-and-unsafe-anesthetics. Individuals who have biallelic (homozygous or compound heterozygous) pathogenic variants in CACNA1S generally will have autosomal recessive myopathies and should be managed according to the standard of care for those disorders. Although some may, indeed, have susceptibility to anesthetic agents, the recommendations described here cannot adequately address such patients, and they should be managed by a physician who is knowledgeable regarding those disorders.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166323583", - "name" : "Recommendation Annotation PA166323583", - "alternateDrugAvailable" : false, + "id" : "PA166323581", + "name" : "Recommendation Annotation PA166323581", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, "parents" : [], @@ -36964,9 +36972,9 @@ }, "dosingInformation" : false, "implications" : [ - "RYR1: These results do not eliminate the chance that this patient is susceptible to malignant hyperthermia (MH). The genetic cause of about half of all MH survivors, with MH susceptibility confirmed by contracture test, remains unknown (PMID 28902675)." + "CACNA1S: Individuals are at increased risk of developing malignant hyperthermia if administered halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine, RYR1: These results do not eliminate the chance that this patient is susceptible to malignant hyperthermia (MH). The genetic cause of about half of all MH survivors, with MH susceptibility confirmed by contracture test, remains unknown (PMID 28902675)." ], - "lookupKey" : {"RYR1": "Uncertain Susceptibility", "CACNA1S": "No Result"}, + "lookupKey" : {"RYR1": "Uncertain Susceptibility", "CACNA1S": "Malignant Hyperthermia Susceptibility"}, "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ @@ -36974,26 +36982,26 @@ "objCls" : "Chemical", "id" : "PA451522", "name" : "succinylcholine", - "version" : 7 + "version" : 26 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166303941", "name" : "Annotation of CPIC Guideline for desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, succinylcholine and CACNA1S, RYR1", - "version" : 2 + "version" : 13 }, "text" : { - "id" : 1452326702, - "html" : "

No CACNA1S genotype is available. Based on RYR1 status, clinical findings, family history, further genetic testing and other laboratory data should guide use of halogenated volatile anesthetics or depolarizing muscle relaxants.

\n", + "id" : 1452326700, + "html" : "

Halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine are relatively contraindicated in persons with malignant hyperthermia susceptibility (MHS). They should not be used, except in extraordinary circumstances where the benefits outweigh the risks. In general, alternative anesthetics are widely available and effective in patients with MHS.

\n

A list of unsafe halogenated volatile anesthetics or depolarizing muscle relaxants and alternative anesthetics can be found at http://www.mhaus.org/healthcare-professionals/be-prepared/safe-and-unsafe-anesthetics. Individuals who have biallelic (homozygous or compound heterozygous) pathogenic variants in CACNA1S generally will have autosomal recessive myopathies and should be managed according to the standard of care for those disorders. Although some may, indeed, have susceptibility to anesthetic agents, the recommendations described here cannot adequately address such patients, and they should be managed by a physician who is knowledgeable regarding those disorders.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166323584", - "name" : "Recommendation Annotation PA166323584", + "id" : "PA166323582", + "name" : "Recommendation Annotation PA166323582", "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, @@ -37006,9 +37014,9 @@ }, "dosingInformation" : false, "implications" : [ - "RYR1: Individuals are at increased risk of developing malignant hyperthermia if administered halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine, CACNA1S: These results do not eliminate the chance that this patient is susceptible to malignant hyperthermia (MH). The genetic cause of about half of all MH survivors, with MH susceptibility confirmed by contracture test, remains unknown (PMID 28902675)." + "RYR1: Individuals are at increased risk of developing malignant hyperthermia if administered halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine" ], - "lookupKey" : {"RYR1": "Malignant Hyperthermia Susceptibility", "CACNA1S": "Uncertain Susceptibility"}, + "lookupKey" : {"RYR1": "Malignant Hyperthermia Susceptibility", "CACNA1S": "No Result"}, "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ @@ -37016,27 +37024,27 @@ "objCls" : "Chemical", "id" : "PA451522", "name" : "succinylcholine", - "version" : 7 + "version" : 26 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166303941", "name" : "Annotation of CPIC Guideline for desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, succinylcholine and CACNA1S, RYR1", - "version" : 2 + "version" : 13 }, "text" : { - "id" : 1452326703, - "html" : "

Halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine are relatively contraindicated in persons with malignant hyperthermia susceptibility (MHS). They should not be used, except in extraordinary circumstances where the benefits outweigh the risks. In general, alternative anesthetics are widely available and effective in patients with MHS.

\n

A list of unsafe halogenated volatile anesthetics or depolarizing muscle relaxants and alternative anesthetics can be found at http://www.mhaus.org/healthcare-professionals/be-prepared/safe-and-unsafe-anesthetics. Individuals who have biallelic (homozygous or compound heterozygous) pathogenic variants in RYR1 generally will have autosomal recessive myopathies and should be managed according to the standard of care for those disorders. Although some may, indeed, have susceptibility to anesthetic agents, the recommendations described here cannot adequately address such patients, and they should be managed by a physician who is knowledgeable regarding those disorders.

\n", + "id" : 1452326701, + "html" : "

Based on RYR1 status, halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine are relatively contraindicated in persons with malignant hyperthermia susceptibility (MHS). They should not be used, except in extraordinary circumstances where the benefits outweigh the risks. In general, alternative anesthetics are widely available and effective in patients with MHS.

\n

Based on RYR1 status, halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine are relatively contraindicated in persons with malignant hyperthermia susceptibility (MHS). They should not be used, except in extraordinary circumstances where the benefits outweigh the risks. In general, alternative anesthetics are widely available and effective in patients with MHS.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166323564", - "name" : "Recommendation Annotation PA166323564", - "alternateDrugAvailable" : true, + "id" : "PA166323583", + "name" : "Recommendation Annotation PA166323583", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, "parents" : [], @@ -37048,9 +37056,9 @@ }, "dosingInformation" : false, "implications" : [ - "CACNA1S: Individuals are at increased risk of developing malignant hyperthermia if administered halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine" + "RYR1: These results do not eliminate the chance that this patient is susceptible to malignant hyperthermia (MH). The genetic cause of about half of all MH survivors, with MH susceptibility confirmed by contracture test, remains unknown (PMID 28902675)." ], - "lookupKey" : {"RYR1": "No Result", "CACNA1S": "Malignant Hyperthermia Susceptibility"}, + "lookupKey" : {"RYR1": "Uncertain Susceptibility", "CACNA1S": "No Result"}, "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ @@ -37058,27 +37066,27 @@ "objCls" : "Chemical", "id" : "PA451522", "name" : "succinylcholine", - "version" : 7 + "version" : 26 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166303941", "name" : "Annotation of CPIC Guideline for desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, succinylcholine and CACNA1S, RYR1", - "version" : 2 + "version" : 13 }, "text" : { - "id" : 1452326683, - "html" : "

Based on CACNA1S status, halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine are relatively contraindicated in persons with malignant hyperthermia susceptibility (MHS). They should not be used, except in extraordinary circumstances where the benefits outweigh the risks. In general, alternative anesthetics are widely available and effective in patients with MHS.

\n

A list of unsafe halogenated volatile anesthetics or depolarizing muscle relaxants and alternative anesthetics can be found at http://www.mhaus.org/healthcare-professionals/be-prepared/safe-and-unsafe-anesthetics. Individuals who have biallelic (homozygous or compound heterozygous) pathogenic variants in CACNA1S generally will have autosomal recessive myopathies and should be managed according to the standard of care for those disorders. Although some may, indeed, have susceptibility to anesthetic agents, the recommendations described here cannot adequately address such patients, and they should be managed by a physician who is knowledgeable regarding those disorders.

\n", + "id" : 1452326702, + "html" : "

No CACNA1S genotype is available. Based on RYR1 status, clinical findings, family history, further genetic testing and other laboratory data should guide use of halogenated volatile anesthetics or depolarizing muscle relaxants.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166323585", - "name" : "Recommendation Annotation PA166323585", - "alternateDrugAvailable" : false, + "id" : "PA166323584", + "name" : "Recommendation Annotation PA166323584", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, "parents" : [], @@ -37090,9 +37098,9 @@ }, "dosingInformation" : false, "implications" : [ - "CACNA1S: These results do not eliminate the chance that this patient is susceptible to malignant hyperthermia (MH). The genetic cause of about half of all MH survivors, with MH susceptibility confirmed by contracture test, remains unknown (PMID 28902675)." + "RYR1: Individuals are at increased risk of developing malignant hyperthermia if administered halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine, CACNA1S: These results do not eliminate the chance that this patient is susceptible to malignant hyperthermia (MH). The genetic cause of about half of all MH survivors, with MH susceptibility confirmed by contracture test, remains unknown (PMID 28902675)." ], - "lookupKey" : {"RYR1": "No Result", "CACNA1S": "Uncertain Susceptibility"}, + "lookupKey" : {"RYR1": "Malignant Hyperthermia Susceptibility", "CACNA1S": "Uncertain Susceptibility"}, "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ @@ -37100,27 +37108,27 @@ "objCls" : "Chemical", "id" : "PA451522", "name" : "succinylcholine", - "version" : 7 + "version" : 26 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166303941", "name" : "Annotation of CPIC Guideline for desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, succinylcholine and CACNA1S, RYR1", - "version" : 2 + "version" : 13 }, "text" : { - "id" : 1452326704, - "html" : "

No RYR1 genotype is available. Based on CACNA1S status, clinical findings, family history, further genetic testing and other laboratory data should guide use of halogenated volatile anesthetics or depolarizing muscle relaxants.

\n", + "id" : 1452326703, + "html" : "

Halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine are relatively contraindicated in persons with malignant hyperthermia susceptibility (MHS). They should not be used, except in extraordinary circumstances where the benefits outweigh the risks. In general, alternative anesthetics are widely available and effective in patients with MHS.

\n

A list of unsafe halogenated volatile anesthetics or depolarizing muscle relaxants and alternative anesthetics can be found at http://www.mhaus.org/healthcare-professionals/be-prepared/safe-and-unsafe-anesthetics. Individuals who have biallelic (homozygous or compound heterozygous) pathogenic variants in RYR1 generally will have autosomal recessive myopathies and should be managed according to the standard of care for those disorders. Although some may, indeed, have susceptibility to anesthetic agents, the recommendations described here cannot adequately address such patients, and they should be managed by a physician who is knowledgeable regarding those disorders.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166323563", - "name" : "Recommendation Annotation PA166323563", - "alternateDrugAvailable" : true, + "id" : "PA166323585", + "name" : "Recommendation Annotation PA166323585", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, "parents" : [], @@ -37132,9 +37140,9 @@ }, "dosingInformation" : false, "implications" : [ - "Individuals are at increased risk of developing malignant hyperthermia if administered halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine" + "CACNA1S: These results do not eliminate the chance that this patient is susceptible to malignant hyperthermia (MH). The genetic cause of about half of all MH survivors, with MH susceptibility confirmed by contracture test, remains unknown (PMID 28902675)." ], - "lookupKey" : {"RYR1": "Malignant Hyperthermia Susceptibility", "CACNA1S": "Malignant Hyperthermia Susceptibility"}, + "lookupKey" : {"RYR1": "No Result", "CACNA1S": "Uncertain Susceptibility"}, "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ @@ -37142,18 +37150,18 @@ "objCls" : "Chemical", "id" : "PA451522", "name" : "succinylcholine", - "version" : 7 + "version" : 26 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166303941", "name" : "Annotation of CPIC Guideline for desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, succinylcholine and CACNA1S, RYR1", - "version" : 2 + "version" : 13 }, "text" : { - "id" : 1452326682, - "html" : "

Halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine are relatively contraindicated in persons with malignant hyperthermia susceptibility (MHS). They should not be used, except in extraordinary circumstances where the benefits outweigh the risks. In general, alternative anesthetics are widely available and effective in patients with MHS.

\n

A list of unsafe halogenated volatile anesthetics or depolarizing muscle relaxants and alternative anesthetics can be found at http://www.mhaus.org/healthcare-professionals/be-prepared/safe-and-unsafe-anesthetics. Individuals who have biallelic (homozygous or compound heterozygous) pathogenic variants in RYR1 or CACNA1S generally will have autosomal recessive myopathies and should be managed according to the standard of care for those disorders. Although some may, indeed, have susceptibility to anesthetic agents, the recommendations described here cannot adequately address such patients, and they should be managed by a physician who is knowledgeable regarding those disorders.

\n", + "id" : 1452326704, + "html" : "

No RYR1 genotype is available. Based on CACNA1S status, clinical findings, family history, further genetic testing and other laboratory data should guide use of halogenated volatile anesthetics or depolarizing muscle relaxants.

\n", "version" : 0 }, "version" : 0 @@ -37184,14 +37192,14 @@ "objCls" : "Chemical", "id" : "PA451522", "name" : "succinylcholine", - "version" : 7 + "version" : 26 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166303941", "name" : "Annotation of CPIC Guideline for desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, succinylcholine and CACNA1S, RYR1", - "version" : 2 + "version" : 13 }, "text" : { "id" : 1452326705, @@ -37202,8 +37210,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166323581", - "name" : "Recommendation Annotation PA166323581", + "id" : "PA166323531", + "name" : "Recommendation Annotation PA166323531", "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, @@ -37216,31 +37224,31 @@ }, "dosingInformation" : false, "implications" : [ - "CACNA1S: Individuals are at increased risk of developing malignant hyperthermia if administered halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine, RYR1: These results do not eliminate the chance that this patient is susceptible to malignant hyperthermia (MH). The genetic cause of about half of all MH survivors, with MH susceptibility confirmed by contracture test, remains unknown (PMID 28902675)." + "RYR1: Individuals are at increased risk of developing malignant hyperthermia if administered halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine" ], - "lookupKey" : {"RYR1": "Uncertain Susceptibility", "CACNA1S": "Malignant Hyperthermia Susceptibility"}, + "lookupKey" : {"RYR1": "Malignant Hyperthermia Susceptibility", "CACNA1S": "No Result"}, "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA451522", - "name" : "succinylcholine", - "version" : 7 + "id" : "PA450434", + "name" : "methoxyflurane", + "version" : 34 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166303941", "name" : "Annotation of CPIC Guideline for desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, succinylcholine and CACNA1S, RYR1", - "version" : 2 + "version" : 13 }, "text" : { - "id" : 1452326700, - "html" : "

Halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine are relatively contraindicated in persons with malignant hyperthermia susceptibility (MHS). They should not be used, except in extraordinary circumstances where the benefits outweigh the risks. In general, alternative anesthetics are widely available and effective in patients with MHS.

\n

A list of unsafe halogenated volatile anesthetics or depolarizing muscle relaxants and alternative anesthetics can be found at http://www.mhaus.org/healthcare-professionals/be-prepared/safe-and-unsafe-anesthetics. Individuals who have biallelic (homozygous or compound heterozygous) pathogenic variants in CACNA1S generally will have autosomal recessive myopathies and should be managed according to the standard of care for those disorders. Although some may, indeed, have susceptibility to anesthetic agents, the recommendations described here cannot adequately address such patients, and they should be managed by a physician who is knowledgeable regarding those disorders.

\n", + "id" : 1452326650, + "html" : "

Based on RYR1 status, halogenated volatile anesthetics or the depolarizing muscle relaxant succinylcholine are relatively contraindicated in persons with malignant hyperthermia susceptibility (MHS). They should not be used, except in extraordinary circumstances where the benefits outweigh the risks. In general, alternative anesthetics are widely available and effective in patients with MHS.

\n

A list of unsafe halogenated volatile anesthetics or depolarizing muscle relaxants and alternative anesthetics can be found at http://www.mhaus.org/healthcare-professionals/be-prepared/safe-and-unsafe-anesthetics. Individuals who have biallelic (homozygous or compound heterozygous) pathogenic variants in RYR1 generally will have autosomal recessive myopathies and should be managed according to the standard of care for those disorders. Although some may, indeed, have susceptibility to anesthetic agents, the recommendations described here cannot adequately address such patients, and they should be managed by a physician who is knowledgeable regarding those disorders.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166303941" @@ -37474,7 +37482,7 @@ "pediatricMarkdown" : { "id" : 1451266642, "html" : "

Guideline excerpt: "There are scarce studies focusing solely on CYP2D6 or CYP2C19 genotype and association with pharmacokinetic parameters or treatment outcomes of TCAs in pediatric patients. Although further genomic ontogeny studies are needed, there is a lack of evidence suggesting that this guideline cannot be extrapolated to pediatric patients."

\n", - "version" : 0 + "version" : 1 }, "recommendation" : true, "relatedAlleles" : [], @@ -37483,7 +37491,7 @@ "objCls" : "Chemical", "id" : "PA449233", "name" : "desipramine", - "version" : 17 + "version" : 45 } ], "relatedGenes" : [ @@ -37492,14 +37500,14 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "CPIC", "summaryMarkdown" : { "id" : 1447981946, "html" : "

Tricyclic antidepressants have comparable pharmacokinetic properties, it may be reasonable to apply the CPIC Dosing Guideline for amitriptyline/nortriptyline and CYP2C19, CYP2D6 to other tricyclics including desipramine. The CPIC Dosing Guideline update for nortriptyline recommends a 25% dose reduction for CYP2D6 intermediate metabolizers. For CYP2D6 ultrarapid or poor metabolizers, an alternative drug should be considered. If nortriptyline is warranted, consider a 50% dose reduction in CYP2D6 poor metabolizers.

\n", - "version" : 1 + "version" : 2 }, "terms" : [], "textMarkdown" : { @@ -37508,13 +37516,13 @@ "version" : 0 }, "userId" : "whaleyr", - "version" : 44 + "version" : 109 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166297650", - "name" : "Recommendation PA166297650", + "id" : "PA166297133", + "name" : "Recommendation PA166297133", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -37529,7 +37537,7 @@ "implications" : [ "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "2.25"}, + "lookupKey" : {"CYP2D6": "1.75"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -37537,26 +37545,26 @@ "objCls" : "Chemical", "id" : "PA449233", "name" : "desipramine", - "version" : 17 + "version" : 45 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105002", "name" : "Annotation of CPIC Guideline for desipramine and CYP2D6", - "version" : 44 + "version" : 109 }, "text" : { - "id" : 1452060252, + "id" : 1452059735, "html" : "

Initiate therapy with recommended starting dose

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297663", - "name" : "Recommendation PA166297663", + "id" : "PA166297664", + "name" : "Recommendation PA166297664", "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, @@ -37571,7 +37579,7 @@ "implications" : [ "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers. Higher plasma concentrations of active drug will increase the probability of side effects." ], - "lookupKey" : {"CYP2D6": "0.5"}, + "lookupKey" : {"CYP2D6": "0.25"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -37579,41 +37587,71 @@ "objCls" : "Chemical", "id" : "PA449233", "name" : "desipramine", - "version" : 17 + "version" : 45 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105002", "name" : "Annotation of CPIC Guideline for desipramine and CYP2D6", - "version" : 44 + "version" : 109 }, "text" : { - "id" : 1452060265, + "id" : 1452060266, "html" : "

Consider a 25% reduction of recommended starting dose. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297632", - "name" : "Recommendation PA166297632", + "id" : "PA166301322", + "name" : "Recommendation Annotation PA166301322", "alternateDrugAvailable" : false, + "dosingInformation" : false, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA449233", + "name" : "desipramine", + "version" : 45 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166105002", + "name" : "Annotation of CPIC Guideline for desipramine and CYP2D6", + "version" : 109 + }, + "text" : { + "id" : 1452095641, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166297625", + "name" : "Recommendation PA166297625", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2D6: Normal metabolism of TCAs" + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers. Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure." ], - "lookupKey" : {"CYP2D6": "1.25"}, + "lookupKey" : {"CYP2D6": "4.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -37621,26 +37659,26 @@ "objCls" : "Chemical", "id" : "PA449233", "name" : "desipramine", - "version" : 17 + "version" : 45 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105002", "name" : "Annotation of CPIC Guideline for desipramine and CYP2D6", - "version" : 44 + "version" : 109 }, "text" : { - "id" : 1452060234, - "html" : "

Initiate therapy with recommended starting dose

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060227, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Utilize therapeutic drug monitoring to guide dose adjustments.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297658", - "name" : "Recommendation PA166297658", + "id" : "PA166297638", + "name" : "Recommendation PA166297638", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -37655,7 +37693,7 @@ "implications" : [ "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers. Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure." ], - "lookupKey" : {"CYP2D6": "≥3.5"}, + "lookupKey" : {"CYP2D6": "3.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -37663,17 +37701,59 @@ "objCls" : "Chemical", "id" : "PA449233", "name" : "desipramine", - "version" : 17 + "version" : 45 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105002", "name" : "Annotation of CPIC Guideline for desipramine and CYP2D6", - "version" : 44 + "version" : 109 }, "text" : { - "id" : 1452060260, + "id" : 1452060240, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Utilize therapeutic drug monitoring to guide dose adjustments.

\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166297649", + "name" : "Recommendation PA166297649", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981565059, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers. Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure." + ], + "lookupKey" : {"CYP2D6": "2.5"}, + "otherPrescribingGuidance" : false, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA449233", + "name" : "desipramine", + "version" : 45 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166105002", + "name" : "Annotation of CPIC Guideline for desipramine and CYP2D6", + "version" : 109 + }, + "text" : { + "id" : 1452060251, "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Utilize therapeutic drug monitoring to guide dose adjustments.

\n", "version" : 0 }, @@ -37705,14 +37785,14 @@ "objCls" : "Chemical", "id" : "PA449233", "name" : "desipramine", - "version" : 17 + "version" : 45 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105002", "name" : "Annotation of CPIC Guideline for desipramine and CYP2D6", - "version" : 44 + "version" : 109 }, "text" : { "id" : 1452060256, @@ -37723,8 +37803,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297637", - "name" : "Recommendation PA166297637", + "id" : "PA166297655", + "name" : "Recommendation PA166297655", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -37739,7 +37819,7 @@ "implications" : [ "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers. Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure." ], - "lookupKey" : {"CYP2D6": "2.75"}, + "lookupKey" : {"CYP2D6": "≥5.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -37747,17 +37827,17 @@ "objCls" : "Chemical", "id" : "PA449233", "name" : "desipramine", - "version" : 17 + "version" : 45 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105002", "name" : "Annotation of CPIC Guideline for desipramine and CYP2D6", - "version" : 44 + "version" : 109 }, "text" : { - "id" : 1452060239, + "id" : 1452060257, "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Utilize therapeutic drug monitoring to guide dose adjustments.

\n", "version" : 0 }, @@ -37765,8 +37845,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297659", - "name" : "Recommendation PA166297659", + "id" : "PA166297657", + "name" : "Recommendation PA166297657", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -37781,7 +37861,7 @@ "implications" : [ "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers. Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure." ], - "lookupKey" : {"CYP2D6": "≥3.25"}, + "lookupKey" : {"CYP2D6": "≥4.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -37789,17 +37869,17 @@ "objCls" : "Chemical", "id" : "PA449233", "name" : "desipramine", - "version" : 17 + "version" : 45 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105002", "name" : "Annotation of CPIC Guideline for desipramine and CYP2D6", - "version" : 44 + "version" : 109 }, "text" : { - "id" : 1452060261, + "id" : 1452060259, "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Utilize therapeutic drug monitoring to guide dose adjustments.

\n", "version" : 0 }, @@ -37807,92 +37887,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297664", - "name" : "Recommendation PA166297664", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 981565059, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : true, - "implications" : [ - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers. Higher plasma concentrations of active drug will increase the probability of side effects." - ], - "lookupKey" : {"CYP2D6": "0.25"}, - "otherPrescribingGuidance" : false, - "population" : "general", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA449233", - "name" : "desipramine", - "version" : 17 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166105002", - "name" : "Annotation of CPIC Guideline for desipramine and CYP2D6", - "version" : 44 - }, - "text" : { - "id" : 1452060266, - "html" : "

Consider a 25% reduction of recommended starting dose. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166297651", - "name" : "Recommendation PA166297651", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 981501930, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "CYP2D6: Normal metabolism of TCAs" - ], - "lookupKey" : {"CYP2D6": "2.0"}, - "otherPrescribingGuidance" : false, - "population" : "general", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA449233", - "name" : "desipramine", - "version" : 17 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166105002", - "name" : "Annotation of CPIC Guideline for desipramine and CYP2D6", - "version" : 44 - }, - "text" : { - "id" : 1452060253, - "html" : "

Initiate therapy with recommended starting dose

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166297655", - "name" : "Recommendation PA166297655", + "id" : "PA166297658", + "name" : "Recommendation PA166297658", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -37907,7 +37903,7 @@ "implications" : [ "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers. Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure." ], - "lookupKey" : {"CYP2D6": "≥5.0"}, + "lookupKey" : {"CYP2D6": "≥3.5"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -37915,17 +37911,17 @@ "objCls" : "Chemical", "id" : "PA449233", "name" : "desipramine", - "version" : 17 + "version" : 45 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105002", "name" : "Annotation of CPIC Guideline for desipramine and CYP2D6", - "version" : 44 + "version" : 109 }, "text" : { - "id" : 1452060257, + "id" : 1452060260, "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Utilize therapeutic drug monitoring to guide dose adjustments.

\n", "version" : 0 }, @@ -37933,8 +37929,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297625", - "name" : "Recommendation PA166297625", + "id" : "PA166297659", + "name" : "Recommendation PA166297659", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -37949,7 +37945,7 @@ "implications" : [ "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers. Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure." ], - "lookupKey" : {"CYP2D6": "4.0"}, + "lookupKey" : {"CYP2D6": "≥3.25"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -37957,17 +37953,17 @@ "objCls" : "Chemical", "id" : "PA449233", "name" : "desipramine", - "version" : 17 + "version" : 45 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105002", "name" : "Annotation of CPIC Guideline for desipramine and CYP2D6", - "version" : 44 + "version" : 109 }, "text" : { - "id" : 1452060227, + "id" : 1452060261, "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Utilize therapeutic drug monitoring to guide dose adjustments.

\n", "version" : 0 }, @@ -37975,8 +37971,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297638", - "name" : "Recommendation PA166297638", + "id" : "PA166297660", + "name" : "Recommendation PA166297660", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -37991,7 +37987,7 @@ "implications" : [ "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers. Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure." ], - "lookupKey" : {"CYP2D6": "3.0"}, + "lookupKey" : {"CYP2D6": "≥3.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -37999,17 +37995,17 @@ "objCls" : "Chemical", "id" : "PA449233", "name" : "desipramine", - "version" : 17 + "version" : 45 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105002", "name" : "Annotation of CPIC Guideline for desipramine and CYP2D6", - "version" : 44 + "version" : 109 }, "text" : { - "id" : 1452060240, + "id" : 1452060262, "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Utilize therapeutic drug monitoring to guide dose adjustments.

\n", "version" : 0 }, @@ -38017,23 +38013,23 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297660", - "name" : "Recommendation PA166297660", - "alternateDrugAvailable" : true, + "id" : "PA166297626", + "name" : "Recommendation PA166297626", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers. Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure." + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥3.0"}, + "lookupKey" : {"CYP2D6": "1.5"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -38041,41 +38037,41 @@ "objCls" : "Chemical", "id" : "PA449233", "name" : "desipramine", - "version" : 17 + "version" : 45 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105002", "name" : "Annotation of CPIC Guideline for desipramine and CYP2D6", - "version" : 44 + "version" : 109 }, "text" : { - "id" : 1452060262, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Utilize therapeutic drug monitoring to guide dose adjustments.

\n", + "id" : 1452060228, + "html" : "

Initiate therapy with recommended starting dose

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297665", - "name" : "Recommendation PA166297665", - "alternateDrugAvailable" : true, + "id" : "PA166297632", + "name" : "Recommendation PA166297632", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers. Higher plasma concentrations of active drug will increase the probability of side effects." + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "0.0"}, + "lookupKey" : {"CYP2D6": "1.25"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -38083,41 +38079,41 @@ "objCls" : "Chemical", "id" : "PA449233", "name" : "desipramine", - "version" : 17 + "version" : 45 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105002", "name" : "Annotation of CPIC Guideline for desipramine and CYP2D6", - "version" : 44 + "version" : 109 }, "text" : { - "id" : 1452060267, - "html" : "

Avoid tricyclic use due to potential for side effects. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider a 50% reduction of recommended starting dose. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452060234, + "html" : "

Initiate therapy with recommended starting dose

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297656", - "name" : "Recommendation PA166297656", - "alternateDrugAvailable" : true, + "id" : "PA166297650", + "name" : "Recommendation PA166297650", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers. Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure." + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥3.75"}, + "lookupKey" : {"CYP2D6": "2.25"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -38125,26 +38121,26 @@ "objCls" : "Chemical", "id" : "PA449233", "name" : "desipramine", - "version" : 17 + "version" : 45 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105002", "name" : "Annotation of CPIC Guideline for desipramine and CYP2D6", - "version" : 44 + "version" : 109 }, "text" : { - "id" : 1452060258, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Utilize therapeutic drug monitoring to guide dose adjustments.

\n", + "id" : 1452060252, + "html" : "

Initiate therapy with recommended starting dose

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297626", - "name" : "Recommendation PA166297626", + "id" : "PA166297651", + "name" : "Recommendation PA166297651", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -38159,7 +38155,7 @@ "implications" : [ "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "1.5"}, + "lookupKey" : {"CYP2D6": "2.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -38167,41 +38163,41 @@ "objCls" : "Chemical", "id" : "PA449233", "name" : "desipramine", - "version" : 17 + "version" : 45 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105002", "name" : "Annotation of CPIC Guideline for desipramine and CYP2D6", - "version" : 44 + "version" : 109 }, "text" : { - "id" : 1452060228, + "id" : 1452060253, "html" : "

Initiate therapy with recommended starting dose

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297133", - "name" : "Recommendation PA166297133", + "id" : "PA166297661", + "name" : "Recommendation PA166297661", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2D6: Normal metabolism of TCAs" + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers. Higher plasma concentrations of active drug will increase the probability of side effects." ], - "lookupKey" : {"CYP2D6": "1.75"}, + "lookupKey" : {"CYP2D6": "1.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -38209,26 +38205,26 @@ "objCls" : "Chemical", "id" : "PA449233", "name" : "desipramine", - "version" : 17 + "version" : 45 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105002", "name" : "Annotation of CPIC Guideline for desipramine and CYP2D6", - "version" : 44 + "version" : 109 }, "text" : { - "id" : 1452059735, - "html" : "

Initiate therapy with recommended starting dose

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060263, + "html" : "

Consider a 25% reduction of recommended starting dose. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297661", - "name" : "Recommendation PA166297661", + "id" : "PA166297662", + "name" : "Recommendation PA166297662", "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, @@ -38243,7 +38239,7 @@ "implications" : [ "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers. Higher plasma concentrations of active drug will increase the probability of side effects." ], - "lookupKey" : {"CYP2D6": "1.0"}, + "lookupKey" : {"CYP2D6": "0.75"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -38251,26 +38247,26 @@ "objCls" : "Chemical", "id" : "PA449233", "name" : "desipramine", - "version" : 17 + "version" : 45 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105002", "name" : "Annotation of CPIC Guideline for desipramine and CYP2D6", - "version" : 44 + "version" : 109 }, "text" : { - "id" : 1452060263, + "id" : 1452060264, "html" : "

Consider a 25% reduction of recommended starting dose. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297662", - "name" : "Recommendation PA166297662", + "id" : "PA166297663", + "name" : "Recommendation PA166297663", "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, @@ -38285,7 +38281,7 @@ "implications" : [ "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers. Higher plasma concentrations of active drug will increase the probability of side effects." ], - "lookupKey" : {"CYP2D6": "0.75"}, + "lookupKey" : {"CYP2D6": "0.5"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -38293,26 +38289,26 @@ "objCls" : "Chemical", "id" : "PA449233", "name" : "desipramine", - "version" : 17 + "version" : 45 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105002", "name" : "Annotation of CPIC Guideline for desipramine and CYP2D6", - "version" : 44 + "version" : 109 }, "text" : { - "id" : 1452060264, + "id" : 1452060265, "html" : "

Consider a 25% reduction of recommended starting dose. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297657", - "name" : "Recommendation PA166297657", + "id" : "PA166297637", + "name" : "Recommendation PA166297637", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -38327,7 +38323,7 @@ "implications" : [ "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers. Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure." ], - "lookupKey" : {"CYP2D6": "≥4.0"}, + "lookupKey" : {"CYP2D6": "2.75"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -38335,71 +38331,83 @@ "objCls" : "Chemical", "id" : "PA449233", "name" : "desipramine", - "version" : 17 + "version" : 45 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105002", "name" : "Annotation of CPIC Guideline for desipramine and CYP2D6", - "version" : 44 + "version" : 109 }, "text" : { - "id" : 1452060259, + "id" : 1452060239, "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Utilize therapeutic drug monitoring to guide dose adjustments.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301322", - "name" : "Recommendation Annotation PA166301322", - "alternateDrugAvailable" : false, - "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations"}, + "id" : "PA166297656", + "name" : "Recommendation PA166297656", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981565059, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers. Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure." + ], + "lookupKey" : {"CYP2D6": "≥3.75"}, "otherPrescribingGuidance" : false, + "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449233", "name" : "desipramine", - "version" : 17 + "version" : 45 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105002", "name" : "Annotation of CPIC Guideline for desipramine and CYP2D6", - "version" : 44 + "version" : 109 }, "text" : { - "id" : 1452095641, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "id" : 1452060258, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Utilize therapeutic drug monitoring to guide dose adjustments.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297666", - "name" : "Recommendation PA166297666", - "alternateDrugAvailable" : false, + "id" : "PA166297665", + "name" : "Recommendation PA166297665", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2D6: n/a" + "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers. Higher plasma concentrations of active drug will increase the probability of side effects." ], - "lookupKey" : {"CYP2D6": "n/a"}, + "lookupKey" : {"CYP2D6": "0.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -38407,41 +38415,41 @@ "objCls" : "Chemical", "id" : "PA449233", "name" : "desipramine", - "version" : 17 + "version" : 45 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105002", "name" : "Annotation of CPIC Guideline for desipramine and CYP2D6", - "version" : 44 + "version" : 109 }, "text" : { - "id" : 1452060268, - "html" : "

No recommendation

\n", + "id" : 1452060267, + "html" : "

Avoid tricyclic use due to potential for side effects. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider a 50% reduction of recommended starting dose. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297649", - "name" : "Recommendation PA166297649", - "alternateDrugAvailable" : true, + "id" : "PA166297666", + "name" : "Recommendation PA166297666", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers. Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure." + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "2.5"}, + "lookupKey" : {"CYP2D6": "n/a"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -38449,21 +38457,21 @@ "objCls" : "Chemical", "id" : "PA449233", "name" : "desipramine", - "version" : 17 + "version" : 45 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105002", "name" : "Annotation of CPIC Guideline for desipramine and CYP2D6", - "version" : 44 + "version" : 109 }, "text" : { - "id" : 1452060251, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Utilize therapeutic drug monitoring to guide dose adjustments.

\n", + "id" : 1452060268, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166105002" @@ -38608,7 +38616,7 @@ "objCls" : "Chemical", "id" : "PA166110257", "name" : "dexlansoprazole", - "version" : 6 + "version" : 8 } ], "relatedGenes" : [ @@ -38617,7 +38625,7 @@ "id" : "PA124", "symbol" : "CYP2C19", "name" : "cytochrome P450 family 2 subfamily C member 19", - "version" : 7210 + "version" : 7266 } ], "source" : "CPIC", @@ -38633,13 +38641,13 @@ "version" : 2 }, "userId" : "katrin", - "version" : 8 + "version" : 40 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166297667", - "name" : "Recommendation PA166297667", + "id" : "PA166297644", + "name" : "Recommendation PA166297644", "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, @@ -38652,9 +38660,9 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Decreased plasma concentrations of PPIs compared to CYP2C19 NMs; increased risk of therapeutic failure" + "CYP2C19: Increased plasma concentration of PPI compared to CYP2C19 NMs; increased chance of efficacy and potentially toxicity" ], - "lookupKey" : {"CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -38662,26 +38670,26 @@ "objCls" : "Chemical", "id" : "PA166110257", "name" : "dexlansoprazole", - "version" : 6 + "version" : 8 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166219301", "name" : "Annotation of CPIC Guideline for dexlansoprazole and CYP2C19", - "version" : 8 + "version" : 40 }, "text" : { - "id" : 1452060269, - "html" : "

Increase starting daily dose by 100%. Daily dose may be given in divided doses. Monitor for efficacy.

\n", + "id" : 1452060246, + "html" : "

Initiate standard starting daily dose. For chronic therapy (>12 weeks) and efficacy achieved, consider 50% reduction in daily dose and monitor for continued efficacy.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297672", - "name" : "Recommendation PA166297672", + "id" : "PA166297667", + "name" : "Recommendation PA166297667", "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, @@ -38694,9 +38702,9 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased plasma concentration of PPI compared to CYP2C19 NMs; increased chance of efficacy and potentially toxicity" + "CYP2C19: Decreased plasma concentrations of PPIs compared to CYP2C19 NMs; increased risk of therapeutic failure" ], - "lookupKey" : {"CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -38704,18 +38712,18 @@ "objCls" : "Chemical", "id" : "PA166110257", "name" : "dexlansoprazole", - "version" : 6 + "version" : 8 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166219301", "name" : "Annotation of CPIC Guideline for dexlansoprazole and CYP2C19", - "version" : 8 + "version" : 40 }, "text" : { - "id" : 1452060274, - "html" : "

Initiate standard starting daily dose. For chronic therapy (>12 weeks) and efficacy achieved, consider 50% reduction in daily dose and monitor for continued efficacy.

\n", + "id" : 1452060269, + "html" : "

Increase starting daily dose by 100%. Daily dose may be given in divided doses. Monitor for efficacy.

\n", "version" : 0 }, "version" : 0 @@ -38746,14 +38754,14 @@ "objCls" : "Chemical", "id" : "PA166110257", "name" : "dexlansoprazole", - "version" : 6 + "version" : 8 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166219301", "name" : "Annotation of CPIC Guideline for dexlansoprazole and CYP2C19", - "version" : 8 + "version" : 40 }, "text" : { "id" : 1452060270, @@ -38764,23 +38772,23 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297673", - "name" : "Recommendation PA166297673", + "id" : "PA166297669", + "name" : "Recommendation PA166297669", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a" + "CYP2C19: Normal PPI metabolism; may be at increased risk of therapeutic failure compared to CYP2C19 IMs and PMs" ], - "lookupKey" : {"CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -38788,26 +38796,26 @@ "objCls" : "Chemical", "id" : "PA166110257", "name" : "dexlansoprazole", - "version" : 6 + "version" : 8 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166219301", "name" : "Annotation of CPIC Guideline for dexlansoprazole and CYP2C19", - "version" : 8 + "version" : 40 }, "text" : { - "id" : 1452060275, - "html" : "

No recommendation

\n", + "id" : 1452060271, + "html" : "

Initiate standard starting daily dose. Consider increasing dose by 50-100% for the treatment of H. pylori infection and erosive esophagitis. Daily dose may be given in divided doses.\nMonitor for efficacy.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297669", - "name" : "Recommendation PA166297669", + "id" : "PA166297670", + "name" : "Recommendation PA166297670", "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, @@ -38820,9 +38828,9 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal PPI metabolism; may be at increased risk of therapeutic failure compared to CYP2C19 IMs and PMs" + "CYP2C19: Likely increased plasma concentration of PPI compared to CYP2C19 NMs; likely increased chance of efficacy and potentially toxicity" ], - "lookupKey" : {"CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -38830,26 +38838,26 @@ "objCls" : "Chemical", "id" : "PA166110257", "name" : "dexlansoprazole", - "version" : 6 + "version" : 8 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166219301", "name" : "Annotation of CPIC Guideline for dexlansoprazole and CYP2C19", - "version" : 8 + "version" : 40 }, "text" : { - "id" : 1452060271, - "html" : "

Initiate standard starting daily dose. Consider increasing dose by 50-100% for the treatment of H. pylori infection and erosive esophagitis. Daily dose may be given in divided doses.\nMonitor for efficacy.

\n", + "id" : 1452060272, + "html" : "

Initiate standard starting daily dose. For chronic therapy (>12 weeks) and efficacy achieved, consider 50% reduction in daily dose and monitor for continued efficacy.

\n

Other Considerations

\n

The strength of recommendation for "likely" phenotypes are the same as their respective confirmed phenotypes. "Likely" indicates the uncertainty in the phenotype assignment, but it is reasonable to apply the recommendation for the confirmed phenotype to the corresponding "likely" phenotype.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297670", - "name" : "Recommendation PA166297670", + "id" : "PA166297671", + "name" : "Recommendation PA166297671", "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, @@ -38864,7 +38872,7 @@ "implications" : [ "CYP2C19: Likely increased plasma concentration of PPI compared to CYP2C19 NMs; likely increased chance of efficacy and potentially toxicity" ], - "lookupKey" : {"CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -38872,17 +38880,17 @@ "objCls" : "Chemical", "id" : "PA166110257", "name" : "dexlansoprazole", - "version" : 6 + "version" : 8 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166219301", "name" : "Annotation of CPIC Guideline for dexlansoprazole and CYP2C19", - "version" : 8 + "version" : 40 }, "text" : { - "id" : 1452060272, + "id" : 1452060273, "html" : "

Initiate standard starting daily dose. For chronic therapy (>12 weeks) and efficacy achieved, consider 50% reduction in daily dose and monitor for continued efficacy.

\n

Other Considerations

\n

The strength of recommendation for "likely" phenotypes are the same as their respective confirmed phenotypes. "Likely" indicates the uncertainty in the phenotype assignment, but it is reasonable to apply the recommendation for the confirmed phenotype to the corresponding "likely" phenotype.

\n", "version" : 0 }, @@ -38890,8 +38898,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297644", - "name" : "Recommendation PA166297644", + "id" : "PA166297672", + "name" : "Recommendation PA166297672", "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, @@ -38906,7 +38914,7 @@ "implications" : [ "CYP2C19: Increased plasma concentration of PPI compared to CYP2C19 NMs; increased chance of efficacy and potentially toxicity" ], - "lookupKey" : {"CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -38914,17 +38922,17 @@ "objCls" : "Chemical", "id" : "PA166110257", "name" : "dexlansoprazole", - "version" : 6 + "version" : 8 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166219301", "name" : "Annotation of CPIC Guideline for dexlansoprazole and CYP2C19", - "version" : 8 + "version" : 40 }, "text" : { - "id" : 1452060246, + "id" : 1452060274, "html" : "

Initiate standard starting daily dose. For chronic therapy (>12 weeks) and efficacy achieved, consider 50% reduction in daily dose and monitor for continued efficacy.

\n", "version" : 0 }, @@ -38932,23 +38940,23 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297671", - "name" : "Recommendation PA166297671", + "id" : "PA166297673", + "name" : "Recommendation PA166297673", "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Likely increased plasma concentration of PPI compared to CYP2C19 NMs; likely increased chance of efficacy and potentially toxicity" + "CYP2C19: n/a" ], - "lookupKey" : {"CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -38956,21 +38964,21 @@ "objCls" : "Chemical", "id" : "PA166110257", "name" : "dexlansoprazole", - "version" : 6 + "version" : 8 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166219301", "name" : "Annotation of CPIC Guideline for dexlansoprazole and CYP2C19", - "version" : 8 + "version" : 40 }, "text" : { - "id" : 1452060273, - "html" : "

Initiate standard starting daily dose. For chronic therapy (>12 weeks) and efficacy achieved, consider 50% reduction in daily dose and monitor for continued efficacy.

\n

Other Considerations

\n

The strength of recommendation for "likely" phenotypes are the same as their respective confirmed phenotypes. "Likely" indicates the uncertainty in the phenotype assignment, but it is reasonable to apply the recommendation for the confirmed phenotype to the corresponding "likely" phenotype.

\n", + "id" : 1452060275, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166219301" @@ -39211,7 +39219,7 @@ "pediatricMarkdown" : { "id" : 1451266664, "html" : "

Guideline excerpt: "There are scarce studies focusing solely on CYP2D6 or CYP2C19 genotype and association with pharmacokinetic parameters or treatment outcomes of TCAs in pediatric patients. CYP2D6 activity is fully mature by early childhood, but CYP2C19 activity may be increased in children relative to adults. Although further genomic ontogeny studies are needed, there is a lack of evidence suggesting that this guideline cannot be extrapolated to pediatric patients."

\n", - "version" : 0 + "version" : 1 }, "recommendation" : true, "relatedAlleles" : [], @@ -39220,7 +39228,7 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "relatedGenes" : [ @@ -39229,21 +39237,21 @@ "id" : "PA124", "symbol" : "CYP2C19", "name" : "cytochrome P450 family 2 subfamily C member 19", - "version" : 7210 + "version" : 7266 }, { "objCls" : "Gene", "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "CPIC", "summaryMarkdown" : { "id" : 1447981938, "html" : "

Tricyclic antidepressants have comparable pharmacokinetic properties, it may be reasonable to apply the CPIC Dosing Guideline for amitriptyline and CYP2C19, CYP2D6 to other tricyclics including doxepin. The CPIC Dosing Guideline update for amitriptyline recommends an alternative drug for CYP2D6 ultrarapid or poor metabolizers and CYP2C19 ultrarapid, rapid or poor metabolizers. If amitriptyline is warranted, consider a 50% dose reduction in CYP2D6 or CYP2C19 poor metabolizers. For CYP2D6 intermediate metabolizers, a 25% dose reduction should be considered.

\n", - "version" : 1 + "version" : 2 }, "terms" : [], "textMarkdown" : { @@ -39252,14 +39260,14 @@ "version" : 1 }, "userId" : "whaleyr", - "version" : 47 + "version" : 99 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166297870", - "name" : "Recommendation PA166297870", - "alternateDrugAvailable" : true, + "id" : "PA166297717", + "name" : "Recommendation PA166297717", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -39269,12 +39277,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -39282,69 +39290,296 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060472, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060319, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "version" : 0 + }, + "version" : 1 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166301381", + "name" : "Recommendation Annotation PA166301381", + "alternateDrugAvailable" : false, + "dosingInformation" : false, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Indeterminate"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA449409", + "name" : "doxepin", + "version" : 38 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166105000", + "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", + "version" : 99 + }, + "text" : { + "id" : 1452095720, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297773", - "name" : "Recommendation PA166297773", - "alternateDrugAvailable" : true, - "classification" : { - "id" : 981565059, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", - "valid" : true, + "id" : "PA166301382", + "name" : "Recommendation Annotation PA166301382", + "alternateDrugAvailable" : false, + "dosingInformation" : false, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Intermediate Metabolizer"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA449409", + "name" : "doxepin", + "version" : 38 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166105000", + "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", + "version" : 99 + }, + "text" : { + "id" : 1452095721, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", "version" : 0 }, - "dosingInformation" : true, - "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166301383", + "name" : "Recommendation Annotation PA166301383", + "alternateDrugAvailable" : false, + "dosingInformation" : false, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Likely Intermediate Metabolizer"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA449409", + "name" : "doxepin", + "version" : 38 + } ], - "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Intermediate Metabolizer"}, + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166105000", + "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", + "version" : 99 + }, + "text" : { + "id" : 1452095722, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166301384", + "name" : "Recommendation Annotation PA166301384", + "alternateDrugAvailable" : false, + "dosingInformation" : false, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, - "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060375, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452095723, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297689", - "name" : "Recommendation PA166297689", + "id" : "PA166301385", + "name" : "Recommendation Annotation PA166301385", + "alternateDrugAvailable" : false, + "dosingInformation" : false, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "No Result"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA449409", + "name" : "doxepin", + "version" : 38 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166105000", + "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", + "version" : 99 + }, + "text" : { + "id" : 1452095724, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166301386", + "name" : "Recommendation Annotation PA166301386", + "alternateDrugAvailable" : false, + "dosingInformation" : false, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Normal Metabolizer"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA449409", + "name" : "doxepin", + "version" : 38 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166105000", + "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", + "version" : 99 + }, + "text" : { + "id" : 1452095725, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166301387", + "name" : "Recommendation Annotation PA166301387", + "alternateDrugAvailable" : false, + "dosingInformation" : false, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Poor Metabolizer"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA449409", + "name" : "doxepin", + "version" : 38 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166105000", + "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", + "version" : 99 + }, + "text" : { + "id" : 1452095726, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166301388", + "name" : "Recommendation Annotation PA166301388", + "alternateDrugAvailable" : false, + "dosingInformation" : false, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Rapid Metabolizer"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA449409", + "name" : "doxepin", + "version" : 38 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166105000", + "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", + "version" : 99 + }, + "text" : { + "id" : 1452095727, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166301389", + "name" : "Recommendation Annotation PA166301389", + "alternateDrugAvailable" : false, + "dosingInformation" : false, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Ultrarapid Metabolizer"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA449409", + "name" : "doxepin", + "version" : 38 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166105000", + "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", + "version" : 99 + }, + "text" : { + "id" : 1452095728, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166297772", + "name" : "Recommendation PA166297772", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -39357,10 +39592,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -39368,27 +39603,27 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060291, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060374, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297676", - "name" : "Recommendation PA166297676", - "alternateDrugAvailable" : false, + "id" : "PA166297822", + "name" : "Recommendation PA166297822", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -39400,10 +39635,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -39411,26 +39646,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060278, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060424, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297839", - "name" : "Recommendation PA166297839", + "id" : "PA166297684", + "name" : "Recommendation PA166297684", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -39443,10 +39678,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -39454,26 +39689,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060441, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060286, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297883", - "name" : "Recommendation PA166297883", + "id" : "PA166297685", + "name" : "Recommendation PA166297685", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -39487,9 +39722,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: n/a" + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -39497,26 +39732,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060485, - "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. For tertiary amines, consider a 50% reduction of the recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060287, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297786", - "name" : "Recommendation PA166297786", + "id" : "PA166297687", + "name" : "Recommendation PA166297687", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -39529,10 +39764,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -39540,26 +39775,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060388, - "html" : "

Avoid doxepin use; If doxepin is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", + "id" : 1452060289, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297799", - "name" : "Recommendation PA166297799", + "id" : "PA166297688", + "name" : "Recommendation PA166297688", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -39573,9 +39808,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -39583,27 +39818,27 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060401, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060290, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297707", - "name" : "Recommendation PA166297707", - "alternateDrugAvailable" : false, + "id" : "PA166297689", + "name" : "Recommendation PA166297689", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -39615,10 +39850,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -39626,26 +39861,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060309, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060291, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297804", - "name" : "Recommendation PA166297804", + "id" : "PA166297690", + "name" : "Recommendation PA166297690", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -39659,9 +39894,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -39669,56 +39904,69 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060406, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452060292, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301382", - "name" : "Recommendation Annotation PA166301382", - "alternateDrugAvailable" : false, - "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Intermediate Metabolizer"}, + "id" : "PA166297691", + "name" : "Recommendation PA166297691", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981565059, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + ], + "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, + "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452095721, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "id" : 1452060293, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297795", - "name" : "Recommendation PA166297795", + "id" : "PA166297693", + "name" : "Recommendation PA166297693", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -39731,10 +39979,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -39742,27 +39990,27 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060397, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060295, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297698", - "name" : "Recommendation PA166297698", - "alternateDrugAvailable" : false, + "id" : "PA166297694", + "name" : "Recommendation PA166297694", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -39772,12 +40020,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -39785,27 +40033,27 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060300, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060296, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297716", - "name" : "Recommendation PA166297716", - "alternateDrugAvailable" : false, + "id" : "PA166297695", + "name" : "Recommendation PA166297695", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -39817,10 +40065,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -39828,26 +40076,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060318, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452060297, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297813", - "name" : "Recommendation PA166297813", + "id" : "PA166297696", + "name" : "Recommendation PA166297696", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -39861,9 +40109,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -39871,26 +40119,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060415, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452060298, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297760", - "name" : "Recommendation PA166297760", + "id" : "PA166297697", + "name" : "Recommendation PA166297697", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -39903,10 +40151,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -39914,26 +40162,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060362, - "html" : "

Avoid doxepin use. If a doxepin is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452060299, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297729", - "name" : "Recommendation PA166297729", + "id" : "PA166297708", + "name" : "Recommendation PA166297708", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -39947,9 +40195,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -39957,26 +40205,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060331, - "html" : "

Avoid doxepin use. If doxepin is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060310, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297826", - "name" : "Recommendation PA166297826", + "id" : "PA166297709", + "name" : "Recommendation PA166297709", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -39989,10 +40237,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -40000,26 +40248,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060428, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060311, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297874", - "name" : "Recommendation PA166297874", + "id" : "PA166297710", + "name" : "Recommendation PA166297710", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -40032,10 +40280,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: n/a" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -40043,27 +40291,27 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060476, - "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. If a tertiary amine is warranted, utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060312, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297887", - "name" : "Recommendation PA166297887", - "alternateDrugAvailable" : false, + "id" : "PA166297712", + "name" : "Recommendation PA166297712", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -40073,12 +40321,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: n/a" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -40086,42 +40334,42 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060489, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060314, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297742", - "name" : "Recommendation PA166297742", - "alternateDrugAvailable" : false, + "id" : "PA166297724", + "name" : "Recommendation PA166297724", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -40129,26 +40377,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060344, - "html" : "

No recommendation

\n", + "id" : 1452060326, + "html" : "

Avoid doxepin use. If doxepin is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297808", - "name" : "Recommendation PA166297808", + "id" : "PA166297725", + "name" : "Recommendation PA166297725", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -40161,10 +40409,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -40172,42 +40420,42 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060410, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452060327, + "html" : "

Avoid doxepin use. If doxepin is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297755", - "name" : "Recommendation PA166297755", - "alternateDrugAvailable" : false, + "id" : "PA166297726", + "name" : "Recommendation PA166297726", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -40215,26 +40463,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060357, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060328, + "html" : "

Avoid doxepin use. If doxepin is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297751", - "name" : "Recommendation PA166297751", + "id" : "PA166297727", + "name" : "Recommendation PA166297727", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -40250,7 +40498,7 @@ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -40258,17 +40506,17 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060353, + "id" : 1452060329, "html" : "

Avoid doxepin use. If doxepin is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, @@ -40276,24 +40524,24 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297817", - "name" : "Recommendation PA166297817", - "alternateDrugAvailable" : true, + "id" : "PA166297723", + "name" : "Recommendation PA166297723", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -40301,27 +40549,27 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060419, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452060325, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297861", - "name" : "Recommendation PA166297861", - "alternateDrugAvailable" : true, + "id" : "PA166297705", + "name" : "Recommendation PA166297705", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -40331,12 +40579,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -40344,42 +40592,42 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060463, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060307, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297764", - "name" : "Recommendation PA166297764", - "alternateDrugAvailable" : true, + "id" : "PA166297722", + "name" : "Recommendation PA166297722", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -40387,27 +40635,27 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060366, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060324, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297777", - "name" : "Recommendation PA166297777", - "alternateDrugAvailable" : true, + "id" : "PA166297698", + "name" : "Recommendation PA166297698", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -40417,12 +40665,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -40430,21 +40678,21 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060379, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060300, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -40473,27 +40721,27 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { "id" : 1452060323, "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297734", - "name" : "Recommendation PA166297734", - "alternateDrugAvailable" : true, + "id" : "PA166297678", + "name" : "Recommendation PA166297678", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -40503,12 +40751,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -40516,42 +40764,42 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060336, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060280, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297879", - "name" : "Recommendation PA166297879", - "alternateDrugAvailable" : true, + "id" : "PA166297720", + "name" : "Recommendation PA166297720", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: n/a" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -40559,27 +40807,27 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060481, - "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. For tertiary amines, consider a 50% reduction of the recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060322, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297831", - "name" : "Recommendation PA166297831", - "alternateDrugAvailable" : true, + "id" : "PA166297718", + "name" : "Recommendation PA166297718", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -40589,12 +40837,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -40602,42 +40850,42 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060433, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060320, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297747", - "name" : "Recommendation PA166297747", + "id" : "PA166297719", + "name" : "Recommendation PA166297719", "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: Normal metabolism of tertiary amines", "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -40645,26 +40893,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060349, + "id" : 1452060321, "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297681", - "name" : "Recommendation PA166297681", + "id" : "PA166297683", + "name" : "Recommendation PA166297683", "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, @@ -40680,7 +40928,7 @@ "CYP2C19: Normal metabolism of tertiary amines", "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -40688,27 +40936,27 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060283, + "id" : 1452060285, "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297844", - "name" : "Recommendation PA166297844", - "alternateDrugAvailable" : true, + "id" : "PA166297716", + "name" : "Recommendation PA166297716", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -40720,10 +40968,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: n/a", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -40731,27 +40979,27 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060446, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060318, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297840", - "name" : "Recommendation PA166297840", - "alternateDrugAvailable" : true, + "id" : "PA166297707", + "name" : "Recommendation PA166297707", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -40764,9 +41012,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -40774,42 +41022,42 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060442, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060309, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297743", - "name" : "Recommendation PA166297743", + "id" : "PA166297677", + "name" : "Recommendation PA166297677", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -40817,42 +41065,42 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060345, - "html" : "

No recommendation

\n", + "id" : 1452060279, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297756", - "name" : "Recommendation PA166297756", + "id" : "PA166297702", + "name" : "Recommendation PA166297702", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ "CYP2C19: n/a", - "CYP2D6: Normal metabolism of TCAs" + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -40860,27 +41108,27 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060358, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060304, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297809", - "name" : "Recommendation PA166297809", - "alternateDrugAvailable" : true, + "id" : "PA166297682", + "name" : "Recommendation PA166297682", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -40892,10 +41140,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -40903,27 +41151,27 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060411, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452060284, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297690", - "name" : "Recommendation PA166297690", - "alternateDrugAvailable" : true, + "id" : "PA166297715", + "name" : "Recommendation PA166297715", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -40935,10 +41183,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: n/a", "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -40946,27 +41194,27 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060292, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060317, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297853", - "name" : "Recommendation PA166297853", - "alternateDrugAvailable" : true, + "id" : "PA166297706", + "name" : "Recommendation PA166297706", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -40978,10 +41226,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -40989,27 +41237,27 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060455, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060308, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297769", - "name" : "Recommendation PA166297769", - "alternateDrugAvailable" : true, + "id" : "PA166297676", + "name" : "Recommendation PA166297676", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -41022,9 +41270,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -41032,27 +41280,27 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060371, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060278, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297866", - "name" : "Recommendation PA166297866", - "alternateDrugAvailable" : true, + "id" : "PA166297701", + "name" : "Recommendation PA166297701", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -41065,9 +41313,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -41075,27 +41323,27 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060468, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060303, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297738", - "name" : "Recommendation PA166297738", - "alternateDrugAvailable" : true, + "id" : "PA166297681", + "name" : "Recommendation PA166297681", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -41107,10 +41355,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -41118,27 +41366,27 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060340, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060283, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297835", - "name" : "Recommendation PA166297835", - "alternateDrugAvailable" : true, + "id" : "PA166297714", + "name" : "Recommendation PA166297714", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -41151,9 +41399,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -41161,27 +41409,27 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060437, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060316, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297782", - "name" : "Recommendation PA166297782", - "alternateDrugAvailable" : true, + "id" : "PA166297704", + "name" : "Recommendation PA166297704", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -41193,10 +41441,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -41204,27 +41452,27 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060384, - "html" : "

Avoid doxepin use; If doxepin is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", + "id" : 1452060306, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297685", - "name" : "Recommendation PA166297685", - "alternateDrugAvailable" : true, + "id" : "PA166297675", + "name" : "Recommendation PA166297675", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -41236,10 +41484,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -41247,26 +41495,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060287, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060277, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297703", - "name" : "Recommendation PA166297703", + "id" : "PA166297700", + "name" : "Recommendation PA166297700", "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, @@ -41279,10 +41527,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: n/a", "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -41290,27 +41538,27 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060305, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060302, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297800", - "name" : "Recommendation PA166297800", - "alternateDrugAvailable" : true, + "id" : "PA166297680", + "name" : "Recommendation PA166297680", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -41322,10 +41570,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -41333,27 +41581,27 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060402, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060282, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297848", - "name" : "Recommendation PA166297848", - "alternateDrugAvailable" : true, + "id" : "PA166297713", + "name" : "Recommendation PA166297713", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -41365,10 +41613,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: n/a", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -41376,57 +41624,70 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060450, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060315, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301386", - "name" : "Recommendation Annotation PA166301386", + "id" : "PA166297703", + "name" : "Recommendation PA166297703", "alternateDrugAvailable" : false, - "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Normal Metabolizer"}, + "classification" : { + "id" : 981565059, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + ], + "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, + "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452095725, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "id" : 1452060305, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297791", - "name" : "Recommendation PA166297791", - "alternateDrugAvailable" : true, + "id" : "PA166297674", + "name" : "Recommendation PA166297674", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -41438,10 +41699,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -41449,26 +41710,69 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060393, - "html" : "

Avoid doxepin use; If doxepin is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", + "id" : 1452060276, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297712", - "name" : "Recommendation PA166297712", + "id" : "PA166297699", + "name" : "Recommendation PA166297699", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 981565059, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "CYP2C19: n/a", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + ], + "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Indeterminate"}, + "otherPrescribingGuidance" : false, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA449409", + "name" : "doxepin", + "version" : 38 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166105000", + "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", + "version" : 99 + }, + "text" : { + "id" : 1452060301, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "version" : 0 + }, + "version" : 1 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166297729", + "name" : "Recommendation PA166297729", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -41482,9 +41786,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -41492,26 +41796,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060314, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060331, + "html" : "

Avoid doxepin use. If doxepin is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297694", - "name" : "Recommendation PA166297694", + "id" : "PA166297730", + "name" : "Recommendation PA166297730", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -41525,9 +41829,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -41535,26 +41839,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060296, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060332, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297857", - "name" : "Recommendation PA166297857", + "id" : "PA166297731", + "name" : "Recommendation PA166297731", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -41567,10 +41871,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -41578,26 +41882,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060459, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060333, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297725", - "name" : "Recommendation PA166297725", + "id" : "PA166297732", + "name" : "Recommendation PA166297732", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -41610,10 +41914,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -41621,26 +41925,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060327, - "html" : "

Avoid doxepin use. If doxepin is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060334, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297822", - "name" : "Recommendation PA166297822", + "id" : "PA166297733", + "name" : "Recommendation PA166297733", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -41654,9 +41958,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -41664,26 +41968,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060424, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452060335, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297761", - "name" : "Recommendation PA166297761", + "id" : "PA166297734", + "name" : "Recommendation PA166297734", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -41696,10 +42000,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -41707,26 +42011,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060363, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060336, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297827", - "name" : "Recommendation PA166297827", + "id" : "PA166297736", + "name" : "Recommendation PA166297736", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -41739,10 +42043,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -41750,27 +42054,27 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060429, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060338, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297871", - "name" : "Recommendation PA166297871", - "alternateDrugAvailable" : false, + "id" : "PA166297737", + "name" : "Recommendation PA166297737", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -41780,12 +42084,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: n/a" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -41793,26 +42097,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060473, - "html" : "

No recommendation

\n", + "id" : 1452060339, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297774", - "name" : "Recommendation PA166297774", + "id" : "PA166297738", + "name" : "Recommendation PA166297738", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -41825,10 +42129,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -41836,27 +42140,27 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060376, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060340, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297677", - "name" : "Recommendation PA166297677", - "alternateDrugAvailable" : false, + "id" : "PA166297739", + "name" : "Recommendation PA166297739", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -41868,10 +42172,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -41879,27 +42183,27 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060279, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060341, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297880", - "name" : "Recommendation PA166297880", - "alternateDrugAvailable" : false, + "id" : "PA166297740", + "name" : "Recommendation PA166297740", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -41909,12 +42213,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: n/a" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -41922,26 +42226,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060482, - "html" : "

No recommendation

\n", + "id" : 1452060342, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297783", - "name" : "Recommendation PA166297783", + "id" : "PA166297750", + "name" : "Recommendation PA166297750", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -41954,10 +42258,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -41965,27 +42269,27 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060385, - "html" : "

Avoid doxepin use; If doxepin is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", + "id" : 1452060352, + "html" : "

Avoid doxepin use. If doxepin is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297704", - "name" : "Recommendation PA166297704", - "alternateDrugAvailable" : false, + "id" : "PA166297751", + "name" : "Recommendation PA166297751", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -41997,10 +42301,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -42008,56 +42312,69 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060306, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060353, + "html" : "

Avoid doxepin use. If doxepin is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301381", - "name" : "Recommendation Annotation PA166301381", - "alternateDrugAvailable" : false, - "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Indeterminate"}, + "id" : "PA166297752", + "name" : "Recommendation PA166297752", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981565059, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" + ], + "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, + "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452095720, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "id" : 1452060354, + "html" : "

Avoid doxepin use. If doxepin is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297801", - "name" : "Recommendation PA166297801", + "id" : "PA166297753", + "name" : "Recommendation PA166297753", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -42071,9 +42388,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -42081,26 +42398,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060403, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060355, + "html" : "

Avoid doxepin use. If doxepin is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297849", - "name" : "Recommendation PA166297849", + "id" : "PA166297754", + "name" : "Recommendation PA166297754", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -42114,9 +42431,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -42124,26 +42441,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060451, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060356, + "html" : "

Avoid doxepin use. If doxepin is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297796", - "name" : "Recommendation PA166297796", + "id" : "PA166297759", + "name" : "Recommendation PA166297759", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -42156,10 +42473,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -42167,27 +42484,27 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060398, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060361, + "html" : "

Avoid doxepin use. If a doxepin is warranted, consider a 50% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297699", - "name" : "Recommendation PA166297699", - "alternateDrugAvailable" : false, + "id" : "PA166297760", + "name" : "Recommendation PA166297760", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -42199,10 +42516,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -42210,27 +42527,27 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060301, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452060362, + "html" : "

Avoid doxepin use. If a doxepin is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297717", - "name" : "Recommendation PA166297717", - "alternateDrugAvailable" : false, + "id" : "PA166297761", + "name" : "Recommendation PA166297761", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -42240,12 +42557,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -42253,26 +42570,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060319, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060363, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297814", - "name" : "Recommendation PA166297814", + "id" : "PA166297762", + "name" : "Recommendation PA166297762", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -42286,9 +42603,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -42296,26 +42613,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060416, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452060364, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297862", - "name" : "Recommendation PA166297862", + "id" : "PA166297764", + "name" : "Recommendation PA166297764", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -42328,10 +42645,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -42339,18 +42656,18 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060464, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060366, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 @@ -42382,14 +42699,14 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { "id" : 1452060367, @@ -42400,8 +42717,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297778", - "name" : "Recommendation PA166297778", + "id" : "PA166297766", + "name" : "Recommendation PA166297766", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -42415,9 +42732,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -42425,26 +42742,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060380, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060368, + "html" : "

Avoid doxepin use. If a doxepin is warranted, consider a 50% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297875", - "name" : "Recommendation PA166297875", + "id" : "PA166297767", + "name" : "Recommendation PA166297767", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -42457,10 +42774,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: n/a" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -42468,26 +42785,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060477, - "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. If a tertiary amine is warranted, utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060369, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297730", - "name" : "Recommendation PA166297730", + "id" : "PA166297768", + "name" : "Recommendation PA166297768", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -42500,10 +42817,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: n/a", + "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -42511,26 +42828,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060332, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060370, + "html" : "

Avoid tricyclic use due to potential for side effects. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297884", - "name" : "Recommendation PA166297884", + "id" : "PA166297769", + "name" : "Recommendation PA166297769", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -42543,10 +42860,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: n/a" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -42554,26 +42871,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060486, - "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. If a tertiary amine is warranted, utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060371, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297787", - "name" : "Recommendation PA166297787", + "id" : "PA166297771", + "name" : "Recommendation PA166297771", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -42586,10 +42903,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -42597,26 +42914,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060389, - "html" : "

Avoid doxepin use; If doxepin is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", + "id" : 1452060373, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297708", - "name" : "Recommendation PA166297708", + "id" : "PA166297773", + "name" : "Recommendation PA166297773", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -42629,10 +42946,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -42640,26 +42957,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060310, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060375, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297805", - "name" : "Recommendation PA166297805", + "id" : "PA166297774", + "name" : "Recommendation PA166297774", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -42672,10 +42989,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -42683,26 +43000,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060407, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452060376, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297752", - "name" : "Recommendation PA166297752", + "id" : "PA166297775", + "name" : "Recommendation PA166297775", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -42715,10 +43032,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -42726,26 +43043,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060354, - "html" : "

Avoid doxepin use. If doxepin is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060377, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297818", - "name" : "Recommendation PA166297818", + "id" : "PA166297776", + "name" : "Recommendation PA166297776", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -42758,10 +43075,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -42769,42 +43086,42 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060420, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452060378, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297722", - "name" : "Recommendation PA166297722", - "alternateDrugAvailable" : false, + "id" : "PA166297777", + "name" : "Recommendation PA166297777", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -42812,26 +43129,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060324, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060379, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297867", - "name" : "Recommendation PA166297867", + "id" : "PA166297779", + "name" : "Recommendation PA166297779", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -42844,10 +43161,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -42855,27 +43172,27 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060469, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060381, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297735", - "name" : "Recommendation PA166297735", - "alternateDrugAvailable" : false, + "id" : "PA166297780", + "name" : "Recommendation PA166297780", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -42885,12 +43202,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Normal metabolism of TCAs" + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -42898,26 +43215,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060337, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060382, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297832", - "name" : "Recommendation PA166297832", + "id" : "PA166297781", + "name" : "Recommendation PA166297781", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -42930,10 +43247,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Normal metabolism of tertiary amines", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -42941,26 +43258,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060434, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060383, + "html" : "

Avoid doxepin use; If doxepin is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297731", - "name" : "Recommendation PA166297731", + "id" : "PA166297782", + "name" : "Recommendation PA166297782", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -42973,10 +43290,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -42984,42 +43301,42 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060333, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060384, + "html" : "

Avoid doxepin use; If doxepin is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297744", - "name" : "Recommendation PA166297744", - "alternateDrugAvailable" : false, + "id" : "PA166297784", + "name" : "Recommendation PA166297784", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -43027,26 +43344,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060346, - "html" : "

No recommendation

\n", + "id" : 1452060386, + "html" : "

Avoid doxepin use; If doxepin is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297889", - "name" : "Recommendation PA166297889", + "id" : "PA166297785", + "name" : "Recommendation PA166297785", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -43059,10 +43376,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: n/a" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -43070,26 +43387,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060491, - "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. For tertiary amines, consider a 50% reduction of the recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060387, + "html" : "

Avoid doxepin use; If doxepin is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297841", - "name" : "Recommendation PA166297841", + "id" : "PA166297786", + "name" : "Recommendation PA166297786", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -43102,10 +43419,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: Normal metabolism of tertiary amines", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -43113,72 +43430,42 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060443, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166301389", - "name" : "Recommendation Annotation PA166301389", - "alternateDrugAvailable" : false, - "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Ultrarapid Metabolizer"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA449409", - "name" : "doxepin", - "version" : 9 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166105000", - "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 - }, - "text" : { - "id" : 1452095728, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "id" : 1452060388, + "html" : "

Avoid doxepin use; If doxepin is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297757", - "name" : "Recommendation PA166297757", - "alternateDrugAvailable" : false, + "id" : "PA166297787", + "name" : "Recommendation PA166297787", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -43186,26 +43473,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060359, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060389, + "html" : "

Avoid doxepin use; If doxepin is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297691", - "name" : "Recommendation PA166297691", + "id" : "PA166297788", + "name" : "Recommendation PA166297788", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -43218,10 +43505,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -43229,26 +43516,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060293, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060390, + "html" : "

Avoid doxepin use; If doxepin is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297854", - "name" : "Recommendation PA166297854", + "id" : "PA166297763", + "name" : "Recommendation PA166297763", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -43261,10 +43548,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Normal metabolism of tertiary amines", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -43272,26 +43559,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060456, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060365, + "html" : "

Avoid doxepin use; If doxepin is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297726", - "name" : "Recommendation PA166297726", + "id" : "PA166297778", + "name" : "Recommendation PA166297778", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -43304,10 +43591,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -43315,26 +43602,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060328, - "html" : "

Avoid doxepin use. If doxepin is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060380, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297823", - "name" : "Recommendation PA166297823", + "id" : "PA166297783", + "name" : "Recommendation PA166297783", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -43347,10 +43634,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Normal metabolism of tertiary amines", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -43358,42 +43645,42 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060425, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452060385, + "html" : "

Avoid doxepin use; If doxepin is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297739", - "name" : "Recommendation PA166297739", - "alternateDrugAvailable" : true, + "id" : "PA166297758", + "name" : "Recommendation PA166297758", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: n/a", "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -43401,27 +43688,27 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060341, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060360, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297836", - "name" : "Recommendation PA166297836", - "alternateDrugAvailable" : true, + "id" : "PA166297749", + "name" : "Recommendation PA166297749", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -43431,12 +43718,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -43444,42 +43731,42 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060438, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060351, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297700", - "name" : "Recommendation PA166297700", + "id" : "PA166297745", + "name" : "Recommendation PA166297745", "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ "CYP2C19: n/a", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -43487,42 +43774,42 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060302, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452060347, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297682", - "name" : "Recommendation PA166297682", + "id" : "PA166297757", + "name" : "Recommendation PA166297757", "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: n/a", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -43530,21 +43817,21 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060284, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452060359, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -43573,42 +43860,42 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { "id" : 1452060350, "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297845", - "name" : "Recommendation PA166297845", - "alternateDrugAvailable" : true, + "id" : "PA166297744", + "name" : "Recommendation PA166297744", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: n/a", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -43616,57 +43903,70 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060447, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060346, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301385", - "name" : "Recommendation Annotation PA166301385", + "id" : "PA166297756", + "name" : "Recommendation PA166297756", "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501930, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", + "valid" : true, + "version" : 0 + }, "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "No Result"}, + "implications" : [ + "CYP2C19: n/a", + "CYP2D6: Normal metabolism of TCAs" + ], + "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, + "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452095724, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "id" : 1452060358, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297792", - "name" : "Recommendation PA166297792", - "alternateDrugAvailable" : true, + "id" : "PA166297747", + "name" : "Recommendation PA166297747", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -43676,12 +43976,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -43689,42 +43989,42 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060394, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060349, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297713", - "name" : "Recommendation PA166297713", + "id" : "PA166297743", + "name" : "Recommendation PA166297743", "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ "CYP2C19: n/a", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -43732,42 +44032,42 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060315, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452060345, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297695", - "name" : "Recommendation PA166297695", - "alternateDrugAvailable" : true, + "id" : "PA166297755", + "name" : "Recommendation PA166297755", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: n/a", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -43775,27 +44075,27 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060297, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060357, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297810", - "name" : "Recommendation PA166297810", - "alternateDrugAvailable" : true, + "id" : "PA166297735", + "name" : "Recommendation PA166297735", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -43805,12 +44105,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -43818,42 +44118,42 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060412, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452060337, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297858", - "name" : "Recommendation PA166297858", - "alternateDrugAvailable" : true, + "id" : "PA166297742", + "name" : "Recommendation PA166297742", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: n/a", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -43861,57 +44161,70 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060460, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060344, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301384", - "name" : "Recommendation Annotation PA166301384", + "id" : "PA166297746", + "name" : "Recommendation PA166297746", "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501930, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", + "valid" : true, + "version" : 0 + }, "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Likely Poor Metabolizer"}, + "implications" : [ + "CYP2C19: n/a", + "CYP2D6: Normal metabolism of TCAs" + ], + "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, + "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452095723, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "id" : 1452060348, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297797", - "name" : "Recommendation PA166297797", - "alternateDrugAvailable" : true, + "id" : "PA166297728", + "name" : "Recommendation PA166297728", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -43921,12 +44234,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -43934,42 +44247,42 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060399, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060330, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297718", - "name" : "Recommendation PA166297718", + "id" : "PA166297741", + "name" : "Recommendation PA166297741", "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: n/a", "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -43977,26 +44290,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060320, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060343, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297815", - "name" : "Recommendation PA166297815", + "id" : "PA166297790", + "name" : "Recommendation PA166297790", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -44009,10 +44322,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Normal metabolism of tertiary amines", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -44020,27 +44333,27 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060417, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452060392, + "html" : "

Avoid doxepin use; If doxepin is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297678", - "name" : "Recommendation PA166297678", - "alternateDrugAvailable" : false, + "id" : "PA166297791", + "name" : "Recommendation PA166297791", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -44050,12 +44363,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -44063,26 +44376,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060280, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060393, + "html" : "

Avoid doxepin use; If doxepin is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297762", - "name" : "Recommendation PA166297762", + "id" : "PA166297792", + "name" : "Recommendation PA166297792", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -44095,10 +44408,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -44106,26 +44419,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060364, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060394, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297828", - "name" : "Recommendation PA166297828", + "id" : "PA166297793", + "name" : "Recommendation PA166297793", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -44138,10 +44451,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -44149,26 +44462,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060430, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060395, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297771", - "name" : "Recommendation PA166297771", + "id" : "PA166297795", + "name" : "Recommendation PA166297795", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -44181,10 +44494,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -44192,27 +44505,27 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060373, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060397, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297674", - "name" : "Recommendation PA166297674", - "alternateDrugAvailable" : false, + "id" : "PA166297796", + "name" : "Recommendation PA166297796", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -44224,10 +44537,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -44235,27 +44548,27 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060276, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060398, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297881", - "name" : "Recommendation PA166297881", - "alternateDrugAvailable" : false, + "id" : "PA166297797", + "name" : "Recommendation PA166297797", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -44265,12 +44578,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: n/a" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -44278,26 +44591,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060483, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060399, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297784", - "name" : "Recommendation PA166297784", + "id" : "PA166297798", + "name" : "Recommendation PA166297798", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -44310,10 +44623,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -44321,26 +44634,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060386, - "html" : "

Avoid doxepin use; If doxepin is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", + "id" : 1452060400, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297687", - "name" : "Recommendation PA166297687", + "id" : "PA166297799", + "name" : "Recommendation PA166297799", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -44354,9 +44667,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -44364,27 +44677,27 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060289, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060401, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297705", - "name" : "Recommendation PA166297705", - "alternateDrugAvailable" : false, + "id" : "PA166297801", + "name" : "Recommendation PA166297801", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -44394,12 +44707,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -44407,18 +44720,18 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060307, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060403, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 @@ -44450,14 +44763,14 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { "id" : 1452060404, @@ -44468,8 +44781,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297850", - "name" : "Recommendation PA166297850", + "id" : "PA166297803", + "name" : "Recommendation PA166297803", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -44482,10 +44795,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -44493,26 +44806,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060452, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060405, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297753", - "name" : "Recommendation PA166297753", + "id" : "PA166297804", + "name" : "Recommendation PA166297804", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -44525,10 +44838,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -44536,26 +44849,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060355, - "html" : "

Avoid doxepin use. If doxepin is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060406, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297819", - "name" : "Recommendation PA166297819", + "id" : "PA166297806", + "name" : "Recommendation PA166297806", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -44571,7 +44884,7 @@ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -44579,17 +44892,17 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060421, + "id" : 1452060408, "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, @@ -44597,8 +44910,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297766", - "name" : "Recommendation PA166297766", + "id" : "PA166297807", + "name" : "Recommendation PA166297807", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -44611,10 +44924,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -44622,26 +44935,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060368, - "html" : "

Avoid doxepin use. If a doxepin is warranted, consider a 50% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060409, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297863", - "name" : "Recommendation PA166297863", + "id" : "PA166297808", + "name" : "Recommendation PA166297808", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -44654,10 +44967,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -44665,26 +44978,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060465, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060410, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297779", - "name" : "Recommendation PA166297779", + "id" : "PA166297809", + "name" : "Recommendation PA166297809", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -44697,10 +45010,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -44708,27 +45021,27 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060381, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060411, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297876", - "name" : "Recommendation PA166297876", - "alternateDrugAvailable" : false, + "id" : "PA166297810", + "name" : "Recommendation PA166297810", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -44738,55 +45051,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, - "implications" : [ - "CYP2C19: n/a", - "CYP2D6: n/a" - ], - "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Indeterminate"}, - "otherPrescribingGuidance" : false, - "population" : "general", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA449409", - "name" : "doxepin", - "version" : 9 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166105000", - "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 - }, - "text" : { - "id" : 1452060478, - "html" : "

No recommendation

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166297872", - "name" : "Recommendation PA166297872", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 981501930, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: n/a" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -44794,26 +45064,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060474, - "html" : "

No recommendation

\n", + "id" : 1452060412, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297775", - "name" : "Recommendation PA166297775", + "id" : "PA166297812", + "name" : "Recommendation PA166297812", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -44826,10 +45096,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -44837,26 +45107,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060377, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060414, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297788", - "name" : "Recommendation PA166297788", + "id" : "PA166297813", + "name" : "Recommendation PA166297813", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -44869,10 +45139,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -44880,26 +45150,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060390, - "html" : "

Avoid doxepin use; If doxepin is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", + "id" : 1452060415, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297885", - "name" : "Recommendation PA166297885", + "id" : "PA166297814", + "name" : "Recommendation PA166297814", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -44913,9 +45183,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: n/a" + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -44923,26 +45193,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060487, - "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. If a tertiary amine is warranted, utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060416, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297740", - "name" : "Recommendation PA166297740", + "id" : "PA166297815", + "name" : "Recommendation PA166297815", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -44956,9 +45226,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -44966,26 +45236,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060342, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060417, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297709", - "name" : "Recommendation PA166297709", + "id" : "PA166297817", + "name" : "Recommendation PA166297817", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -44998,10 +45268,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -45009,26 +45279,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060311, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060419, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297806", - "name" : "Recommendation PA166297806", + "id" : "PA166297818", + "name" : "Recommendation PA166297818", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -45044,7 +45314,7 @@ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -45052,17 +45322,17 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060408, + "id" : 1452060420, "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, @@ -45070,8 +45340,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297842", - "name" : "Recommendation PA166297842", + "id" : "PA166297819", + "name" : "Recommendation PA166297819", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -45084,53 +45354,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Likely Intermediate Metabolizer"}, - "otherPrescribingGuidance" : false, - "population" : "general", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA449409", - "name" : "doxepin", - "version" : 9 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166105000", - "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 - }, - "text" : { - "id" : 1452060444, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166297758", - "name" : "Recommendation PA166297758", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 981501930, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Normal metabolism of TCAs" - ], - "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -45138,26 +45365,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060360, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060421, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297855", - "name" : "Recommendation PA166297855", + "id" : "PA166297820", + "name" : "Recommendation PA166297820", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -45170,10 +45397,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -45181,26 +45408,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060457, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060422, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297710", - "name" : "Recommendation PA166297710", + "id" : "PA166297821", + "name" : "Recommendation PA166297821", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -45213,53 +45440,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" - ], - "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Likely Poor Metabolizer"}, - "otherPrescribingGuidance" : false, - "population" : "general", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA449409", - "name" : "doxepin", - "version" : 9 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166105000", - "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 - }, - "text" : { - "id" : 1452060312, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166297723", - "name" : "Recommendation PA166297723", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 981501930, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -45267,26 +45451,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060325, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060423, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297868", - "name" : "Recommendation PA166297868", + "id" : "PA166297823", + "name" : "Recommendation PA166297823", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -45299,10 +45483,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -45310,26 +45494,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060470, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060425, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297864", - "name" : "Recommendation PA166297864", + "id" : "PA166297824", + "name" : "Recommendation PA166297824", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -45342,10 +45526,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -45353,27 +45537,27 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060466, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060426, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297877", - "name" : "Recommendation PA166297877", - "alternateDrugAvailable" : false, + "id" : "PA166297825", + "name" : "Recommendation PA166297825", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -45383,12 +45567,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: n/a" + "CYP2C19: n/a", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -45396,26 +45580,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060479, - "html" : "

No recommendation

\n", + "id" : 1452060427, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297732", - "name" : "Recommendation PA166297732", + "id" : "PA166297826", + "name" : "Recommendation PA166297826", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -45427,54 +45611,11 @@ "version" : 0 }, "dosingInformation" : true, - "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" - ], - "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Rapid Metabolizer"}, - "otherPrescribingGuidance" : false, - "population" : "general", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA449409", - "name" : "doxepin", - "version" : 9 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166105000", - "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 - }, - "text" : { - "id" : 1452060334, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166297745", - "name" : "Recommendation PA166297745", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 981501930, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, "implications" : [ "CYP2C19: n/a", - "CYP2D6: Normal metabolism of TCAs" + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -45482,56 +45623,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166105000", - "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 - }, - "text" : { - "id" : 1452060347, - "html" : "

No recommendation

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166301388", - "name" : "Recommendation Annotation PA166301388", - "alternateDrugAvailable" : false, - "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Rapid Metabolizer"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA449409", - "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452095727, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "id" : 1452060428, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297793", - "name" : "Recommendation PA166297793", + "id" : "PA166297828", + "name" : "Recommendation PA166297828", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -45544,10 +45655,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -45555,26 +45666,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060395, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060430, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297696", - "name" : "Recommendation PA166297696", + "id" : "PA166297829", + "name" : "Recommendation PA166297829", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -45587,10 +45698,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: n/a", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -45598,27 +45709,27 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060298, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060431, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297714", - "name" : "Recommendation PA166297714", - "alternateDrugAvailable" : false, + "id" : "PA166297830", + "name" : "Recommendation PA166297830", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -45631,9 +45742,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: n/a", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -45641,26 +45752,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060316, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452060432, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297811", - "name" : "Recommendation PA166297811", + "id" : "PA166297831", + "name" : "Recommendation PA166297831", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -45673,10 +45784,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -45684,26 +45795,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060413, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452060433, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297859", - "name" : "Recommendation PA166297859", + "id" : "PA166297832", + "name" : "Recommendation PA166297832", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -45716,10 +45827,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -45727,26 +45838,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060461, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060434, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297727", - "name" : "Recommendation PA166297727", + "id" : "PA166297834", + "name" : "Recommendation PA166297834", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -45759,10 +45870,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: n/a", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -45770,26 +45881,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060329, - "html" : "

Avoid doxepin use. If doxepin is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060436, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297824", - "name" : "Recommendation PA166297824", + "id" : "PA166297835", + "name" : "Recommendation PA166297835", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -45802,10 +45913,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -45813,26 +45924,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060426, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452060437, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297820", - "name" : "Recommendation PA166297820", + "id" : "PA166297836", + "name" : "Recommendation PA166297836", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -45845,10 +45956,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -45856,26 +45967,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060422, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452060438, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297736", - "name" : "Recommendation PA166297736", + "id" : "PA166297838", + "name" : "Recommendation PA166297838", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -45888,10 +45999,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -45899,26 +46010,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060338, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060440, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297833", - "name" : "Recommendation PA166297833", + "id" : "PA166297840", + "name" : "Recommendation PA166297840", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -45931,10 +46042,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -45942,26 +46053,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060435, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060442, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297780", - "name" : "Recommendation PA166297780", + "id" : "PA166297841", + "name" : "Recommendation PA166297841", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -45977,7 +46088,7 @@ "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -45985,17 +46096,17 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060382, + "id" : 1452060443, "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, @@ -46003,9 +46114,9 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297701", - "name" : "Recommendation PA166297701", - "alternateDrugAvailable" : false, + "id" : "PA166297842", + "name" : "Recommendation PA166297842", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -46017,10 +46128,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -46028,27 +46139,27 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060303, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452060444, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297749", - "name" : "Recommendation PA166297749", - "alternateDrugAvailable" : false, + "id" : "PA166297843", + "name" : "Recommendation PA166297843", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -46058,12 +46169,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Normal metabolism of TCAs" + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -46071,27 +46182,27 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060351, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060445, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297683", - "name" : "Recommendation PA166297683", - "alternateDrugAvailable" : false, + "id" : "PA166297844", + "name" : "Recommendation PA166297844", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -46103,10 +46214,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -46114,18 +46225,18 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060285, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452060446, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 @@ -46157,14 +46268,14 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { "id" : 1452060448, @@ -46175,24 +46286,24 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297882", - "name" : "Recommendation PA166297882", - "alternateDrugAvailable" : false, + "id" : "PA166297847", + "name" : "Recommendation PA166297847", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: n/a" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -46200,26 +46311,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060484, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060449, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297785", - "name" : "Recommendation PA166297785", + "id" : "PA166297848", + "name" : "Recommendation PA166297848", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -46232,10 +46343,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -46243,26 +46354,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060387, - "html" : "

Avoid doxepin use; If doxepin is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", + "id" : 1452060450, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297688", - "name" : "Recommendation PA166297688", + "id" : "PA166297849", + "name" : "Recommendation PA166297849", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -46276,9 +46387,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -46286,27 +46397,27 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060290, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060451, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297706", - "name" : "Recommendation PA166297706", - "alternateDrugAvailable" : false, + "id" : "PA166297794", + "name" : "Recommendation PA166297794", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -46318,10 +46429,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -46329,26 +46440,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060308, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060396, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297803", - "name" : "Recommendation PA166297803", + "id" : "PA166297800", + "name" : "Recommendation PA166297800", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -46361,10 +46472,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -46372,26 +46483,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060405, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452060402, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297750", - "name" : "Recommendation PA166297750", + "id" : "PA166297805", + "name" : "Recommendation PA166297805", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -46404,10 +46515,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -46415,56 +46526,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166105000", - "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 - }, - "text" : { - "id" : 1452060352, - "html" : "

Avoid doxepin use. If doxepin is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166301383", - "name" : "Recommendation Annotation PA166301383", - "alternateDrugAvailable" : false, - "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Likely Intermediate Metabolizer"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA449409", - "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452095722, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "id" : 1452060407, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297798", - "name" : "Recommendation PA166297798", + "id" : "PA166297811", + "name" : "Recommendation PA166297811", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -46477,10 +46558,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -46488,42 +46569,42 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060400, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060413, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297719", - "name" : "Recommendation PA166297719", - "alternateDrugAvailable" : false, + "id" : "PA166297816", + "name" : "Recommendation PA166297816", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -46531,26 +46612,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060321, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060418, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297816", - "name" : "Recommendation PA166297816", + "id" : "PA166297827", + "name" : "Recommendation PA166297827", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -46563,10 +46644,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -46574,27 +46655,27 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060418, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452060429, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297728", - "name" : "Recommendation PA166297728", - "alternateDrugAvailable" : false, + "id" : "PA166297833", + "name" : "Recommendation PA166297833", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -46604,12 +46685,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: n/a", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -46617,26 +46698,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060330, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060435, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297825", - "name" : "Recommendation PA166297825", + "id" : "PA166297839", + "name" : "Recommendation PA166297839", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -46649,10 +46730,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -46660,26 +46741,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060427, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060441, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297772", - "name" : "Recommendation PA166297772", + "id" : "PA166297845", + "name" : "Recommendation PA166297845", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -46695,7 +46776,7 @@ "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -46703,27 +46784,27 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060374, + "id" : 1452060447, "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297675", - "name" : "Recommendation PA166297675", - "alternateDrugAvailable" : false, + "id" : "PA166297850", + "name" : "Recommendation PA166297850", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -46735,10 +46816,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -46746,26 +46827,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060277, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060452, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297838", - "name" : "Recommendation PA166297838", + "id" : "PA166297851", + "name" : "Recommendation PA166297851", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -46778,10 +46859,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -46789,27 +46870,27 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060440, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060453, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297886", - "name" : "Recommendation PA166297886", - "alternateDrugAvailable" : false, + "id" : "PA166297853", + "name" : "Recommendation PA166297853", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -46819,12 +46900,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: n/a" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -46832,42 +46913,42 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060488, - "html" : "

No recommendation

\n", + "id" : 1452060455, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297741", - "name" : "Recommendation PA166297741", - "alternateDrugAvailable" : false, + "id" : "PA166297854", + "name" : "Recommendation PA166297854", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -46875,26 +46956,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060343, - "html" : "

No recommendation

\n", + "id" : 1452060456, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297807", - "name" : "Recommendation PA166297807", + "id" : "PA166297855", + "name" : "Recommendation PA166297855", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -46907,10 +46988,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -46918,26 +46999,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060409, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452060457, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297851", - "name" : "Recommendation PA166297851", + "id" : "PA166297856", + "name" : "Recommendation PA166297856", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -46953,7 +47034,7 @@ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -46961,17 +47042,17 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060453, + "id" : 1452060458, "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, @@ -46979,8 +47060,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297754", - "name" : "Recommendation PA166297754", + "id" : "PA166297858", + "name" : "Recommendation PA166297858", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -46994,9 +47075,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -47004,26 +47085,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060356, - "html" : "

Avoid doxepin use. If doxepin is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060460, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297767", - "name" : "Recommendation PA166297767", + "id" : "PA166297859", + "name" : "Recommendation PA166297859", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -47037,9 +47118,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -47047,17 +47128,17 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060369, + "id" : 1452060461, "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, @@ -47090,14 +47171,14 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { "id" : 1452060462, @@ -47108,8 +47189,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297763", - "name" : "Recommendation PA166297763", + "id" : "PA166297861", + "name" : "Recommendation PA166297861", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -47122,10 +47203,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", + "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -47133,26 +47214,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060365, - "html" : "

Avoid doxepin use; If doxepin is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", + "id" : 1452060463, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297829", - "name" : "Recommendation PA166297829", + "id" : "PA166297863", + "name" : "Recommendation PA166297863", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -47168,7 +47249,7 @@ "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -47176,17 +47257,17 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060431, + "id" : 1452060465, "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, @@ -47194,8 +47275,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297873", - "name" : "Recommendation PA166297873", + "id" : "PA166297864", + "name" : "Recommendation PA166297864", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -47208,10 +47289,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: n/a" + "CYP2C19: n/a", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -47219,26 +47300,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060475, - "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. For tertiary amines, consider a 50% reduction of the recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060466, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297776", - "name" : "Recommendation PA166297776", + "id" : "PA166297865", + "name" : "Recommendation PA166297865", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -47251,10 +47332,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -47262,26 +47343,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060378, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060467, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297830", - "name" : "Recommendation PA166297830", + "id" : "PA166297866", + "name" : "Recommendation PA166297866", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -47297,7 +47378,7 @@ "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -47305,17 +47386,17 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060432, + "id" : 1452060468, "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, @@ -47323,24 +47404,24 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297746", - "name" : "Recommendation PA166297746", - "alternateDrugAvailable" : false, + "id" : "PA166297867", + "name" : "Recommendation PA166297867", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ "CYP2C19: n/a", - "CYP2D6: Normal metabolism of TCAs" + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -47348,27 +47429,27 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060348, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060469, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297680", - "name" : "Recommendation PA166297680", - "alternateDrugAvailable" : false, + "id" : "PA166297869", + "name" : "Recommendation PA166297869", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -47380,10 +47461,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: n/a", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -47391,26 +47472,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060282, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452060471, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297843", - "name" : "Recommendation PA166297843", + "id" : "PA166297870", + "name" : "Recommendation PA166297870", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -47423,10 +47504,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -47434,26 +47515,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060445, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060472, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297790", - "name" : "Recommendation PA166297790", + "id" : "PA166297873", + "name" : "Recommendation PA166297873", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -47466,10 +47547,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -47477,26 +47558,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060392, - "html" : "

Avoid doxepin use; If doxepin is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", + "id" : 1452060475, + "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. For tertiary amines, consider a 50% reduction of the recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297693", - "name" : "Recommendation PA166297693", + "id" : "PA166297874", + "name" : "Recommendation PA166297874", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -47510,9 +47591,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -47520,26 +47601,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060295, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060476, + "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. If a tertiary amine is warranted, utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297759", - "name" : "Recommendation PA166297759", + "id" : "PA166297875", + "name" : "Recommendation PA166297875", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -47552,10 +47633,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -47563,26 +47644,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060361, - "html" : "

Avoid doxepin use. If a doxepin is warranted, consider a 50% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060477, + "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. If a tertiary amine is warranted, utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297856", - "name" : "Recommendation PA166297856", + "id" : "PA166297879", + "name" : "Recommendation PA166297879", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -47596,9 +47677,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -47606,26 +47687,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060458, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060481, + "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. For tertiary amines, consider a 50% reduction of the recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297768", - "name" : "Recommendation PA166297768", + "id" : "PA166297883", + "name" : "Recommendation PA166297883", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -47638,10 +47719,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -47649,26 +47730,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060370, - "html" : "

Avoid tricyclic use due to potential for side effects. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452060485, + "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. For tertiary amines, consider a 50% reduction of the recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297865", - "name" : "Recommendation PA166297865", + "id" : "PA166297884", + "name" : "Recommendation PA166297884", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -47681,53 +47762,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" - ], - "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "No Result"}, - "otherPrescribingGuidance" : false, - "population" : "general", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA449409", - "name" : "doxepin", - "version" : 9 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166105000", - "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 - }, - "text" : { - "id" : 1452060467, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166297720", - "name" : "Recommendation PA166297720", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 981501930, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -47735,26 +47773,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060322, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060486, + "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. If a tertiary amine is warranted, utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297733", - "name" : "Recommendation PA166297733", + "id" : "PA166297885", + "name" : "Recommendation PA166297885", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -47768,9 +47806,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -47778,26 +47816,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060335, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060487, + "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. If a tertiary amine is warranted, utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297781", - "name" : "Recommendation PA166297781", + "id" : "PA166297889", + "name" : "Recommendation PA166297889", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -47810,10 +47848,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -47821,27 +47859,27 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060383, - "html" : "

Avoid doxepin use; If doxepin is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", + "id" : 1452060491, + "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. For tertiary amines, consider a 50% reduction of the recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297702", - "name" : "Recommendation PA166297702", - "alternateDrugAvailable" : false, + "id" : "PA166297857", + "name" : "Recommendation PA166297857", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -47853,10 +47891,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -47864,26 +47902,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060304, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452060459, + "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297684", - "name" : "Recommendation PA166297684", + "id" : "PA166297862", + "name" : "Recommendation PA166297862", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -47896,10 +47934,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: n/a", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -47907,26 +47945,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060286, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060464, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297847", - "name" : "Recommendation PA166297847", + "id" : "PA166297868", + "name" : "Recommendation PA166297868", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -47939,10 +47977,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -47950,72 +47988,42 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060449, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060470, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301387", - "name" : "Recommendation Annotation PA166301387", + "id" : "PA166297872", + "name" : "Recommendation PA166297872", "alternateDrugAvailable" : false, - "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Poor Metabolizer"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA449409", - "name" : "doxepin", - "version" : 9 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166105000", - "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 - }, - "text" : { - "id" : 1452095726, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166297794", - "name" : "Recommendation PA166297794", - "alternateDrugAvailable" : true, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -48023,27 +48031,27 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060396, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060474, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297697", - "name" : "Recommendation PA166297697", - "alternateDrugAvailable" : true, + "id" : "PA166297880", + "name" : "Recommendation PA166297880", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -48053,12 +48061,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: n/a", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -48066,26 +48074,26 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060299, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060482, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297715", - "name" : "Recommendation PA166297715", + "id" : "PA166297877", + "name" : "Recommendation PA166297877", "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, @@ -48096,12 +48104,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -48109,27 +48117,27 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060317, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452060479, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297812", - "name" : "Recommendation PA166297812", - "alternateDrugAvailable" : true, + "id" : "PA166297871", + "name" : "Recommendation PA166297871", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -48139,12 +48147,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -48152,27 +48160,27 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060414, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452060473, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297724", - "name" : "Recommendation PA166297724", - "alternateDrugAvailable" : true, + "id" : "PA166297876", + "name" : "Recommendation PA166297876", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -48182,12 +48190,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: n/a", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -48195,42 +48203,42 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060326, - "html" : "

Avoid doxepin use. If doxepin is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060478, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297821", - "name" : "Recommendation PA166297821", - "alternateDrugAvailable" : true, + "id" : "PA166297882", + "name" : "Recommendation PA166297882", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -48238,27 +48246,27 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060423, - "html" : "

Avoid doxepin use; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452060484, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297869", - "name" : "Recommendation PA166297869", - "alternateDrugAvailable" : true, + "id" : "PA166297887", + "name" : "Recommendation PA166297887", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -48268,12 +48276,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -48281,27 +48289,27 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060471, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060489, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297737", - "name" : "Recommendation PA166297737", - "alternateDrugAvailable" : true, + "id" : "PA166297881", + "name" : "Recommendation PA166297881", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -48311,12 +48319,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -48324,27 +48332,27 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060339, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If doxepin is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060483, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297834", - "name" : "Recommendation PA166297834", - "alternateDrugAvailable" : true, + "id" : "PA166297886", + "name" : "Recommendation PA166297886", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -48354,12 +48362,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -48367,21 +48375,21 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105000", "name" : "Annotation of CPIC Guideline for doxepin and CYP2C19, CYP2D6", - "version" : 47 + "version" : 99 }, "text" : { - "id" : 1452060436, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060488, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166105000" @@ -48494,7 +48502,7 @@ "date" : "2019-05-01T00:00:00-07:00", "description" : "released", "type" : "Update", - "version" : 1 + "version" : 2 }, { "id" : 1450806133, @@ -48535,7 +48543,7 @@ "objCls" : "Chemical", "id" : "PA449441", "name" : "efavirenz", - "version" : 9 + "version" : 40 } ], "relatedGenes" : [ @@ -48544,14 +48552,14 @@ "id" : "PA123", "symbol" : "CYP2B6", "name" : "cytochrome P450 family 2 subfamily B member 6", - "version" : 6788 + "version" : 6829 } ], "source" : "CPIC", "summaryMarkdown" : { "id" : 1450380342, "html" : "

Consider initiating efavirenz with a decreased dose of either 400 or 200 mg/day for patients who are CYP2B6 poor metabolizers. Consider initiating efavirenz with a decreased dose of 400 mg/day for patients who are CYP2B6 intermediate metabolizers.

\n", - "version" : 0 + "version" : 1 }, "terms" : [], "textMarkdown" : { @@ -48560,13 +48568,13 @@ "version" : 1 }, "userId" : "lgong", - "version" : 10 + "version" : 47 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166297892", - "name" : "Recommendation PA166297892", + "id" : "PA166297890", + "name" : "Recommendation PA166297890", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -48579,9 +48587,9 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2B6: Normal efavirenz metabolism" + "CYP2B6: Slightly lower dose-adjusted trough concentrations of efavirenz compared with normal metabolizers" ], - "lookupKey" : {"CYP2B6": "Normal Metabolizer"}, + "lookupKey" : {"CYP2B6": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "child >40kg_adult", "relatedChemicals" : [ @@ -48589,21 +48597,21 @@ "objCls" : "Chemical", "id" : "PA449441", "name" : "efavirenz", - "version" : 9 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182603", "name" : "Annotation of CPIC Guideline for efavirenz and CYP2B6", - "version" : 10 + "version" : 47 }, "text" : { - "id" : 1452060494, - "html" : "

Initiate efavirenz with standard dosing (600 mg/day)

\n

Other Considerations

\n

The ENCORE study showed that in treatment-naïve patients randomized to initiate efavirenz-based regimens (combined with tenofovir and emtricitabine), 400 mg/day was non-inferior to 600 mg/day regardless of CYP2B6 genotype (PMID 24522178).

\n", + "id" : 1452060492, + "html" : "

Initiate efavirenz with standard dosing (600 mg/day)

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -48631,14 +48639,14 @@ "objCls" : "Chemical", "id" : "PA449441", "name" : "efavirenz", - "version" : 9 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182603", "name" : "Annotation of CPIC Guideline for efavirenz and CYP2B6", - "version" : 10 + "version" : 47 }, "text" : { "id" : 1452060495, @@ -48673,14 +48681,14 @@ "objCls" : "Chemical", "id" : "PA449441", "name" : "efavirenz", - "version" : 9 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182603", "name" : "Annotation of CPIC Guideline for efavirenz and CYP2B6", - "version" : 10 + "version" : 47 }, "text" : { "id" : 1452060496, @@ -48691,8 +48699,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297890", - "name" : "Recommendation PA166297890", + "id" : "PA166297891", + "name" : "Recommendation PA166297891", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -48707,7 +48715,7 @@ "implications" : [ "CYP2B6: Slightly lower dose-adjusted trough concentrations of efavirenz compared with normal metabolizers" ], - "lookupKey" : {"CYP2B6": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2B6": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "child >40kg_adult", "relatedChemicals" : [ @@ -48715,41 +48723,41 @@ "objCls" : "Chemical", "id" : "PA449441", "name" : "efavirenz", - "version" : 9 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182603", "name" : "Annotation of CPIC Guideline for efavirenz and CYP2B6", - "version" : 10 + "version" : 47 }, "text" : { - "id" : 1452060492, + "id" : 1452060493, "html" : "

Initiate efavirenz with standard dosing (600 mg/day)

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297895", - "name" : "Recommendation PA166297895", + "id" : "PA166297892", + "name" : "Recommendation PA166297892", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2B6: n/a" + "CYP2B6: Normal efavirenz metabolism" ], - "lookupKey" : {"CYP2B6": "Indeterminate"}, + "lookupKey" : {"CYP2B6": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "child >40kg_adult", "relatedChemicals" : [ @@ -48757,41 +48765,41 @@ "objCls" : "Chemical", "id" : "PA449441", "name" : "efavirenz", - "version" : 9 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182603", "name" : "Annotation of CPIC Guideline for efavirenz and CYP2B6", - "version" : 10 + "version" : 47 }, "text" : { - "id" : 1452060497, - "html" : "

No recommendation

\n", + "id" : 1452060494, + "html" : "

Initiate efavirenz with standard dosing (600 mg/day)

\n

Other Considerations

\n

The ENCORE study showed that in treatment-naïve patients randomized to initiate efavirenz-based regimens (combined with tenofovir and emtricitabine), 400 mg/day was non-inferior to 600 mg/day regardless of CYP2B6 genotype (PMID 24522178).

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297891", - "name" : "Recommendation PA166297891", + "id" : "PA166297895", + "name" : "Recommendation PA166297895", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2B6: Slightly lower dose-adjusted trough concentrations of efavirenz compared with normal metabolizers" + "CYP2B6: n/a" ], - "lookupKey" : {"CYP2B6": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2B6": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "child >40kg_adult", "relatedChemicals" : [ @@ -48799,21 +48807,21 @@ "objCls" : "Chemical", "id" : "PA449441", "name" : "efavirenz", - "version" : 9 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182603", "name" : "Annotation of CPIC Guideline for efavirenz and CYP2B6", - "version" : 10 + "version" : 47 }, "text" : { - "id" : 1452060493, - "html" : "

Initiate efavirenz with standard dosing (600 mg/day)

\n", + "id" : 1452060497, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166182603" @@ -49055,7 +49063,7 @@ "objCls" : "Chemical", "id" : "PA128406956", "name" : "fluorouracil", - "version" : 17 + "version" : 84 } ], "relatedGenes" : [ @@ -49064,7 +49072,7 @@ "id" : "PA145", "symbol" : "DPYD", "name" : "dihydropyrimidine dehydrogenase", - "version" : 6907 + "version" : 6956 } ], "source" : "CPIC", @@ -49080,177 +49088,9 @@ "version" : 3 }, "userId" : "carrillo", - "version" : 48 + "version" : 136 }, "recommendations" : [ - { - "objCls" : "Recommendation Annotation", - "id" : "PA166297896", - "name" : "Recommendation PA166297896", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 981501930, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "DPYD: Normal DPD activity and \"normal\" risk for fluoropyrimidine toxicity" - ], - "lookupKey" : {"DPYD": "2.0"}, - "otherPrescribingGuidance" : false, - "population" : "general", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA128406956", - "name" : "fluorouracil", - "version" : 17 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166122686", - "name" : "Annotation of CPIC Guideline for fluorouracil and DPYD", - "version" : 48 - }, - "text" : { - "id" : 1452060498, - "html" : "

Based on genotype, there is no indication to change dose or therapy. Use label-recommended dosage and administration.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166297897", - "name" : "Recommendation PA166297897", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 981501931, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : true, - "implications" : [ - "DPYD: Decreased DPD activity (leukocyte DPD activity at 30% to 70% that of the normal population) and increased risk for severe or even fatal drug toxicity when treated with fluoropyrimidine drugs" - ], - "lookupKey" : {"DPYD": "1.5"}, - "otherPrescribingGuidance" : false, - "population" : "general", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA128406956", - "name" : "fluorouracil", - "version" : 17 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166122686", - "name" : "Annotation of CPIC Guideline for fluorouracil and DPYD", - "version" : 48 - }, - "text" : { - "id" : 1452060499, - "html" : "

Reduce starting dose by 50% followed by titration of dose based on toxicity or therapeutic drug monitoring (if available).

\n

Other Considerations

\n

Increase the dose in patients experiencing no or clinically tolerable toxicity in the first two cycles to maintain efficacy; decrease the dose in patients who do not tolerate the starting dose to minimize toxicities.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166297898", - "name" : "Recommendation PA166297898", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 981501930, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : true, - "implications" : [ - "DPYD: Decreased DPD activity (leukocyte DPD activity at 30% to 70% that of the normal population) and increased risk for severe or even fatal drug toxicity when treated with fluoropyrimidine drugs" - ], - "lookupKey" : {"DPYD": "1.0"}, - "otherPrescribingGuidance" : false, - "population" : "general", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA128406956", - "name" : "fluorouracil", - "version" : 17 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166122686", - "name" : "Annotation of CPIC Guideline for fluorouracil and DPYD", - "version" : 48 - }, - "text" : { - "id" : 1452060500, - "html" : "

Reduce starting dose by 50% followed by titration of dose based on toxicity or therapeutic drug monitoring (if available). Patients with the c.2846A>T/c.2846A>T genotype may require >50% reduction in starting dose.

\n

Other Considerations

\n

Increase the dose in patients experiencing no or clinically tolerable toxicity in the first two cycles to maintain efficacy; decrease the dose in patients who do not tolerate the starting dose to minimize toxicities.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166297900", - "name" : "Recommendation PA166297900", - "alternateDrugAvailable" : true, - "classification" : { - "id" : 981501930, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "DPYD: Complete DPD deficiency and increased risk for severe or even fatal drug toxicity when treated with fluoropyrimidine drugs." - ], - "lookupKey" : {"DPYD": "0.0"}, - "otherPrescribingGuidance" : false, - "population" : "general", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA128406956", - "name" : "fluorouracil", - "version" : 17 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166122686", - "name" : "Annotation of CPIC Guideline for fluorouracil and DPYD", - "version" : 48 - }, - "text" : { - "id" : 1452060502, - "html" : "

Avoid use of 5-fluorouracil or 5-fluorouracil prodrug-based regimens.

\n", - "version" : 0 - }, - "version" : 0 - }, { "objCls" : "Recommendation Annotation", "id" : "PA166297899", @@ -49277,14 +49117,14 @@ "objCls" : "Chemical", "id" : "PA128406956", "name" : "fluorouracil", - "version" : 17 + "version" : 84 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122686", "name" : "Annotation of CPIC Guideline for fluorouracil and DPYD", - "version" : 48 + "version" : 136 }, "text" : { "id" : 1452060501, @@ -49292,6 +49132,174 @@ "version" : 0 }, "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166297896", + "name" : "Recommendation PA166297896", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501930, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : false, + "implications" : [ + "DPYD: Normal DPD activity and \"normal\" risk for fluoropyrimidine toxicity" + ], + "lookupKey" : {"DPYD": "2.0"}, + "otherPrescribingGuidance" : false, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA128406956", + "name" : "fluorouracil", + "version" : 84 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166122686", + "name" : "Annotation of CPIC Guideline for fluorouracil and DPYD", + "version" : 136 + }, + "text" : { + "id" : 1452060498, + "html" : "

Based on genotype, there is no indication to change dose or therapy. Use label-recommended dosage and administration.

\n", + "version" : 0 + }, + "version" : 1 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166297897", + "name" : "Recommendation PA166297897", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501931, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "DPYD: Decreased DPD activity (leukocyte DPD activity at 30% to 70% that of the normal population) and increased risk for severe or even fatal drug toxicity when treated with fluoropyrimidine drugs" + ], + "lookupKey" : {"DPYD": "1.5"}, + "otherPrescribingGuidance" : false, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA128406956", + "name" : "fluorouracil", + "version" : 84 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166122686", + "name" : "Annotation of CPIC Guideline for fluorouracil and DPYD", + "version" : 136 + }, + "text" : { + "id" : 1452060499, + "html" : "

Reduce starting dose by 50% followed by titration of dose based on toxicity or therapeutic drug monitoring (if available).

\n

Other Considerations

\n

Increase the dose in patients experiencing no or clinically tolerable toxicity in the first two cycles to maintain efficacy; decrease the dose in patients who do not tolerate the starting dose to minimize toxicities.

\n", + "version" : 0 + }, + "version" : 1 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166297898", + "name" : "Recommendation PA166297898", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501930, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "DPYD: Decreased DPD activity (leukocyte DPD activity at 30% to 70% that of the normal population) and increased risk for severe or even fatal drug toxicity when treated with fluoropyrimidine drugs" + ], + "lookupKey" : {"DPYD": "1.0"}, + "otherPrescribingGuidance" : false, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA128406956", + "name" : "fluorouracil", + "version" : 84 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166122686", + "name" : "Annotation of CPIC Guideline for fluorouracil and DPYD", + "version" : 136 + }, + "text" : { + "id" : 1452060500, + "html" : "

Reduce starting dose by 50% followed by titration of dose based on toxicity or therapeutic drug monitoring (if available). Patients with the c.2846A>T/c.2846A>T genotype may require >50% reduction in starting dose.

\n

Other Considerations

\n

Increase the dose in patients experiencing no or clinically tolerable toxicity in the first two cycles to maintain efficacy; decrease the dose in patients who do not tolerate the starting dose to minimize toxicities.

\n", + "version" : 0 + }, + "version" : 1 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166297900", + "name" : "Recommendation PA166297900", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981501930, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : false, + "implications" : [ + "DPYD: Complete DPD deficiency and increased risk for severe or even fatal drug toxicity when treated with fluoropyrimidine drugs." + ], + "lookupKey" : {"DPYD": "0.0"}, + "otherPrescribingGuidance" : false, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA128406956", + "name" : "fluorouracil", + "version" : 84 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166122686", + "name" : "Annotation of CPIC Guideline for fluorouracil and DPYD", + "version" : 136 + }, + "text" : { + "id" : 1452060502, + "html" : "

Avoid use of 5-fluorouracil or 5-fluorouracil prodrug-based regimens.

\n", + "version" : 0 + }, + "version" : 1 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166122686" @@ -49460,14 +49468,14 @@ "id" : "PA165816543", "symbol" : "CYP2C9*2", "name" : "*2", - "version" : 23 + "version" : 52 }, { "objCls" : "Haplotype", "id" : "PA165816544", "symbol" : "CYP2C9*3", "name" : "*3", - "version" : 25 + "version" : 55 }, { "objCls" : "Variant", @@ -49481,14 +49489,14 @@ "id" : "PA165819265", "symbol" : "SLCO1B1*15", "name" : "*15", - "version" : 23 + "version" : 39 }, { "objCls" : "Haplotype", "id" : "PA165819255", "symbol" : "SLCO1B1*5", "name" : "*5", - "version" : 23 + "version" : 39 } ], "relatedChemicals" : [ @@ -49496,7 +49504,7 @@ "objCls" : "Chemical", "id" : "PA449688", "name" : "fluvastatin", - "version" : 22 + "version" : 47 } ], "relatedGenes" : [ @@ -49505,95 +49513,52 @@ "id" : "PA126", "symbol" : "CYP2C9", "name" : "cytochrome P450 family 2 subfamily C member 9", - "version" : 7877 + "version" : 7952 }, { "objCls" : "Gene", "id" : "PA134865839", "symbol" : "SLCO1B1", "name" : "solute carrier organic anion transporter family member 1B1", - "version" : 49 + "version" : 109 } ], "source" : "CPIC", "summaryMarkdown" : { "id" : 1451672660, "html" : "

CYP2C9 IMs should avoid fluvastatin doses greater than 40mg while CYP2C9 PMs should avoid doses greater than 20mg. If higher doses are required for desired efficacy, an alternative statin should be considered. Patients with SLCO1B1 poor function should also avoid fluvastatin doses greater than 40mg and and adjust doses of fluvastatin based on disease-specific guidelines. Patients with both SLCO1B1 poor function and CYP2C9 IM/PM should be prescribed an alternative statin depending on the desired potency.

\n", - "version" : 0 + "version" : 4 }, "terms" : [], "textMarkdown" : { "id" : 1451672661, "html" : "

This annotation is based on the CPIC® guideline for SLCO1B1, ABCG2, and CYP2C9 and statin-associated musculoskeletal symptoms.

\n

February 2022

\n\n\n

Adapted from Table 1 and 2 of the 2022 guideline update manuscript.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
PhenotypeGenotypeExamples of diplotypes aImplications for fluvastatinDosing recommendations for fluvastatin b,cClassification of recommendations d
SLCO1B1 Normal functionAn individual carrying two normal function alleles or one normal plus one increased function allele*1/*1, *1/*14Typical myopathy risk and statin exposurePrescribe desired starting dose and adjust doses based on disease-specific guidelines.Strong
SLCO1B1 Increased functionAn individual carrying two increased function alleles*14/*14Typical myopathy risk and statin exposurePrescribe desired starting dose and adjust doses based on disease-specific guidelines.Strong
SLCO1B1 Decreased functionAn individual carrying one normal or increased function allele plus one no function allele*1/*5, *1/*15Increased fluvastatin exposure as compared to normal function; Typical myopathy risk with ≤40 mg.Prescribe desired starting dose and adjust doses of fluvastatin based on disease-specific guidelines. Prescriber should be aware of possible increased risk for myopathy especially for doses >40mg per day.Moderate
SLCO1B1 Possible decreased functionAn individual carrying one no function allele plus one uncertain/unknown function allele*5/*6, *15/*10, *5/*43Increased fluvastatin exposure as compared to normal function; Typical myopathy risk with ≤40 mg.Prescribe desired starting dose and adjust doses of fluvastatin based on disease-specific guidelines. Prescriber should be aware of possible increased risk for myopathy especially for doses >40mg per day.Moderate
SLCO1B1 Poor functionAn individual carrying two no function alleles*5/*5, *5/*15, *15/*15Increased fluvastatin exposure as compared to normal and decreased function; Typical myopathy risk with doses less ≤40 mg.Prescribe ≤40mg per day as a starting dose and adjust doses of fluvastatin based on disease-specific guidelines. If patient is tolerating 40mg per day but higher potency is needed, a higher dose (>40mg) or an alternative statin (see Figure 1 for recommendations for alternative statins) or combination therapy (i.e. fluvastatin plus non-statin guideline directed medical therapy) could be considered. Prescriber should be aware of possible increased risk for myopathy with fluvastatin especially with doses >40mg per day.Moderate
SLCO1B1 IndeterminateAn individual carrying one normal function allele plus one uncertain or unknown function allele OR allele combinations with uncertain and/or unknown function alleles*1/*7, *1/*10, *7/*10n/aNo recommendation.No recommendation.
\n\n

Adapted from Table 4 of the 2022 guideline update manuscript.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
PhenotypeGenotypeExamples of diplotypes aImplications for fluvastatinDosing recommendations for fluvastatin b,cClassification of recommendations d
CYP2C9 Normal MetabolizerAn individual carrying two normal function alleles*1/*1Normal exposurePrescribe desired starting dose and adjust doses of fluvastatin based on disease-specific guidelines.Strong
CYP2C9 Intermediate Metabolizer (AS of 1 and 1.5)An individual carrying one normal function allele plus one decreased function allele OR one normal function allele plus one no function allele OR two decreased function alleles*1/*2, *1/*3, *2/*2Increased fluvastatin exposure as compared to normal metabolizer which may translate to increased myopathy risk.Prescribe ≤40mg per day as a starting dose and adjust doses of fluvastatin based on disease-specific guidelines. If dose >40mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., fluvastatin plus non-statin guideline directed medical therapy).Moderate
CYP2C9 Poor Metabolizer (AS 0.5 and 0)An individual carrying one no function allele plus one decreased function allele OR two no function alleles*2/*3, *3/*3Increased fluvastatin exposure as compared to normal and intermediate metabolizer which may translate to increased myopathy risk.Prescribe ≤20mg per day as a starting dose and adjust doses of fluvastatin based on disease-specific guidelines. If dose >20mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., fluvastatin plus non-statin guideline directed medical therapy).Moderate
CYP2C9 IndeterminateAn individual carrying allele combinations with uncertain and/or unknown function alleles*1/*7, *1/*10, *7/*10n/aNo recommendation.No recommendation.
\n\n

Adapted from Table 6 of the 2022 guideline update manuscript.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
PhenotypeCYP2C9 normal metabolizerCYP2C9 Intermediate MetabolizerCYP2C9 Poor Metabolizer
SLCO1B1 normal functionPrescribe desired starting dose and adjust doses of fluvastatin based on disease-specific guidelines. STRONGPrescribe ≤40mg per day as a starting dose and adjust doses of fluvastatin based on disease-specific guidelines. If dose >40mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., fluvastatin plus non-statin guideline directed medical therapy). MODERATEPrescribe ≤20mg per day as a starting dose and adjust doses of fluvastatin based on disease-specific guidelines. If dose >20mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., fluvastatin plus non-statin guideline directed medical therapy). MODERATE
SLCO1B1 increased functionPrescribe desired starting dose and adjust doses of fluvastatin based on disease-specific guidelines. STRONGPrescribe ≤40mg per day as a starting dose and adjust doses of fluvastatin based on disease-specific guidelines. If dose >40mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., fluvastatin plus non-statin guideline directed medical therapy). MODERATEPrescribe ≤20mg per day as a starting dose and adjust doses of fluvastatin based on disease-specific guidelines. If dose >20mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., fluvastatin plus non-statin guideline directed medical therapy). MODERATE
SLCO1B1 decreased functionPrescribe desired starting dose and adjust doses of fluvastatin based on disease-specific guidelines. Prescriber should be aware of possible increased risk for myopathy especially for doses >40mg per day. MODERATEPrescribe ≤20mg per day as a starting dose and adjust doses of fluvastatin based on disease-specific guidelines. If dose >20mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., fluvastatin plus non-statin guideline directed medical therapy). OPTIONALPrescribe an alternative statin depending on the desired potency (see Figure 1 for recommendations for alternative statins). OPTIONAL
SLCO1B1 possible decreased functionPrescribe desired starting dose and adjust doses of fluvastatin based on disease-specific guidelines. Prescriber should be aware of possible increased risk for myopathy especially for doses >40mg per day. MODERATEPrescribe ≤20mg per day as a starting dose and adjust doses of fluvastatin based on disease-specific guidelines. If dose >20mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., fluvastatin plus non-statin guideline directed medical therapy). OPTIONALPrescribe an alternative statin depending on the desired potency (see Figure 1 for recommendations for alternative statins). OPTIONAL
SLCO1B1 poor functionPrescribe ≤40mg per day as a starting dose and adjust doses of fluvastatin based on disease-specific guidelines. If patient is tolerating 40mg per day but higher potency is needed, a higher dose (>40mg) or an alternative statin (see Tables 1 and Figure 1 for recommendations for alternative statins) or combination therapy (i.e. fluvastatin plus non-statin guideline directed medical therapy) could be considered. Prescriber should be aware of possible increased risk for myopathy with fluvastatin especially with doses >40mg per day. MODERATEPrescribe an alternative statin depending on the desired potency (see Table 1 and Figure 1 for recommendations for alternative statins). OPTIONALPrescribe an alternative statin depending on the desired potency (see Table 1 and Figure 1 for recommendations for alternative statins). OPTIONAL
\n

Figure 1 : SLCO1B1 recommendations with intensity and statin dose stratified by SLCO1B1 phenotype; all doses assume adult dosing.

\n

Adapted from Figure 1 of the 2022 guideline manuscript

\n

\"Fig1\"

\n\n", - "version" : 3 + "version" : 11 }, "userId" : "lgong", - "version" : 6 + "version" : 28 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166297923", - "name" : "Recommendation PA166297923", - "alternateDrugAvailable" : true, + "id" : "PA166297878", + "name" : "Recommendation PA166297878", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2C9: Increased fluvastatin exposure as compared to normal and intermediate metabolizer which may translate to increased myopathy risk.", - "SLCO1B1: Increased fluvastatin exposure as compared to normal and decreased function; Typical myopathy risk with doses less ≤40 mg." - ], - "lookupKey" : {"CYP2C9": "0.5", "SLCO1B1": "Poor Function"}, - "otherPrescribingGuidance" : false, - "population" : "general", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA449688", - "name" : "fluvastatin", - "version" : 22 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166262341", - "name" : "Annotation of CPIC Guideline for fluvastatin and CYP2C9, SLCO1B1", - "version" : 6 - }, - "text" : { - "id" : 1452060525, - "html" : "

Prescribe an alternative statin depending on the desired potency (see Table 2 and Figure 1 of PMID: 35152405 for recommendations for alternative statins).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166297910", - "name" : "Recommendation PA166297910", - "alternateDrugAvailable" : true, - "classification" : { - "id" : 981501931, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : true, - "implications" : [ - "CYP2C9: Increased fluvastatin exposure as compared to normal and intermediate metabolizer which may translate to increased myopathy risk.", + "CYP2C9: Normal exposure.", "SLCO1B1: Typical myopathy risk and statin exposure." ], - "lookupKey" : {"CYP2C9": "0.0", "SLCO1B1": "Increased Function"}, + "lookupKey" : {"CYP2C9": "2.0", "SLCO1B1": "Increased Function"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -49601,26 +49566,26 @@ "objCls" : "Chemical", "id" : "PA449688", "name" : "fluvastatin", - "version" : 22 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262341", "name" : "Annotation of CPIC Guideline for fluvastatin and CYP2C9, SLCO1B1", - "version" : 6 + "version" : 28 }, "text" : { - "id" : 1452060512, - "html" : "

Prescribe ≤20mg per day as a starting dose and adjust doses of fluvastatin based on disease-specific guidelines. If dose >20mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., fluvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452060480, + "html" : "

Prescribe desired starting dose and adjust doses of fluvastatin based on disease-specific guidelines.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and ancestry should be evaluated prior to initiating a statin.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297949", - "name" : "Recommendation PA166297949", + "id" : "PA166297917", + "name" : "Recommendation PA166297917", "alternateDrugAvailable" : true, "classification" : { "id" : 981501931, @@ -49633,10 +49598,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C9: Increased fluvastatin exposure as compared to normal and intermediate metabolizer which may translate to increased myopathy risk.", - "SLCO1B1: n/a" + "CYP2C9: Normal exposure.", + "SLCO1B1: Increased fluvastatin exposure as compared to normal and decreased function; Typical myopathy risk with doses less ≤40 mg." ], - "lookupKey" : {"CYP2C9": "0.0", "SLCO1B1": "Indeterminate"}, + "lookupKey" : {"CYP2C9": "2.0", "SLCO1B1": "Poor Function"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -49644,27 +49609,27 @@ "objCls" : "Chemical", "id" : "PA449688", "name" : "fluvastatin", - "version" : 22 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262341", "name" : "Annotation of CPIC Guideline for fluvastatin and CYP2C9, SLCO1B1", - "version" : 6 + "version" : 28 }, "text" : { - "id" : 1452060551, - "html" : "

Based on CYP2C9 status, prescribe ≤20mg per day as a starting dose and adjust doses of fluvastatin based on disease-specific guidelines. If dose >20mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., fluvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391). SLCO1B1 phenotype could not be assigned based on genotyping.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452060519, + "html" : "

Prescribe ≤40mg per day as a starting dose and adjust doses of fluvastatin based on disease-specific guidelines. If patient is tolerating 40mg per day but higher potency is needed, a higher dose (>40mg) or an alternative statin or combination therapy (i.e. fluvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391) could be considered. Prescriber should be aware of possible increased risk for myopathy with fluvastatin especially with doses >40mg per day.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297936", - "name" : "Recommendation PA166297936", - "alternateDrugAvailable" : true, + "id" : "PA166297947", + "name" : "Recommendation PA166297947", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, "parents" : [], @@ -49674,55 +49639,55 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ "CYP2C9: n/a", - "SLCO1B1: Increased fluvastatin exposure as compared to normal and decreased function; Typical myopathy risk with doses less ≤40 mg." + "SLCO1B1: Increased fluvastatin exposure as compared to normal function; Typical myopathy risk with ≤40 mg." ], - "lookupKey" : {"CYP2C9": "n/a", "SLCO1B1": "Poor Function"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"CYP2C9": "No Result", "SLCO1B1": "Possible Decreased Function"}, + "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449688", "name" : "fluvastatin", - "version" : 22 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262341", "name" : "Annotation of CPIC Guideline for fluvastatin and CYP2C9, SLCO1B1", - "version" : 6 + "version" : 28 }, "text" : { - "id" : 1452060538, - "html" : "

Based on SLCO1B1 status, prescribe ≤40mg per day as a starting dose and adjust doses of fluvastatin based on disease-specific guidelines. If patient is tolerating 40mg per day but higher potency is needed, a higher dose (>40mg) or an alternative statin (see Figure 1 of PMID: 35152405 for recommendations for alternative statins) or combination therapy (i.e. fluvastatin plus non-statin guideline directed medical therapy)(PMID: 30423391) could be considered. Prescriber should be aware of possible increased risk for myopathy with fluvastatin especially with doses >40mg per day. CYP2C9 phenotype could not be assigned based on genotyping.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452060549, + "html" : "

Based on SLCO1B1 status, prescribe desired starting dose and adjust doses of fluvastatin based on disease-specific guidelines. Prescriber should be aware of possible increased risk for myopathy especially for doses >40mg per day. CYP2C9 genotype result is not available.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297914", - "name" : "Recommendation PA166297914", + "id" : "PA166297904", + "name" : "Recommendation PA166297904", "alternateDrugAvailable" : true, "classification" : { - "id" : 981501931, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ "CYP2C9: Increased fluvastatin exposure as compared to normal metabolizer which may translate to increased myopathy risk.", - "SLCO1B1: Typical myopathy risk and statin exposure." + "SLCO1B1: Increased fluvastatin exposure as compared to normal function; Typical myopathy risk with ≤40 mg." ], - "lookupKey" : {"CYP2C9": "1.0", "SLCO1B1": "Increased Function"}, + "lookupKey" : {"CYP2C9": "1.0", "SLCO1B1": "Possible Decreased Function"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -49730,18 +49695,18 @@ "objCls" : "Chemical", "id" : "PA449688", "name" : "fluvastatin", - "version" : 22 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262341", "name" : "Annotation of CPIC Guideline for fluvastatin and CYP2C9, SLCO1B1", - "version" : 6 + "version" : 28 }, "text" : { - "id" : 1452060516, - "html" : "

Prescribe ≤40mg per day as a starting dose and adjust doses of fluvastatin based on disease-specific guidelines. If dose >40mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., fluvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452060506, + "html" : "

Prescribe ≤20mg per day as a starting dose and adjust doses of fluvastatin based on disease-specific guidelines. If dose >20mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., fluvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, "version" : 0 @@ -49773,14 +49738,14 @@ "objCls" : "Chemical", "id" : "PA449688", "name" : "fluvastatin", - "version" : 22 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262341", "name" : "Annotation of CPIC Guideline for fluvastatin and CYP2C9, SLCO1B1", - "version" : 6 + "version" : 28 }, "text" : { "id" : 1452060507, @@ -49791,8 +49756,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297919", - "name" : "Recommendation PA166297919", + "id" : "PA166297906", + "name" : "Recommendation PA166297906", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -49803,55 +49768,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, - "implications" : [ - "CYP2C9: Increased fluvastatin exposure as compared to normal and intermediate metabolizer which may translate to increased myopathy risk.", - "SLCO1B1: Increased fluvastatin exposure as compared to normal function; Typical myopathy risk with ≤40 mg." - ], - "lookupKey" : {"CYP2C9": "0.0", "SLCO1B1": "Decreased Function"}, - "otherPrescribingGuidance" : false, - "population" : "general", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA449688", - "name" : "fluvastatin", - "version" : 22 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166262341", - "name" : "Annotation of CPIC Guideline for fluvastatin and CYP2C9, SLCO1B1", - "version" : 6 - }, - "text" : { - "id" : 1452060521, - "html" : "

Prescribe an alternative statin depending on the desired potency (see Figure 1 of PMID: 35152405 for recommendations for alternative statins).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166297950", - "name" : "Recommendation PA166297950", - "alternateDrugAvailable" : true, - "classification" : { - "id" : 981501931, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", - "valid" : true, - "version" : 0 - }, "dosingInformation" : true, "implications" : [ - "CYP2C9: Increased fluvastatin exposure as compared to normal and intermediate metabolizer which may translate to increased myopathy risk.", - "SLCO1B1: n/a" + "CYP2C9: Increased fluvastatin exposure as compared to normal metabolizer which may translate to increased myopathy risk.", + "SLCO1B1: Increased fluvastatin exposure as compared to normal function; Typical myopathy risk with ≤40 mg." ], - "lookupKey" : {"CYP2C9": "0.5", "SLCO1B1": "Indeterminate"}, + "lookupKey" : {"CYP2C9": "1.5", "SLCO1B1": "Possible Decreased Function"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -49859,26 +49781,26 @@ "objCls" : "Chemical", "id" : "PA449688", "name" : "fluvastatin", - "version" : 22 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262341", "name" : "Annotation of CPIC Guideline for fluvastatin and CYP2C9, SLCO1B1", - "version" : 6 + "version" : 28 }, "text" : { - "id" : 1452060552, - "html" : "

Based on CYP2C9 status, prescribe ≤20mg per day as a starting dose and adjust doses of fluvastatin based on disease-specific guidelines. If dose >20mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., fluvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391). SLCO1B1 phenotype could not be assigned based on genotyping.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452060508, + "html" : "

Prescribe ≤20mg per day as a starting dose and adjust doses of fluvastatin based on disease-specific guidelines. If dose >20mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., fluvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297906", - "name" : "Recommendation PA166297906", + "id" : "PA166297907", + "name" : "Recommendation PA166297907", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -49894,7 +49816,7 @@ "CYP2C9: Increased fluvastatin exposure as compared to normal metabolizer which may translate to increased myopathy risk.", "SLCO1B1: Increased fluvastatin exposure as compared to normal function; Typical myopathy risk with ≤40 mg." ], - "lookupKey" : {"CYP2C9": "1.5", "SLCO1B1": "Possible Decreased Function"}, + "lookupKey" : {"CYP2C9": "1.5", "SLCO1B1": "Decreased Function"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -49902,17 +49824,17 @@ "objCls" : "Chemical", "id" : "PA449688", "name" : "fluvastatin", - "version" : 22 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262341", "name" : "Annotation of CPIC Guideline for fluvastatin and CYP2C9, SLCO1B1", - "version" : 6 + "version" : 28 }, "text" : { - "id" : 1452060508, + "id" : 1452060509, "html" : "

Prescribe ≤20mg per day as a starting dose and adjust doses of fluvastatin based on disease-specific guidelines. If dose >20mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., fluvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, @@ -49920,8 +49842,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297941", - "name" : "Recommendation PA166297941", + "id" : "PA166297908", + "name" : "Recommendation PA166297908", "alternateDrugAvailable" : true, "classification" : { "id" : 981501931, @@ -49934,53 +49856,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C9: Increased fluvastatin exposure as compared to normal metabolizer which may translate to increased myopathy risk.", - "SLCO1B1: n/a" - ], - "lookupKey" : {"CYP2C9": "1.5", "SLCO1B1": "No Result"}, - "otherPrescribingGuidance" : false, - "population" : "general", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA449688", - "name" : "fluvastatin", - "version" : 22 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166262341", - "name" : "Annotation of CPIC Guideline for fluvastatin and CYP2C9, SLCO1B1", - "version" : 6 - }, - "text" : { - "id" : 1452060543, - "html" : "

Based on CYP2C9 status, prescribe ≤40mg per day as a starting dose and adjust doses of fluvastatin based on disease-specific guidelines. If dose >40mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., fluvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391). SLCO1B1 genotype result is not available.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166297945", - "name" : "Recommendation PA166297945", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 981501930, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "CYP2C9: n/a", + "CYP2C9: Increased fluvastatin exposure as compared to normal and intermediate metabolizer which may translate to increased myopathy risk.", "SLCO1B1: Typical myopathy risk and statin exposure." ], - "lookupKey" : {"CYP2C9": "No Result", "SLCO1B1": "Normal Function"}, + "lookupKey" : {"CYP2C9": "0.0", "SLCO1B1": "Normal Function"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -49988,42 +49867,42 @@ "objCls" : "Chemical", "id" : "PA449688", "name" : "fluvastatin", - "version" : 22 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262341", "name" : "Annotation of CPIC Guideline for fluvastatin and CYP2C9, SLCO1B1", - "version" : 6 + "version" : 28 }, "text" : { - "id" : 1452060547, - "html" : "

Based on SLCO1B1 status, prescribe desired starting dose and adjust doses based on disease-specific guidelines. CYP2C9 genotype result is not available.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and ancestry should be evaluated prior to initiating a statin.

\n", + "id" : 1452060510, + "html" : "

Prescribe ≤20mg per day as a starting dose and adjust doses of fluvastatin based on disease-specific guidelines. If dose >20mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., fluvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297932", - "name" : "Recommendation PA166297932", - "alternateDrugAvailable" : false, + "id" : "PA166297910", + "name" : "Recommendation PA166297910", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C9: n/a", + "CYP2C9: Increased fluvastatin exposure as compared to normal and intermediate metabolizer which may translate to increased myopathy risk.", "SLCO1B1: Typical myopathy risk and statin exposure." ], - "lookupKey" : {"CYP2C9": "n/a", "SLCO1B1": "Increased Function"}, + "lookupKey" : {"CYP2C9": "0.0", "SLCO1B1": "Increased Function"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -50031,18 +49910,18 @@ "objCls" : "Chemical", "id" : "PA449688", "name" : "fluvastatin", - "version" : 22 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262341", "name" : "Annotation of CPIC Guideline for fluvastatin and CYP2C9, SLCO1B1", - "version" : 6 + "version" : 28 }, "text" : { - "id" : 1452060534, - "html" : "

Based on SLCO1B1 status, prescribe desired starting dose and adjust doses based on disease-specific guidelines. CYP2C9 phenotype could not be assigned based on genotyping.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and ancestry should be evaluated prior to initiating a statin.

\n", + "id" : 1452060512, + "html" : "

Prescribe ≤20mg per day as a starting dose and adjust doses of fluvastatin based on disease-specific guidelines. If dose >20mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., fluvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, "version" : 0 @@ -50074,14 +49953,14 @@ "objCls" : "Chemical", "id" : "PA449688", "name" : "fluvastatin", - "version" : 22 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262341", "name" : "Annotation of CPIC Guideline for fluvastatin and CYP2C9, SLCO1B1", - "version" : 6 + "version" : 28 }, "text" : { "id" : 1452060513, @@ -50092,8 +49971,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297946", - "name" : "Recommendation PA166297946", + "id" : "PA166297912", + "name" : "Recommendation PA166297912", "alternateDrugAvailable" : true, "classification" : { "id" : 981501931, @@ -50106,10 +49985,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C9: n/a", - "SLCO1B1: Increased fluvastatin exposure as compared to normal and decreased function; Typical myopathy risk with doses less ≤40 mg." + "CYP2C9: Increased fluvastatin exposure as compared to normal and intermediate metabolizer which may translate to increased myopathy risk.", + "SLCO1B1: Typical myopathy risk and statin exposure." ], - "lookupKey" : {"CYP2C9": "No Result", "SLCO1B1": "Poor Function"}, + "lookupKey" : {"CYP2C9": "0.5", "SLCO1B1": "Increased Function"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -50117,26 +49996,26 @@ "objCls" : "Chemical", "id" : "PA449688", "name" : "fluvastatin", - "version" : 22 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262341", "name" : "Annotation of CPIC Guideline for fluvastatin and CYP2C9, SLCO1B1", - "version" : 6 + "version" : 28 }, "text" : { - "id" : 1452060548, - "html" : "

Based on SLCO1B1 status, prescribe ≤40mg per day as a starting dose and adjust doses of fluvastatin based on disease-specific guidelines. If patient is tolerating 40mg per day but higher potency is needed, a higher dose (>40mg) or an alternative statin (see Figure 1 of PMID: 35152405 for recommendations for alternative statins) or combination therapy (i.e. fluvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391) could be considered. Prescriber should be aware of possible increased risk for myopathy with fluvastatin especially with doses >40mg per day. CYP2C9 genotype result is not available.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452060514, + "html" : "

Prescribe ≤20mg per day as a starting dose and adjust doses of fluvastatin based on disease-specific guidelines. If dose >20mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., fluvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297937", - "name" : "Recommendation PA166297937", + "id" : "PA166297913", + "name" : "Recommendation PA166297913", "alternateDrugAvailable" : true, "classification" : { "id" : 981501931, @@ -50150,9 +50029,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C9: Increased fluvastatin exposure as compared to normal metabolizer which may translate to increased myopathy risk.", - "SLCO1B1: n/a" + "SLCO1B1: Typical myopathy risk and statin exposure." ], - "lookupKey" : {"CYP2C9": "1.0", "SLCO1B1": "Indeterminate"}, + "lookupKey" : {"CYP2C9": "1.0", "SLCO1B1": "Normal Function"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -50160,42 +50039,42 @@ "objCls" : "Chemical", "id" : "PA449688", "name" : "fluvastatin", - "version" : 22 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262341", "name" : "Annotation of CPIC Guideline for fluvastatin and CYP2C9, SLCO1B1", - "version" : 6 + "version" : 28 }, "text" : { - "id" : 1452060539, - "html" : "

Based on CYP2C9 status, prescribe ≤40mg per day as a starting dose and adjust doses of fluvastatin based on disease-specific guidelines. If dose >40mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., fluvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391). SLCO1B1 phenotype could not be assigned based on genotyping.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452060515, + "html" : "

Prescribe ≤40mg per day as a starting dose and adjust doses of fluvastatin based on disease-specific guidelines. If dose >40mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., fluvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297924", - "name" : "Recommendation PA166297924", + "id" : "PA166297914", + "name" : "Recommendation PA166297914", "alternateDrugAvailable" : true, "classification" : { - "id" : 981565059, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ "CYP2C9: Increased fluvastatin exposure as compared to normal metabolizer which may translate to increased myopathy risk.", - "SLCO1B1: Increased fluvastatin exposure as compared to normal and decreased function; Typical myopathy risk with doses less ≤40 mg." + "SLCO1B1: Typical myopathy risk and statin exposure." ], - "lookupKey" : {"CYP2C9": "1.0", "SLCO1B1": "Poor Function"}, + "lookupKey" : {"CYP2C9": "1.0", "SLCO1B1": "Increased Function"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -50203,18 +50082,18 @@ "objCls" : "Chemical", "id" : "PA449688", "name" : "fluvastatin", - "version" : 22 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262341", "name" : "Annotation of CPIC Guideline for fluvastatin and CYP2C9, SLCO1B1", - "version" : 6 + "version" : 28 }, "text" : { - "id" : 1452060526, - "html" : "

Prescribe an alternative statin depending on the desired potency. (see Table 2 and Figure 1 of PMID: 35152405 for recommendations for alternative statins).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452060516, + "html" : "

Prescribe ≤40mg per day as a starting dose and adjust doses of fluvastatin based on disease-specific guidelines. If dose >40mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., fluvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, "version" : 0 @@ -50246,14 +50125,14 @@ "objCls" : "Chemical", "id" : "PA449688", "name" : "fluvastatin", - "version" : 22 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262341", "name" : "Annotation of CPIC Guideline for fluvastatin and CYP2C9, SLCO1B1", - "version" : 6 + "version" : 28 }, "text" : { "id" : 1452060517, @@ -50289,85 +50168,85 @@ "objCls" : "Chemical", "id" : "PA449688", "name" : "fluvastatin", - "version" : 22 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262341", "name" : "Annotation of CPIC Guideline for fluvastatin and CYP2C9, SLCO1B1", - "version" : 6 + "version" : 28 }, "text" : { "id" : 1452060490, "html" : "

Based on CYP2C9 status, prescribe desired starting dose and adjust doses of fluvastatin based on disease-specific guidelines. SLCO1B1 phenotype could not be assigned based on genotyping.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297928", - "name" : "Recommendation PA166297928", + "id" : "PA166297909", + "name" : "Recommendation PA166297909", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ "CYP2C9: Normal exposure.", - "SLCO1B1: Increased fluvastatin exposure as compared to normal function; Typical myopathy risk with ≤40 mg." + "SLCO1B1: n/a" ], - "lookupKey" : {"CYP2C9": "2.0", "SLCO1B1": "Possible Decreased Function"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"CYP2C9": "2.0", "SLCO1B1": "No Result"}, + "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449688", "name" : "fluvastatin", - "version" : 22 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262341", "name" : "Annotation of CPIC Guideline for fluvastatin and CYP2C9, SLCO1B1", - "version" : 6 + "version" : 28 }, "text" : { - "id" : 1452060530, - "html" : "

Prescribe desired starting dose and adjust doses of fluvastatin based on disease-specific guidelines. Prescriber should be aware of possible increased risk for myopathy especially for doses >40mg per day.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452060511, + "html" : "

Based on CYP2C9 status, prescribe desired starting dose and adjust doses of fluvastatin based on disease-specific guidelines. SLCO1B1 genotype result is not available.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297907", - "name" : "Recommendation PA166297907", + "id" : "PA166297916", + "name" : "Recommendation PA166297916", "alternateDrugAvailable" : true, "classification" : { - "id" : 981565059, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ "CYP2C9: Increased fluvastatin exposure as compared to normal metabolizer which may translate to increased myopathy risk.", - "SLCO1B1: Increased fluvastatin exposure as compared to normal function; Typical myopathy risk with ≤40 mg." + "SLCO1B1: Typical myopathy risk and statin exposure." ], - "lookupKey" : {"CYP2C9": "1.5", "SLCO1B1": "Decreased Function"}, + "lookupKey" : {"CYP2C9": "1.5", "SLCO1B1": "Increased Function"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -50375,26 +50254,26 @@ "objCls" : "Chemical", "id" : "PA449688", "name" : "fluvastatin", - "version" : 22 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262341", "name" : "Annotation of CPIC Guideline for fluvastatin and CYP2C9, SLCO1B1", - "version" : 6 + "version" : 28 }, "text" : { - "id" : 1452060509, - "html" : "

Prescribe ≤20mg per day as a starting dose and adjust doses of fluvastatin based on disease-specific guidelines. If dose >20mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., fluvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452060518, + "html" : "

Prescribe ≤40mg per day as a starting dose and adjust doses of fluvastatin based on disease-specific guidelines. If dose >40mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., fluvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297951", - "name" : "Recommendation PA166297951", + "id" : "PA166297937", + "name" : "Recommendation PA166297937", "alternateDrugAvailable" : true, "classification" : { "id" : 981501931, @@ -50407,10 +50286,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C9: Increased fluvastatin exposure as compared to normal and intermediate metabolizer which may translate to increased myopathy risk.", + "CYP2C9: Increased fluvastatin exposure as compared to normal metabolizer which may translate to increased myopathy risk.", "SLCO1B1: n/a" ], - "lookupKey" : {"CYP2C9": "0.0", "SLCO1B1": "No Result"}, + "lookupKey" : {"CYP2C9": "1.0", "SLCO1B1": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -50418,27 +50297,27 @@ "objCls" : "Chemical", "id" : "PA449688", "name" : "fluvastatin", - "version" : 22 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262341", "name" : "Annotation of CPIC Guideline for fluvastatin and CYP2C9, SLCO1B1", - "version" : 6 + "version" : 28 }, "text" : { - "id" : 1452060553, - "html" : "

Based on CYP2C9 status, prescribe ≤20mg per day as a starting dose and adjust doses of fluvastatin based on disease-specific guidelines. If dose >20mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., fluvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391). SLCO1B1 genotype result is not available.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452060539, + "html" : "

Based on CYP2C9 status, prescribe ≤40mg per day as a starting dose and adjust doses of fluvastatin based on disease-specific guidelines. If dose >40mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., fluvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391). SLCO1B1 phenotype could not be assigned based on genotyping.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297942", - "name" : "Recommendation PA166297942", - "alternateDrugAvailable" : false, + "id" : "PA166297939", + "name" : "Recommendation PA166297939", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501931, "parents" : [], @@ -50448,56 +50327,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, - "implications" : [ - "CYP2C9: n/a", - "SLCO1B1: Increased fluvastatin exposure as compared to normal function; Typical myopathy risk with ≤40 mg." - ], - "lookupKey" : {"CYP2C9": "No Result", "SLCO1B1": "Decreased Function"}, - "otherPrescribingGuidance" : true, - "population" : "general", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA449688", - "name" : "fluvastatin", - "version" : 22 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166262341", - "name" : "Annotation of CPIC Guideline for fluvastatin and CYP2C9, SLCO1B1", - "version" : 6 - }, - "text" : { - "id" : 1452060544, - "html" : "

Based on SLCO1B1 status, prescribe desired starting dose and adjust doses of fluvastatin based on disease-specific guidelines. Prescriber should be aware of possible increased risk for myopathy especially for doses >40mg per day. CYP2C9 genotype result is not available.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166297933", - "name" : "Recommendation PA166297933", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 981501929, - "description" : "Not Applicable", - "parents" : [], - "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", - "valid" : true, - "version" : 1 - }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C9: n/a", + "CYP2C9: Increased fluvastatin exposure as compared to normal metabolizer which may translate to increased myopathy risk.", "SLCO1B1: n/a" ], - "lookupKey" : {"CYP2C9": "n/a", "SLCO1B1": "Indeterminate"}, + "lookupKey" : {"CYP2C9": "1.5", "SLCO1B1": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -50505,42 +50340,42 @@ "objCls" : "Chemical", "id" : "PA449688", "name" : "fluvastatin", - "version" : 22 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262341", "name" : "Annotation of CPIC Guideline for fluvastatin and CYP2C9, SLCO1B1", - "version" : 6 + "version" : 28 }, "text" : { - "id" : 1452060535, - "html" : "

n/a

\n", + "id" : 1452060541, + "html" : "

Based on CYP2C9 status, prescribe ≤40mg per day as a starting dose and adjust doses of fluvastatin based on disease-specific guidelines. If dose >40mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., fluvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391). SLCO1B1 phenotype could not be assigned based on genotyping.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297920", - "name" : "Recommendation PA166297920", + "id" : "PA166297940", + "name" : "Recommendation PA166297940", "alternateDrugAvailable" : true, "classification" : { - "id" : 981565059, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C9: Increased fluvastatin exposure as compared to normal and intermediate metabolizer which may translate to increased myopathy risk.", - "SLCO1B1: Increased fluvastatin exposure as compared to normal function; Typical myopathy risk with ≤40 mg." + "CYP2C9: Increased fluvastatin exposure as compared to normal metabolizer which may translate to increased myopathy risk.", + "SLCO1B1: n/a" ], - "lookupKey" : {"CYP2C9": "0.5", "SLCO1B1": "Possible Decreased Function"}, + "lookupKey" : {"CYP2C9": "1.0", "SLCO1B1": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -50548,27 +50383,27 @@ "objCls" : "Chemical", "id" : "PA449688", "name" : "fluvastatin", - "version" : 22 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262341", "name" : "Annotation of CPIC Guideline for fluvastatin and CYP2C9, SLCO1B1", - "version" : 6 + "version" : 28 }, "text" : { - "id" : 1452060522, - "html" : "

Prescribe an alternative statin depending on the desired potency (see Figure 1 of PMID: 35152405 for recommendations for alternative statins).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452060542, + "html" : "

Based on CYP2C9 status, prescribe ≤40mg per day as a starting dose and adjust doses of fluvastatin based on disease-specific guidelines. If dose >40mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., fluvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391). SLCO1B1 genotype result is not available.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297947", - "name" : "Recommendation PA166297947", - "alternateDrugAvailable" : false, + "id" : "PA166297941", + "name" : "Recommendation PA166297941", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501931, "parents" : [], @@ -50578,56 +50413,55 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C9: n/a", - "SLCO1B1: Increased fluvastatin exposure as compared to normal function; Typical myopathy risk with ≤40 mg." + "CYP2C9: Increased fluvastatin exposure as compared to normal metabolizer which may translate to increased myopathy risk.", + "SLCO1B1: n/a" ], - "lookupKey" : {"CYP2C9": "No Result", "SLCO1B1": "Possible Decreased Function"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"CYP2C9": "1.5", "SLCO1B1": "No Result"}, + "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449688", "name" : "fluvastatin", - "version" : 22 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262341", "name" : "Annotation of CPIC Guideline for fluvastatin and CYP2C9, SLCO1B1", - "version" : 6 + "version" : 28 }, "text" : { - "id" : 1452060549, - "html" : "

Based on SLCO1B1 status, prescribe desired starting dose and adjust doses of fluvastatin based on disease-specific guidelines. Prescriber should be aware of possible increased risk for myopathy especially for doses >40mg per day. CYP2C9 genotype result is not available.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452060543, + "html" : "

Based on CYP2C9 status, prescribe ≤40mg per day as a starting dose and adjust doses of fluvastatin based on disease-specific guidelines. If dose >40mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., fluvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391). SLCO1B1 genotype result is not available.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297934", - "name" : "Recommendation PA166297934", - "alternateDrugAvailable" : false, + "id" : "PA166297949", + "name" : "Recommendation PA166297949", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, - "version" : 1 + "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C9: n/a", + "CYP2C9: Increased fluvastatin exposure as compared to normal and intermediate metabolizer which may translate to increased myopathy risk.", "SLCO1B1: n/a" ], - "lookupKey" : {"CYP2C9": "n/a", "SLCO1B1": "No Result"}, + "lookupKey" : {"CYP2C9": "0.0", "SLCO1B1": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -50635,42 +50469,42 @@ "objCls" : "Chemical", "id" : "PA449688", "name" : "fluvastatin", - "version" : 22 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262341", "name" : "Annotation of CPIC Guideline for fluvastatin and CYP2C9, SLCO1B1", - "version" : 6 + "version" : 28 }, "text" : { - "id" : 1452060536, - "html" : "

n/a

\n", + "id" : 1452060551, + "html" : "

Based on CYP2C9 status, prescribe ≤20mg per day as a starting dose and adjust doses of fluvastatin based on disease-specific guidelines. If dose >20mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., fluvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391). SLCO1B1 phenotype could not be assigned based on genotyping.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297925", - "name" : "Recommendation PA166297925", + "id" : "PA166297950", + "name" : "Recommendation PA166297950", "alternateDrugAvailable" : true, "classification" : { - "id" : 981565059, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C9: Increased fluvastatin exposure as compared to normal metabolizer which may translate to increased myopathy risk.", - "SLCO1B1: Increased fluvastatin exposure as compared to normal and decreased function; Typical myopathy risk with doses less ≤40 mg." + "CYP2C9: Increased fluvastatin exposure as compared to normal and intermediate metabolizer which may translate to increased myopathy risk.", + "SLCO1B1: n/a" ], - "lookupKey" : {"CYP2C9": "1.5", "SLCO1B1": "Poor Function"}, + "lookupKey" : {"CYP2C9": "0.5", "SLCO1B1": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -50678,26 +50512,26 @@ "objCls" : "Chemical", "id" : "PA449688", "name" : "fluvastatin", - "version" : 22 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262341", "name" : "Annotation of CPIC Guideline for fluvastatin and CYP2C9, SLCO1B1", - "version" : 6 + "version" : 28 }, "text" : { - "id" : 1452060527, - "html" : "

Prescribe an alternative statin depending on the desired potency. (see Table 2 and Figure 1 of PMID: 35152405 for recommendations for alternative statins).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452060552, + "html" : "

Based on CYP2C9 status, prescribe ≤20mg per day as a starting dose and adjust doses of fluvastatin based on disease-specific guidelines. If dose >20mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., fluvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391). SLCO1B1 phenotype could not be assigned based on genotyping.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297912", - "name" : "Recommendation PA166297912", + "id" : "PA166297951", + "name" : "Recommendation PA166297951", "alternateDrugAvailable" : true, "classification" : { "id" : 981501931, @@ -50711,9 +50545,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C9: Increased fluvastatin exposure as compared to normal and intermediate metabolizer which may translate to increased myopathy risk.", - "SLCO1B1: Typical myopathy risk and statin exposure." + "SLCO1B1: n/a" ], - "lookupKey" : {"CYP2C9": "0.5", "SLCO1B1": "Increased Function"}, + "lookupKey" : {"CYP2C9": "0.0", "SLCO1B1": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -50721,27 +50555,27 @@ "objCls" : "Chemical", "id" : "PA449688", "name" : "fluvastatin", - "version" : 22 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262341", "name" : "Annotation of CPIC Guideline for fluvastatin and CYP2C9, SLCO1B1", - "version" : 6 + "version" : 28 }, "text" : { - "id" : 1452060514, - "html" : "

Prescribe ≤20mg per day as a starting dose and adjust doses of fluvastatin based on disease-specific guidelines. If dose >20mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., fluvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452060553, + "html" : "

Based on CYP2C9 status, prescribe ≤20mg per day as a starting dose and adjust doses of fluvastatin based on disease-specific guidelines. If dose >20mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., fluvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391). SLCO1B1 genotype result is not available.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297929", - "name" : "Recommendation PA166297929", - "alternateDrugAvailable" : false, + "id" : "PA166297952", + "name" : "Recommendation PA166297952", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501931, "parents" : [], @@ -50751,39 +50585,39 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C9: Normal exposure.", - "SLCO1B1: Increased fluvastatin exposure as compared to normal function; Typical myopathy risk with ≤40 mg." + "CYP2C9: Increased fluvastatin exposure as compared to normal and intermediate metabolizer which may translate to increased myopathy risk.", + "SLCO1B1: n/a" ], - "lookupKey" : {"CYP2C9": "2.0", "SLCO1B1": "Decreased Function"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"CYP2C9": "0.5", "SLCO1B1": "No Result"}, + "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449688", "name" : "fluvastatin", - "version" : 22 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262341", "name" : "Annotation of CPIC Guideline for fluvastatin and CYP2C9, SLCO1B1", - "version" : 6 + "version" : 28 }, "text" : { - "id" : 1452060531, - "html" : "

Prescribe desired starting dose and adjust doses of fluvastatin based on disease-specific guidelines. Prescriber should be aware of possible increased risk for myopathy especially for doses >40mg per day.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452060554, + "html" : "

Based on CYP2C9 status, prescribe ≤20mg per day as a starting dose and adjust doses of fluvastatin based on disease-specific guidelines. If dose >20mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., fluvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391). SLCO1B1 genotype result is not available.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297916", - "name" : "Recommendation PA166297916", + "id" : "PA166297936", + "name" : "Recommendation PA166297936", "alternateDrugAvailable" : true, "classification" : { "id" : 981501931, @@ -50796,10 +50630,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C9: Increased fluvastatin exposure as compared to normal metabolizer which may translate to increased myopathy risk.", - "SLCO1B1: Typical myopathy risk and statin exposure." + "CYP2C9: n/a", + "SLCO1B1: Increased fluvastatin exposure as compared to normal and decreased function; Typical myopathy risk with doses less ≤40 mg." ], - "lookupKey" : {"CYP2C9": "1.5", "SLCO1B1": "Increased Function"}, + "lookupKey" : {"CYP2C9": "n/a", "SLCO1B1": "Poor Function"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -50807,26 +50641,26 @@ "objCls" : "Chemical", "id" : "PA449688", "name" : "fluvastatin", - "version" : 22 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262341", "name" : "Annotation of CPIC Guideline for fluvastatin and CYP2C9, SLCO1B1", - "version" : 6 + "version" : 28 }, "text" : { - "id" : 1452060518, - "html" : "

Prescribe ≤40mg per day as a starting dose and adjust doses of fluvastatin based on disease-specific guidelines. If dose >40mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., fluvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452060538, + "html" : "

Based on SLCO1B1 status, prescribe ≤40mg per day as a starting dose and adjust doses of fluvastatin based on disease-specific guidelines. If patient is tolerating 40mg per day but higher potency is needed, a higher dose (>40mg) or an alternative statin (see Figure 1 of PMID: 35152405 for recommendations for alternative statins) or combination therapy (i.e. fluvastatin plus non-statin guideline directed medical therapy)(PMID: 30423391) could be considered. Prescriber should be aware of possible increased risk for myopathy with fluvastatin especially with doses >40mg per day. CYP2C9 phenotype could not be assigned based on genotyping.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297952", - "name" : "Recommendation PA166297952", + "id" : "PA166297946", + "name" : "Recommendation PA166297946", "alternateDrugAvailable" : true, "classification" : { "id" : 981501931, @@ -50839,10 +50673,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C9: Increased fluvastatin exposure as compared to normal and intermediate metabolizer which may translate to increased myopathy risk.", - "SLCO1B1: n/a" + "CYP2C9: n/a", + "SLCO1B1: Increased fluvastatin exposure as compared to normal and decreased function; Typical myopathy risk with doses less ≤40 mg." ], - "lookupKey" : {"CYP2C9": "0.5", "SLCO1B1": "No Result"}, + "lookupKey" : {"CYP2C9": "No Result", "SLCO1B1": "Poor Function"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -50850,42 +50684,42 @@ "objCls" : "Chemical", "id" : "PA449688", "name" : "fluvastatin", - "version" : 22 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262341", "name" : "Annotation of CPIC Guideline for fluvastatin and CYP2C9, SLCO1B1", - "version" : 6 + "version" : 28 }, "text" : { - "id" : 1452060554, - "html" : "

Based on CYP2C9 status, prescribe ≤20mg per day as a starting dose and adjust doses of fluvastatin based on disease-specific guidelines. If dose >20mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., fluvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391). SLCO1B1 genotype result is not available.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452060548, + "html" : "

Based on SLCO1B1 status, prescribe ≤40mg per day as a starting dose and adjust doses of fluvastatin based on disease-specific guidelines. If patient is tolerating 40mg per day but higher potency is needed, a higher dose (>40mg) or an alternative statin (see Figure 1 of PMID: 35152405 for recommendations for alternative statins) or combination therapy (i.e. fluvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391) could be considered. Prescriber should be aware of possible increased risk for myopathy with fluvastatin especially with doses >40mg per day. CYP2C9 genotype result is not available.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297908", - "name" : "Recommendation PA166297908", + "id" : "PA166297918", + "name" : "Recommendation PA166297918", "alternateDrugAvailable" : true, "classification" : { - "id" : 981501931, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ "CYP2C9: Increased fluvastatin exposure as compared to normal and intermediate metabolizer which may translate to increased myopathy risk.", - "SLCO1B1: Typical myopathy risk and statin exposure." + "SLCO1B1: Increased fluvastatin exposure as compared to normal function; Typical myopathy risk with ≤40 mg." ], - "lookupKey" : {"CYP2C9": "0.0", "SLCO1B1": "Normal Function"}, + "lookupKey" : {"CYP2C9": "0.0", "SLCO1B1": "Possible Decreased Function"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -50893,42 +50727,42 @@ "objCls" : "Chemical", "id" : "PA449688", "name" : "fluvastatin", - "version" : 22 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262341", "name" : "Annotation of CPIC Guideline for fluvastatin and CYP2C9, SLCO1B1", - "version" : 6 + "version" : 28 }, "text" : { - "id" : 1452060510, - "html" : "

Prescribe ≤20mg per day as a starting dose and adjust doses of fluvastatin based on disease-specific guidelines. If dose >20mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., fluvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452060520, + "html" : "

Prescribe an alternative statin depending on the desired potency (see Figure 1 of PMID: 35152405 for recommendations for alternative statins).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297943", - "name" : "Recommendation PA166297943", - "alternateDrugAvailable" : false, + "id" : "PA166297919", + "name" : "Recommendation PA166297919", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2C9: n/a", - "SLCO1B1: Typical myopathy risk and statin exposure." + "CYP2C9: Increased fluvastatin exposure as compared to normal and intermediate metabolizer which may translate to increased myopathy risk.", + "SLCO1B1: Increased fluvastatin exposure as compared to normal function; Typical myopathy risk with ≤40 mg." ], - "lookupKey" : {"CYP2C9": "No Result", "SLCO1B1": "Increased Function"}, + "lookupKey" : {"CYP2C9": "0.0", "SLCO1B1": "Decreased Function"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -50936,64 +50770,64 @@ "objCls" : "Chemical", "id" : "PA449688", "name" : "fluvastatin", - "version" : 22 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262341", "name" : "Annotation of CPIC Guideline for fluvastatin and CYP2C9, SLCO1B1", - "version" : 6 + "version" : 28 }, "text" : { - "id" : 1452060545, - "html" : "

Based on SLCO1B1 status, prescribe desired starting dose and adjust doses based on disease-specific guidelines. CYP2C9 genotype result is not available.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and ancestry should be evaluated prior to initiating a statin.

\n", + "id" : 1452060521, + "html" : "

Prescribe an alternative statin depending on the desired potency (see Figure 1 of PMID: 35152405 for recommendations for alternative statins).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297930", - "name" : "Recommendation PA166297930", - "alternateDrugAvailable" : false, + "id" : "PA166297920", + "name" : "Recommendation PA166297920", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501931, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2C9: n/a", + "CYP2C9: Increased fluvastatin exposure as compared to normal and intermediate metabolizer which may translate to increased myopathy risk.", "SLCO1B1: Increased fluvastatin exposure as compared to normal function; Typical myopathy risk with ≤40 mg." ], - "lookupKey" : {"CYP2C9": "n/a", "SLCO1B1": "Possible Decreased Function"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"CYP2C9": "0.5", "SLCO1B1": "Possible Decreased Function"}, + "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449688", "name" : "fluvastatin", - "version" : 22 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262341", "name" : "Annotation of CPIC Guideline for fluvastatin and CYP2C9, SLCO1B1", - "version" : 6 + "version" : 28 }, "text" : { - "id" : 1452060532, - "html" : "

Based on SLCO1B1 status, prescribe desired starting dose and adjust doses of fluvastatin based on disease-specific guidelines. Prescriber should be aware of possible increased risk for myopathy especially for doses >40mg per day. CYP2C9 phenotype could not be assigned based on genotyping.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452060522, + "html" : "

Prescribe an alternative statin depending on the desired potency (see Figure 1 of PMID: 35152405 for recommendations for alternative statins).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -51022,42 +50856,42 @@ "objCls" : "Chemical", "id" : "PA449688", "name" : "fluvastatin", - "version" : 22 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262341", "name" : "Annotation of CPIC Guideline for fluvastatin and CYP2C9, SLCO1B1", - "version" : 6 + "version" : 28 }, "text" : { "id" : 1452060523, "html" : "

Prescribe an alternative statin depending on the desired potency (see Figure 1 of PMID: 35152405 for recommendations for alternative statins).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297935", - "name" : "Recommendation PA166297935", - "alternateDrugAvailable" : false, + "id" : "PA166297922", + "name" : "Recommendation PA166297922", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2C9: n/a", - "SLCO1B1: Typical myopathy risk and statin exposure." + "CYP2C9: Increased fluvastatin exposure as compared to normal and intermediate metabolizer which may translate to increased myopathy risk.", + "SLCO1B1: Increased fluvastatin exposure as compared to normal and decreased function; Typical myopathy risk with doses less ≤40 mg." ], - "lookupKey" : {"CYP2C9": "n/a", "SLCO1B1": "Normal Function"}, + "lookupKey" : {"CYP2C9": "0.0", "SLCO1B1": "Poor Function"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -51065,26 +50899,26 @@ "objCls" : "Chemical", "id" : "PA449688", "name" : "fluvastatin", - "version" : 22 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262341", "name" : "Annotation of CPIC Guideline for fluvastatin and CYP2C9, SLCO1B1", - "version" : 6 + "version" : 28 }, "text" : { - "id" : 1452060537, - "html" : "

Based on SLCO1B1 status, prescribe desired starting dose and adjust doses based on disease-specific guidelines. CYP2C9 phenotype could not be assigned based on genotyping.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and ancestry should be evaluated prior to initiating a statin.

\n", + "id" : 1452060524, + "html" : "

Prescribe an alternative statin depending on the desired potency (see Table 2 and Figure 1 of PMID: 35152405 for recommendations for alternative statins).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297922", - "name" : "Recommendation PA166297922", + "id" : "PA166297923", + "name" : "Recommendation PA166297923", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -51100,7 +50934,7 @@ "CYP2C9: Increased fluvastatin exposure as compared to normal and intermediate metabolizer which may translate to increased myopathy risk.", "SLCO1B1: Increased fluvastatin exposure as compared to normal and decreased function; Typical myopathy risk with doses less ≤40 mg." ], - "lookupKey" : {"CYP2C9": "0.0", "SLCO1B1": "Poor Function"}, + "lookupKey" : {"CYP2C9": "0.5", "SLCO1B1": "Poor Function"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -51108,42 +50942,42 @@ "objCls" : "Chemical", "id" : "PA449688", "name" : "fluvastatin", - "version" : 22 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262341", "name" : "Annotation of CPIC Guideline for fluvastatin and CYP2C9, SLCO1B1", - "version" : 6 + "version" : 28 }, "text" : { - "id" : 1452060524, + "id" : 1452060525, "html" : "

Prescribe an alternative statin depending on the desired potency (see Table 2 and Figure 1 of PMID: 35152405 for recommendations for alternative statins).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297913", - "name" : "Recommendation PA166297913", + "id" : "PA166297924", + "name" : "Recommendation PA166297924", "alternateDrugAvailable" : true, "classification" : { - "id" : 981501931, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ "CYP2C9: Increased fluvastatin exposure as compared to normal metabolizer which may translate to increased myopathy risk.", - "SLCO1B1: Typical myopathy risk and statin exposure." + "SLCO1B1: Increased fluvastatin exposure as compared to normal and decreased function; Typical myopathy risk with doses less ≤40 mg." ], - "lookupKey" : {"CYP2C9": "1.0", "SLCO1B1": "Normal Function"}, + "lookupKey" : {"CYP2C9": "1.0", "SLCO1B1": "Poor Function"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -51151,42 +50985,42 @@ "objCls" : "Chemical", "id" : "PA449688", "name" : "fluvastatin", - "version" : 22 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262341", "name" : "Annotation of CPIC Guideline for fluvastatin and CYP2C9, SLCO1B1", - "version" : 6 + "version" : 28 }, "text" : { - "id" : 1452060515, - "html" : "

Prescribe ≤40mg per day as a starting dose and adjust doses of fluvastatin based on disease-specific guidelines. If dose >40mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., fluvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452060526, + "html" : "

Prescribe an alternative statin depending on the desired potency. (see Table 2 and Figure 1 of PMID: 35152405 for recommendations for alternative statins).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297939", - "name" : "Recommendation PA166297939", + "id" : "PA166297925", + "name" : "Recommendation PA166297925", "alternateDrugAvailable" : true, "classification" : { - "id" : 981501931, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ "CYP2C9: Increased fluvastatin exposure as compared to normal metabolizer which may translate to increased myopathy risk.", - "SLCO1B1: n/a" + "SLCO1B1: Increased fluvastatin exposure as compared to normal and decreased function; Typical myopathy risk with doses less ≤40 mg." ], - "lookupKey" : {"CYP2C9": "1.5", "SLCO1B1": "Indeterminate"}, + "lookupKey" : {"CYP2C9": "1.5", "SLCO1B1": "Poor Function"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -51194,21 +51028,21 @@ "objCls" : "Chemical", "id" : "PA449688", "name" : "fluvastatin", - "version" : 22 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262341", "name" : "Annotation of CPIC Guideline for fluvastatin and CYP2C9, SLCO1B1", - "version" : 6 + "version" : 28 }, "text" : { - "id" : 1452060541, - "html" : "

Based on CYP2C9 status, prescribe ≤40mg per day as a starting dose and adjust doses of fluvastatin based on disease-specific guidelines. If dose >40mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., fluvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391). SLCO1B1 phenotype could not be assigned based on genotyping.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452060527, + "html" : "

Prescribe an alternative statin depending on the desired potency. (see Table 2 and Figure 1 of PMID: 35152405 for recommendations for alternative statins).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -51237,27 +51071,27 @@ "objCls" : "Chemical", "id" : "PA449688", "name" : "fluvastatin", - "version" : 22 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262341", "name" : "Annotation of CPIC Guideline for fluvastatin and CYP2C9, SLCO1B1", - "version" : 6 + "version" : 28 }, "text" : { "id" : 1452060528, "html" : "

Prescribe desired starting dose and adjust doses of fluvastatin based on disease-specific guidelines.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and ancestry should be evaluated prior to initiating a statin.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297917", - "name" : "Recommendation PA166297917", - "alternateDrugAvailable" : true, + "id" : "PA166297928", + "name" : "Recommendation PA166297928", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, "parents" : [], @@ -51267,125 +51101,168 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ "CYP2C9: Normal exposure.", - "SLCO1B1: Increased fluvastatin exposure as compared to normal and decreased function; Typical myopathy risk with doses less ≤40 mg." + "SLCO1B1: Increased fluvastatin exposure as compared to normal function; Typical myopathy risk with ≤40 mg." ], - "lookupKey" : {"CYP2C9": "2.0", "SLCO1B1": "Poor Function"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"CYP2C9": "2.0", "SLCO1B1": "Possible Decreased Function"}, + "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449688", "name" : "fluvastatin", - "version" : 22 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262341", "name" : "Annotation of CPIC Guideline for fluvastatin and CYP2C9, SLCO1B1", - "version" : 6 + "version" : 28 }, "text" : { - "id" : 1452060519, - "html" : "

Prescribe ≤40mg per day as a starting dose and adjust doses of fluvastatin based on disease-specific guidelines. If patient is tolerating 40mg per day but higher potency is needed, a higher dose (>40mg) or an alternative statin or combination therapy (i.e. fluvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391) could be considered. Prescriber should be aware of possible increased risk for myopathy with fluvastatin especially with doses >40mg per day.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452060530, + "html" : "

Prescribe desired starting dose and adjust doses of fluvastatin based on disease-specific guidelines. Prescriber should be aware of possible increased risk for myopathy especially for doses >40mg per day.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297904", - "name" : "Recommendation PA166297904", - "alternateDrugAvailable" : true, + "id" : "PA166297929", + "name" : "Recommendation PA166297929", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C9: Increased fluvastatin exposure as compared to normal metabolizer which may translate to increased myopathy risk.", + "CYP2C9: Normal exposure.", "SLCO1B1: Increased fluvastatin exposure as compared to normal function; Typical myopathy risk with ≤40 mg." ], - "lookupKey" : {"CYP2C9": "1.0", "SLCO1B1": "Possible Decreased Function"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"CYP2C9": "2.0", "SLCO1B1": "Decreased Function"}, + "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449688", "name" : "fluvastatin", - "version" : 22 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262341", "name" : "Annotation of CPIC Guideline for fluvastatin and CYP2C9, SLCO1B1", - "version" : 6 + "version" : 28 }, "text" : { - "id" : 1452060506, - "html" : "

Prescribe ≤20mg per day as a starting dose and adjust doses of fluvastatin based on disease-specific guidelines. If dose >20mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., fluvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452060531, + "html" : "

Prescribe desired starting dose and adjust doses of fluvastatin based on disease-specific guidelines. Prescriber should be aware of possible increased risk for myopathy especially for doses >40mg per day.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297918", - "name" : "Recommendation PA166297918", - "alternateDrugAvailable" : true, + "id" : "PA166297930", + "name" : "Recommendation PA166297930", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2C9: Increased fluvastatin exposure as compared to normal and intermediate metabolizer which may translate to increased myopathy risk.", + "CYP2C9: n/a", "SLCO1B1: Increased fluvastatin exposure as compared to normal function; Typical myopathy risk with ≤40 mg." ], - "lookupKey" : {"CYP2C9": "0.0", "SLCO1B1": "Possible Decreased Function"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"CYP2C9": "n/a", "SLCO1B1": "Possible Decreased Function"}, + "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449688", "name" : "fluvastatin", - "version" : 22 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262341", "name" : "Annotation of CPIC Guideline for fluvastatin and CYP2C9, SLCO1B1", - "version" : 6 + "version" : 28 }, "text" : { - "id" : 1452060520, - "html" : "

Prescribe an alternative statin depending on the desired potency (see Figure 1 of PMID: 35152405 for recommendations for alternative statins).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452060532, + "html" : "

Based on SLCO1B1 status, prescribe desired starting dose and adjust doses of fluvastatin based on disease-specific guidelines. Prescriber should be aware of possible increased risk for myopathy especially for doses >40mg per day. CYP2C9 phenotype could not be assigned based on genotyping.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297909", - "name" : "Recommendation PA166297909", + "id" : "PA166297931", + "name" : "Recommendation PA166297931", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501931, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : false, + "implications" : [ + "CYP2C9: n/a", + "SLCO1B1: Increased fluvastatin exposure as compared to normal function; Typical myopathy risk with ≤40 mg." + ], + "lookupKey" : {"CYP2C9": "n/a", "SLCO1B1": "Decreased Function"}, + "otherPrescribingGuidance" : true, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA449688", + "name" : "fluvastatin", + "version" : 47 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166262341", + "name" : "Annotation of CPIC Guideline for fluvastatin and CYP2C9, SLCO1B1", + "version" : 28 + }, + "text" : { + "id" : 1452060533, + "html" : "

Based on SLCO1B1 status, prescribe desired starting dose and adjust doses of fluvastatin based on disease-specific guidelines. Prescriber should be aware of possible increased risk for myopathy especially for doses >40mg per day. CYP2C9 phenotype could not be assigned based on genotyping.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "version" : 0 + }, + "version" : 1 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166297932", + "name" : "Recommendation PA166297932", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -51398,10 +51275,10 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2C9: Normal exposure.", - "SLCO1B1: n/a" + "CYP2C9: n/a", + "SLCO1B1: Typical myopathy risk and statin exposure." ], - "lookupKey" : {"CYP2C9": "2.0", "SLCO1B1": "No Result"}, + "lookupKey" : {"CYP2C9": "n/a", "SLCO1B1": "Increased Function"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -51409,42 +51286,87 @@ "objCls" : "Chemical", "id" : "PA449688", "name" : "fluvastatin", - "version" : 22 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262341", "name" : "Annotation of CPIC Guideline for fluvastatin and CYP2C9, SLCO1B1", - "version" : 6 + "version" : 28 }, "text" : { - "id" : 1452060511, - "html" : "

Based on CYP2C9 status, prescribe desired starting dose and adjust doses of fluvastatin based on disease-specific guidelines. SLCO1B1 genotype result is not available.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin.

\n", + "id" : 1452060534, + "html" : "

Based on SLCO1B1 status, prescribe desired starting dose and adjust doses based on disease-specific guidelines. CYP2C9 phenotype could not be assigned based on genotyping.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and ancestry should be evaluated prior to initiating a statin.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297940", - "name" : "Recommendation PA166297940", - "alternateDrugAvailable" : true, + "id" : "PA166297933", + "name" : "Recommendation PA166297933", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, + "version" : 1 + }, + "dosingInformation" : false, + "implications" : [ + "CYP2C9: n/a", + "SLCO1B1: n/a" + ], + "lookupKey" : {"CYP2C9": "n/a", "SLCO1B1": "Indeterminate"}, + "otherPrescribingGuidance" : false, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA449688", + "name" : "fluvastatin", + "version" : 47 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166262341", + "name" : "Annotation of CPIC Guideline for fluvastatin and CYP2C9, SLCO1B1", + "version" : 28 + }, + "text" : { + "id" : 1452060535, + "html" : "

n/a

\n", "version" : 0 }, - "dosingInformation" : true, + "version" : 1 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166297934", + "name" : "Recommendation PA166297934", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501929, + "description" : "Not Applicable", + "parents" : [], + "resource" : "Guideline Strength", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", + "valid" : true, + "version" : 1 + }, + "dosingInformation" : false, "implications" : [ - "CYP2C9: Increased fluvastatin exposure as compared to normal metabolizer which may translate to increased myopathy risk.", + "CYP2C9: n/a", "SLCO1B1: n/a" ], - "lookupKey" : {"CYP2C9": "1.0", "SLCO1B1": "No Result"}, + "lookupKey" : {"CYP2C9": "n/a", "SLCO1B1": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -51452,26 +51374,26 @@ "objCls" : "Chemical", "id" : "PA449688", "name" : "fluvastatin", - "version" : 22 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262341", "name" : "Annotation of CPIC Guideline for fluvastatin and CYP2C9, SLCO1B1", - "version" : 6 + "version" : 28 }, "text" : { - "id" : 1452060542, - "html" : "

Based on CYP2C9 status, prescribe ≤40mg per day as a starting dose and adjust doses of fluvastatin based on disease-specific guidelines. If dose >40mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., fluvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391). SLCO1B1 genotype result is not available.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452060536, + "html" : "

n/a

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297878", - "name" : "Recommendation PA166297878", + "id" : "PA166297935", + "name" : "Recommendation PA166297935", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -51484,10 +51406,10 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2C9: Normal exposure.", + "CYP2C9: n/a", "SLCO1B1: Typical myopathy risk and statin exposure." ], - "lookupKey" : {"CYP2C9": "2.0", "SLCO1B1": "Increased Function"}, + "lookupKey" : {"CYP2C9": "n/a", "SLCO1B1": "Normal Function"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -51495,26 +51417,26 @@ "objCls" : "Chemical", "id" : "PA449688", "name" : "fluvastatin", - "version" : 22 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262341", "name" : "Annotation of CPIC Guideline for fluvastatin and CYP2C9, SLCO1B1", - "version" : 6 + "version" : 28 }, "text" : { - "id" : 1452060480, - "html" : "

Prescribe desired starting dose and adjust doses of fluvastatin based on disease-specific guidelines.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and ancestry should be evaluated prior to initiating a statin.

\n", + "id" : 1452060537, + "html" : "

Based on SLCO1B1 status, prescribe desired starting dose and adjust doses based on disease-specific guidelines. CYP2C9 phenotype could not be assigned based on genotyping.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and ancestry should be evaluated prior to initiating a statin.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297931", - "name" : "Recommendation PA166297931", + "id" : "PA166297942", + "name" : "Recommendation PA166297942", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -51530,7 +51452,7 @@ "CYP2C9: n/a", "SLCO1B1: Increased fluvastatin exposure as compared to normal function; Typical myopathy risk with ≤40 mg." ], - "lookupKey" : {"CYP2C9": "n/a", "SLCO1B1": "Decreased Function"}, + "lookupKey" : {"CYP2C9": "No Result", "SLCO1B1": "Decreased Function"}, "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ @@ -51538,21 +51460,64 @@ "objCls" : "Chemical", "id" : "PA449688", "name" : "fluvastatin", - "version" : 22 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262341", "name" : "Annotation of CPIC Guideline for fluvastatin and CYP2C9, SLCO1B1", - "version" : 6 + "version" : 28 }, "text" : { - "id" : 1452060533, - "html" : "

Based on SLCO1B1 status, prescribe desired starting dose and adjust doses of fluvastatin based on disease-specific guidelines. Prescriber should be aware of possible increased risk for myopathy especially for doses >40mg per day. CYP2C9 phenotype could not be assigned based on genotyping.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452060544, + "html" : "

Based on SLCO1B1 status, prescribe desired starting dose and adjust doses of fluvastatin based on disease-specific guidelines. Prescriber should be aware of possible increased risk for myopathy especially for doses >40mg per day. CYP2C9 genotype result is not available.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166297943", + "name" : "Recommendation PA166297943", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501930, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : false, + "implications" : [ + "CYP2C9: n/a", + "SLCO1B1: Typical myopathy risk and statin exposure." + ], + "lookupKey" : {"CYP2C9": "No Result", "SLCO1B1": "Increased Function"}, + "otherPrescribingGuidance" : false, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA449688", + "name" : "fluvastatin", + "version" : 47 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166262341", + "name" : "Annotation of CPIC Guideline for fluvastatin and CYP2C9, SLCO1B1", + "version" : 28 + }, + "text" : { + "id" : 1452060545, + "html" : "

Based on SLCO1B1 status, prescribe desired starting dose and adjust doses based on disease-specific guidelines. CYP2C9 genotype result is not available.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and ancestry should be evaluated prior to initiating a statin.

\n", + "version" : 0 + }, + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -51582,21 +51547,64 @@ "objCls" : "Chemical", "id" : "PA449688", "name" : "fluvastatin", - "version" : 22 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262341", "name" : "Annotation of CPIC Guideline for fluvastatin and CYP2C9, SLCO1B1", - "version" : 6 + "version" : 28 }, "text" : { "id" : 1452060546, "html" : "

n/a

\n", "version" : 0 }, - "version" : 0 + "version" : 1 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166297945", + "name" : "Recommendation PA166297945", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501930, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : false, + "implications" : [ + "CYP2C9: n/a", + "SLCO1B1: Typical myopathy risk and statin exposure." + ], + "lookupKey" : {"CYP2C9": "No Result", "SLCO1B1": "Normal Function"}, + "otherPrescribingGuidance" : false, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA449688", + "name" : "fluvastatin", + "version" : 47 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166262341", + "name" : "Annotation of CPIC Guideline for fluvastatin and CYP2C9, SLCO1B1", + "version" : 28 + }, + "text" : { + "id" : 1452060547, + "html" : "

Based on SLCO1B1 status, prescribe desired starting dose and adjust doses based on disease-specific guidelines. CYP2C9 genotype result is not available.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and ancestry should be evaluated prior to initiating a statin.

\n", + "version" : 0 + }, + "version" : 1 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166262341" @@ -51760,6 +51768,7 @@ "version" : 1 } ], + "descriptiveVideoId" : "9Fxi5ALZtPA", "dosingInformation" : true, "hasTestingInfo" : false, "history" : [ @@ -51818,6 +51827,13 @@ "description" : "added CPIC guideline publication", "type" : "Update", "version" : 0 + }, + { + "id" : 1452507040, + "date" : "2024-06-25T03:30:59.680-07:00", + "description" : "Added video", + "type" : "Update", + "version" : 0 } ], "literature" : [ @@ -51829,7 +51845,7 @@ "pediatricMarkdown" : { "id" : 1451266622, "html" : "

Guideline excerpt: "The generalizability of other recommendations to pediatric patients needs to be established. As such, clinicians treating children and adolescents should determine their applicability to younger patients while considering the unique and more limited evidence base for these medications in youth, as well as pediatric-specific differences in tolerability (e.g., activation)and disorder-specific response trajectory. Because CYP2D6, CYP2C19, and CYP2B6 activity reach adult levels by early childhood, it may be appropriate to extrapolate genotype-guided recommendations for antidepressants related to CYP2D6, CYP2C19 and CYP2B6 to adolescents or possibly younger children with close monitoring."

\n", - "version" : 1 + "version" : 2 }, "recommendation" : true, "relatedAlleles" : [], @@ -51838,7 +51854,7 @@ "objCls" : "Chemical", "id" : "PA449690", "name" : "fluvoxamine", - "version" : 8 + "version" : 37 } ], "relatedGenes" : [ @@ -51847,44 +51863,44 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "CPIC", "summaryMarkdown" : { "id" : 1447982315, "html" : "

The CPIC Dosing Guideline for the selective serotonin reuptake inhibitor fluvoxamine recommends to consider a 25-50% reduction of recommended starting dose and slower titration schedule or use an alternative drug not metabolized by CYP2D6 for CYP2D6 poor metabolizers.

\n", - "version" : 1 + "version" : 2 }, "terms" : [], "textMarkdown" : { "id" : 1451433661, "html" : "

This annotation is based on the CPIC® guideline for CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A Genotypes and Serotonin Reuptake Inhibitor Antidepressants. This is an update to the previous CPIC® guideline for Selective Serotonin Reuptake Inhibitors and CYP2D6 and CYP2C19.

\n

February 2023

\n\n

Table 1: Dosing recommendations for fluvoxamine based on CYP2D6 phenotype

\n

Adapted from Tables 1 and 2b of the guideline.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
PhenotypeActivity score
range		Activity scoreExamplesImplicationsTherapeutic
Recommendations		Classification of
recommendationa		Considerations
CYP2D6 ultrarapid metabolizer>2.25>2.25*1/*1xN, *1/*2xN, *2/*2xNcNo data available for CYP2D6 ultrarapid metabolizers.No recommendation due to lack of evidence.No recommendation
CYP2D6 normal metabolizer1.25 <= x <= 2.251.25
1.5
1.75
2.0
2.25		*1/*10
*1/*41, *1/*9
*10/*41x3
*1/*1, *1/*2
*2x2/*10		Normal metabolism.Initiate therapy with recommended starting dose.Strong
CYP2D6 intermediate metabolizer0 < x < 1.250.25
0.5
0.75
1.0		*4/*10
*4/*41, *10/*10
*10/*41
*41/*41, *1/*5		Reduced metabolism of fluvoxamine to less active compounds when compared to CYP2D6 normal metabolizers. Higher plasma concentrations may increase the probability of side effects.Initiate therapy with recommended starting dose.Moderate
CYP2D6 poor metabolizer00*3/*4, *4/*4, *5/*5, *5/*6Greatly reduced metabolism of fluvoxamine to less active compounds when compared to CYP2D6 normal metabolizers. Higher plasma concentrations may increase the probability of side effects.Consider a 25-50% lower starting dose and slower titration schedule as compared to normal metabolizers or consider a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2D6.OptionalDrug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when adjusting dose or selecting an alternative therapy.
CYP2D6 Indeterminaten/aAn individual carrying one or two unknown or uncertain function alleles*1/*22, *1/*25, *22/*25No recommendationNo recommendation
\n

a Rating scheme described in Supplemental Materials.

\n

October 2019 Update

\n

CYP2D6 genotype to phenotype translation changes: Up until August 2019, there were a few inconsistencies in the translation of CYP2D6 genotype to phenotype translation across guidelines (i.e. CPIC and DPWG) and between clinical genetic testing laboratories. CPIC recently conducted a modified-Delphi project to obtain consensus for a uniform system for translating CYP2D6 genotype to phenotype among a panel of international CYP2D6 experts more information. Modifications to CPIC’s prior system include downgrading the value assigned to the CYP2D6*10 allele for activity score calculation from 0.5 to 0.25 and changing the phenotype assignment for an activity score of 1 from normal metabolizer to intermediate metabolizer (table of all previous and new phenotype groupings).

\n

As a result, the following changes have been made in the CYP2D6 allele functionality table, CYP2D6 genotype to phenotype table (access tables below):

\n\n

August 2015

\n

Advanced online publication May 2015

\n\n

Table 1: Dosing recommendations for fluvoxamine based on CYP2D6 phenotype:

\n

Adapted from Tables 1 and 2b of the 2015 guideline manuscript.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Likely phenotypeActivity ScoreGenotypesExamples of CYP2D6 diplotypesImplications for fluvoxamine metabolismTherapeutic RecommendationsClassification of recommendations a
Ultrarapid metabolizer (~1-2% of patients)b> 2.0An individual carrying duplications of functional alleles*1/*1xN, *1/*2xN, *2/*2xN cNo data available for CYP2D6 Ultrarapid Metabolizers.No recommendation due to lack of evidence. dOptional
Extensive metabolizer (~77-92% of patients)2.0-1.0 eAn individual carrying two normal function alleles or two decreased function alleles or one normal function and one no function allele or one normal function and one decreased function allele*1/*1, *1/*2, *1/*4, *1/*5, *1/*9, *1/*41, *2/*2,*41/*41Normal metabolismInitiate therapy with recommended starting dose.Strong
Intermediate metabolizer (~2-11% of patients)0.5An individual carrying one decreased function and one no function allele*4/*10,*4/*41, *5/*9Reduced metabolism when compared to extensive metabolizers. Higher plasma concentrations may increase the probability of side effects.Initiate therapy with recommended starting dose.Moderate
Poor metabolizers (~5-10% of patients)0An individual carrying only no functional alleles*3/*4,*4/*4, *5/*5, *5/*6Greatly reduced metabolism when compared to extensive metabolizers. Higher plasma concentrations may increase the probability of side effects.Consider a 25-50% reduction f of recommended starting dose and titrate to response or use an alternative drug not metabolized by CYP2D6. gOptional
\n

a Rating scheme described in Supplement.

\n

b CYP2D6 metabolizer status frequencies are based on data from Caucasians and may differ from other ethnicities. See Supplemental note for information on the chances of observing specific diplotypes in different major race/ethnic groups.

\n

c Where xN represents the number of CYP2D6 gene copies. For individuals with CYP2D6 duplications or multiplications, see supplemental data for additional information on how to translate diplotypes into phenotypes.

\n

d Data are lacking describing the effect of CYP2D6 ultrarapid metabolism on fluvoxamine therapy; therefore no dosing recommendations are provided for fluvoxamine use for of CYP2D6 ultrarapid metabolizers. It may be reasonable, though, to select an alternative SSRI not extensively metabolized by CYP2D6 due to the lack of data describing how CYP2D6 ultrarapid metabolizer status influences fluvoxamine therapy.

\n

e Patients with an activity score of 1.0 may be classified as intermediate metabolizers by some reference laboratories.

\n

f Dose extrapolations based on differences in pharmacokinetic parameters between phenotype groups suggest a 30% dose reduction of fluvoxamine (1). However, a 30% decrease in dose may not be feasible given the dosage forms, therefore, decreasing the starting dose of fluvoxamine by 25-50% should be considered.

\n

g Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when selecting an alternative therapy.

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Initiate therapy with recommended starting dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297963", - "name" : "Recommendation PA166297963", + "id" : "PA166297968", + "name" : "Recommendation PA166297968", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: No data available for CYP2D6 ultrarapid metabolizers" + "CYP2D6: Normal metabolism" ], - "lookupKey" : {"CYP2D6": "3.0"}, + "lookupKey" : {"CYP2D6": "1.5"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -51934,26 +51950,26 @@ "objCls" : "Chemical", "id" : "PA449690", "name" : "fluvoxamine", - "version" : 8 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127637", "name" : "Annotation of CPIC Guideline for fluvoxamine and CYP2D6", - "version" : 49 + "version" : 141 }, "text" : { - "id" : 1452093834, - "html" : "

No recommendation due to lack of evidence

\n", + "id" : 1452093821, + "html" : "

Initiate therapy with recommended starting dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297967", - "name" : "Recommendation PA166297967", + "id" : "PA166297969", + "name" : "Recommendation PA166297969", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -51968,7 +51984,7 @@ "implications" : [ "CYP2D6: Normal metabolism" ], - "lookupKey" : {"CYP2D6": "1.75"}, + "lookupKey" : {"CYP2D6": "1.25"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -51976,41 +51992,41 @@ "objCls" : "Chemical", "id" : "PA449690", "name" : "fluvoxamine", - "version" : 8 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127637", "name" : "Annotation of CPIC Guideline for fluvoxamine and CYP2D6", - "version" : 49 + "version" : 141 }, "text" : { - "id" : 1452093820, + "id" : 1452093822, "html" : "

Initiate therapy with recommended starting dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297954", - "name" : "Recommendation PA166297954", + "id" : "PA166297970", + "name" : "Recommendation PA166297970", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: No data available for CYP2D6 ultrarapid metabolizers" + "CYP2D6: Reduced metabolism of fluvoxamine to less active compounds when compared to CYP2D6 normal metabolizers. Higher plasma concentrations may increase the probability of side effects." ], - "lookupKey" : {"CYP2D6": "≥5.0"}, + "lookupKey" : {"CYP2D6": "1.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -52018,41 +52034,41 @@ "objCls" : "Chemical", "id" : "PA449690", "name" : "fluvoxamine", - "version" : 8 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127637", "name" : "Annotation of CPIC Guideline for fluvoxamine and CYP2D6", - "version" : 49 + "version" : 141 }, "text" : { - "id" : 1452093837, - "html" : "

No recommendation due to lack of evidence

\n", + "id" : 1452093823, + "html" : "

Initiate therapy with recommended starting dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297959", - "name" : "Recommendation PA166297959", + "id" : "PA166297971", + "name" : "Recommendation PA166297971", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: No data available for CYP2D6 ultrarapid metabolizers" + "CYP2D6: Reduced metabolism of fluvoxamine to less active compounds when compared to CYP2D6 normal metabolizers. Higher plasma concentrations may increase the probability of side effects." ], - "lookupKey" : {"CYP2D6": "≥3.25"}, + "lookupKey" : {"CYP2D6": "0.75"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -52060,21 +52076,21 @@ "objCls" : "Chemical", "id" : "PA449690", "name" : "fluvoxamine", - "version" : 8 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127637", "name" : "Annotation of CPIC Guideline for fluvoxamine and CYP2D6", - "version" : 49 + "version" : 141 }, "text" : { - "id" : 1452093830, - "html" : "

No recommendation due to lack of evidence

\n", + "id" : 1452093824, + "html" : "

Initiate therapy with recommended starting dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", @@ -52102,21 +52118,21 @@ "objCls" : "Chemical", "id" : "PA449690", "name" : "fluvoxamine", - "version" : 8 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127637", "name" : "Annotation of CPIC Guideline for fluvoxamine and CYP2D6", - "version" : 49 + "version" : 141 }, "text" : { "id" : 1452093825, "html" : "

Initiate therapy with recommended starting dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", @@ -52144,26 +52160,26 @@ "objCls" : "Chemical", "id" : "PA449690", "name" : "fluvoxamine", - "version" : 8 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127637", "name" : "Annotation of CPIC Guideline for fluvoxamine and CYP2D6", - "version" : 49 + "version" : 141 }, "text" : { "id" : 1452093826, "html" : "

Initiate therapy with recommended starting dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297964", - "name" : "Recommendation PA166297964", + "id" : "PA166297956", + "name" : "Recommendation PA166297956", "alternateDrugAvailable" : false, "classification" : { "id" : 1448526251, @@ -52178,7 +52194,7 @@ "implications" : [ "CYP2D6: No data available for CYP2D6 ultrarapid metabolizers" ], - "lookupKey" : {"CYP2D6": "2.5"}, + "lookupKey" : {"CYP2D6": "≥4.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -52186,41 +52202,41 @@ "objCls" : "Chemical", "id" : "PA449690", "name" : "fluvoxamine", - "version" : 8 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127637", "name" : "Annotation of CPIC Guideline for fluvoxamine and CYP2D6", - "version" : 49 + "version" : 141 }, "text" : { - "id" : 1452093835, + "id" : 1452093828, "html" : "

No recommendation due to lack of evidence

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297968", - "name" : "Recommendation PA166297968", + "id" : "PA166297957", + "name" : "Recommendation PA166297957", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Normal metabolism" + "CYP2D6: No data available for CYP2D6 ultrarapid metabolizers" ], - "lookupKey" : {"CYP2D6": "1.5"}, + "lookupKey" : {"CYP2D6": "≥3.5"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -52228,56 +52244,26 @@ "objCls" : "Chemical", "id" : "PA449690", "name" : "fluvoxamine", - "version" : 8 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166127637", - "name" : "Annotation of CPIC Guideline for fluvoxamine and CYP2D6", - "version" : 49 - }, - "text" : { - "id" : 1452093821, - "html" : "

Initiate therapy with recommended starting dose.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166301323", - "name" : "Recommendation Annotation PA166301323", - "alternateDrugAvailable" : false, - "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA449690", - "name" : "fluvoxamine", - "version" : 8 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127637", "name" : "Annotation of CPIC Guideline for fluvoxamine and CYP2D6", - "version" : 49 + "version" : 141 }, "text" : { - "id" : 1452095642, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "id" : 1452093829, + "html" : "

No recommendation due to lack of evidence

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297960", - "name" : "Recommendation PA166297960", + "id" : "PA166297959", + "name" : "Recommendation PA166297959", "alternateDrugAvailable" : false, "classification" : { "id" : 1448526251, @@ -52292,7 +52278,7 @@ "implications" : [ "CYP2D6: No data available for CYP2D6 ultrarapid metabolizers" ], - "lookupKey" : {"CYP2D6": "≥3.0"}, + "lookupKey" : {"CYP2D6": "≥3.25"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -52300,26 +52286,26 @@ "objCls" : "Chemical", "id" : "PA449690", "name" : "fluvoxamine", - "version" : 8 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127637", "name" : "Annotation of CPIC Guideline for fluvoxamine and CYP2D6", - "version" : 49 + "version" : 141 }, "text" : { - "id" : 1452093831, + "id" : 1452093830, "html" : "

No recommendation due to lack of evidence

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300881", - "name" : "Recommendation PA166300881", + "id" : "PA166297961", + "name" : "Recommendation PA166297961", "alternateDrugAvailable" : false, "classification" : { "id" : 1448526251, @@ -52334,7 +52320,7 @@ "implications" : [ "CYP2D6: No data available for CYP2D6 ultrarapid metabolizers" ], - "lookupKey" : {"CYP2D6": "≥3.75"}, + "lookupKey" : {"CYP2D6": "4.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -52342,41 +52328,41 @@ "objCls" : "Chemical", "id" : "PA449690", "name" : "fluvoxamine", - "version" : 8 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127637", "name" : "Annotation of CPIC Guideline for fluvoxamine and CYP2D6", - "version" : 49 + "version" : 141 }, "text" : { - "id" : 1452093827, + "id" : 1452093832, "html" : "

No recommendation due to lack of evidence

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297974", - "name" : "Recommendation PA166297974", - "alternateDrugAvailable" : true, + "id" : "PA166297963", + "name" : "Recommendation PA166297963", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2D6: Greatly reduced metabolism of fluvoxamine to less active compounds when compared to CYP2D6 normal metabolizers. Higher plasma concentrations may increase the probability of side effects." + "CYP2D6: No data available for CYP2D6 ultrarapid metabolizers" ], - "lookupKey" : {"CYP2D6": "0.0"}, + "lookupKey" : {"CYP2D6": "3.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -52384,26 +52370,26 @@ "objCls" : "Chemical", "id" : "PA449690", "name" : "fluvoxamine", - "version" : 8 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127637", "name" : "Annotation of CPIC Guideline for fluvoxamine and CYP2D6", - "version" : 49 + "version" : 141 }, "text" : { - "id" : 1452093838, - "html" : "

Consider a 25-50% lower starting dose and slower titration schedule as compared to normal metabolizers or consider a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2D6.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when adjusting dose or selecting an alternative therapy.

\n", + "id" : 1452093834, + "html" : "

No recommendation due to lack of evidence

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297961", - "name" : "Recommendation PA166297961", + "id" : "PA166297964", + "name" : "Recommendation PA166297964", "alternateDrugAvailable" : false, "classification" : { "id" : 1448526251, @@ -52418,7 +52404,7 @@ "implications" : [ "CYP2D6: No data available for CYP2D6 ultrarapid metabolizers" ], - "lookupKey" : {"CYP2D6": "4.0"}, + "lookupKey" : {"CYP2D6": "2.5"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -52426,41 +52412,41 @@ "objCls" : "Chemical", "id" : "PA449690", "name" : "fluvoxamine", - "version" : 8 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127637", "name" : "Annotation of CPIC Guideline for fluvoxamine and CYP2D6", - "version" : 49 + "version" : 141 }, "text" : { - "id" : 1452093832, + "id" : 1452093835, "html" : "

No recommendation due to lack of evidence

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297965", - "name" : "Recommendation PA166297965", + "id" : "PA166297954", + "name" : "Recommendation PA166297954", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Normal metabolism" + "CYP2D6: No data available for CYP2D6 ultrarapid metabolizers" ], - "lookupKey" : {"CYP2D6": "2.25"}, + "lookupKey" : {"CYP2D6": "≥5.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -52468,41 +52454,41 @@ "objCls" : "Chemical", "id" : "PA449690", "name" : "fluvoxamine", - "version" : 8 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127637", "name" : "Annotation of CPIC Guideline for fluvoxamine and CYP2D6", - "version" : 49 + "version" : 141 }, "text" : { - "id" : 1452093818, - "html" : "

Initiate therapy with recommended starting dose.

\n", + "id" : 1452093837, + "html" : "

No recommendation due to lack of evidence

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297969", - "name" : "Recommendation PA166297969", - "alternateDrugAvailable" : false, + "id" : "PA166297974", + "name" : "Recommendation PA166297974", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2D6: Normal metabolism" + "CYP2D6: Greatly reduced metabolism of fluvoxamine to less active compounds when compared to CYP2D6 normal metabolizers. Higher plasma concentrations may increase the probability of side effects." ], - "lookupKey" : {"CYP2D6": "1.25"}, + "lookupKey" : {"CYP2D6": "0.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -52510,26 +52496,26 @@ "objCls" : "Chemical", "id" : "PA449690", "name" : "fluvoxamine", - "version" : 8 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127637", "name" : "Annotation of CPIC Guideline for fluvoxamine and CYP2D6", - "version" : 49 + "version" : 141 }, "text" : { - "id" : 1452093822, - "html" : "

Initiate therapy with recommended starting dose.

\n", + "id" : 1452093838, + "html" : "

Consider a 25-50% lower starting dose and slower titration schedule as compared to normal metabolizers or consider a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2D6.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when adjusting dose or selecting an alternative therapy.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297956", - "name" : "Recommendation PA166297956", + "id" : "PA166297975", + "name" : "Recommendation PA166297975", "alternateDrugAvailable" : false, "classification" : { "id" : 1448526251, @@ -52542,9 +52528,9 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2D6: No data available for CYP2D6 ultrarapid metabolizers" + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "≥4.0"}, + "lookupKey" : {"CYP2D6": "n/a"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -52552,41 +52538,41 @@ "objCls" : "Chemical", "id" : "PA449690", "name" : "fluvoxamine", - "version" : 8 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127637", "name" : "Annotation of CPIC Guideline for fluvoxamine and CYP2D6", - "version" : 49 + "version" : 141 }, "text" : { - "id" : 1452093828, - "html" : "

No recommendation due to lack of evidence

\n", + "id" : 1452093839, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297970", - "name" : "Recommendation PA166297970", + "id" : "PA166300881", + "name" : "Recommendation PA166300881", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Reduced metabolism of fluvoxamine to less active compounds when compared to CYP2D6 normal metabolizers. Higher plasma concentrations may increase the probability of side effects." + "CYP2D6: No data available for CYP2D6 ultrarapid metabolizers" ], - "lookupKey" : {"CYP2D6": "1.0"}, + "lookupKey" : {"CYP2D6": "≥3.75"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -52594,21 +52580,21 @@ "objCls" : "Chemical", "id" : "PA449690", "name" : "fluvoxamine", - "version" : 8 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127637", "name" : "Annotation of CPIC Guideline for fluvoxamine and CYP2D6", - "version" : 49 + "version" : 141 }, "text" : { - "id" : 1452093823, - "html" : "

Initiate therapy with recommended starting dose.

\n", + "id" : 1452093827, + "html" : "

No recommendation due to lack of evidence

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", @@ -52636,26 +52622,56 @@ "objCls" : "Chemical", "id" : "PA449690", "name" : "fluvoxamine", - "version" : 8 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127637", "name" : "Annotation of CPIC Guideline for fluvoxamine and CYP2D6", - "version" : 49 + "version" : 141 }, "text" : { "id" : 1452093833, "html" : "

No recommendation due to lack of evidence

\n", "version" : 0 }, + "version" : 2 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166301323", + "name" : "Recommendation Annotation PA166301323", + "alternateDrugAvailable" : false, + "dosingInformation" : false, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA449690", + "name" : "fluvoxamine", + "version" : 37 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166127637", + "name" : "Annotation of CPIC Guideline for fluvoxamine and CYP2D6", + "version" : 141 + }, + "text" : { + "id" : 1452095642, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "version" : 0 + }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297975", - "name" : "Recommendation PA166297975", + "id" : "PA166297953", + "name" : "Recommendation PA166297953", "alternateDrugAvailable" : false, "classification" : { "id" : 1448526251, @@ -52668,9 +52684,9 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2D6: n/a" + "CYP2D6: No data available for CYP2D6 ultrarapid metabolizers" ], - "lookupKey" : {"CYP2D6": "n/a"}, + "lookupKey" : {"CYP2D6": "≥6.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -52678,26 +52694,26 @@ "objCls" : "Chemical", "id" : "PA449690", "name" : "fluvoxamine", - "version" : 8 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127637", "name" : "Annotation of CPIC Guideline for fluvoxamine and CYP2D6", - "version" : 49 + "version" : 141 }, "text" : { - "id" : 1452093839, - "html" : "

No recommendation

\n", + "id" : 1452093836, + "html" : "

No recommendation due to lack of evidence

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297953", - "name" : "Recommendation PA166297953", + "id" : "PA166297960", + "name" : "Recommendation PA166297960", "alternateDrugAvailable" : false, "classification" : { "id" : 1448526251, @@ -52712,7 +52728,7 @@ "implications" : [ "CYP2D6: No data available for CYP2D6 ultrarapid metabolizers" ], - "lookupKey" : {"CYP2D6": "≥6.0"}, + "lookupKey" : {"CYP2D6": "≥3.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -52720,26 +52736,26 @@ "objCls" : "Chemical", "id" : "PA449690", "name" : "fluvoxamine", - "version" : 8 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127637", "name" : "Annotation of CPIC Guideline for fluvoxamine and CYP2D6", - "version" : 49 + "version" : 141 }, "text" : { - "id" : 1452093836, + "id" : 1452093831, "html" : "

No recommendation due to lack of evidence

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297966", - "name" : "Recommendation PA166297966", + "id" : "PA166297965", + "name" : "Recommendation PA166297965", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -52754,7 +52770,7 @@ "implications" : [ "CYP2D6: Normal metabolism" ], - "lookupKey" : {"CYP2D6": "2.0"}, + "lookupKey" : {"CYP2D6": "2.25"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -52762,41 +52778,41 @@ "objCls" : "Chemical", "id" : "PA449690", "name" : "fluvoxamine", - "version" : 8 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127637", "name" : "Annotation of CPIC Guideline for fluvoxamine and CYP2D6", - "version" : 49 + "version" : 141 }, "text" : { - "id" : 1452093819, + "id" : 1452093818, "html" : "

Initiate therapy with recommended starting dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297957", - "name" : "Recommendation PA166297957", + "id" : "PA166297966", + "name" : "Recommendation PA166297966", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: No data available for CYP2D6 ultrarapid metabolizers" + "CYP2D6: Normal metabolism" ], - "lookupKey" : {"CYP2D6": "≥3.5"}, + "lookupKey" : {"CYP2D6": "2.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -52804,21 +52820,21 @@ "objCls" : "Chemical", "id" : "PA449690", "name" : "fluvoxamine", - "version" : 8 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127637", "name" : "Annotation of CPIC Guideline for fluvoxamine and CYP2D6", - "version" : 49 + "version" : 141 }, "text" : { - "id" : 1452093829, - "html" : "

No recommendation due to lack of evidence

\n", + "id" : 1452093819, + "html" : "

Initiate therapy with recommended starting dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166127637" @@ -53073,7 +53089,7 @@ "id" : "PA165954769", "symbol" : "HLA-B*15:02", "name" : "*15:02", - "version" : 5 + "version" : 21 } ], "relatedChemicals" : [ @@ -53081,13 +53097,13 @@ "objCls" : "Chemical", "id" : "PA164746820", "name" : "fosphenytoin", - "version" : 9 + "version" : 24 }, { "objCls" : "Chemical", "id" : "PA450947", "name" : "phenytoin", - "version" : 14 + "version" : 49 } ], "relatedGenes" : [ @@ -53096,21 +53112,21 @@ "id" : "PA126", "symbol" : "CYP2C9", "name" : "cytochrome P450 family 2 subfamily C member 9", - "version" : 7877 + "version" : 7952 }, { "objCls" : "Gene", "id" : "PA35056", "symbol" : "HLA-B", "name" : "major histocompatibility complex, class I, B", - "version" : 40 + "version" : 2920 } ], "source" : "CPIC", "summaryMarkdown" : { "id" : 1447981650, "html" : "

Phenytoin/fosphenytoin is contraindicated in individuals with the HLA-B*15:02 variant allele ("HLA-B*15:02-positive") due to significantly increased risk of phenytoin-induced cutaneous adverse reactions of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Additionally, patients with the CYP2C9 poor metabolizer phenotype or with a CYP2C9 activity score of 1 may require reduced doses of phenytoin/fosphenytoin.

\n", - "version" : 2 + "version" : 4 }, "terms" : [], "textMarkdown" : { @@ -53119,13 +53135,13 @@ "version" : 1 }, "userId" : "whaleyr", - "version" : 51 + "version" : 268 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166298422", - "name" : "Recommendation PA166298422", + "id" : "PA166298359", + "name" : "Recommendation PA166298359", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -53143,75 +53159,32 @@ ], "lookupKey" : {"HLA-B": "*15:02 negative", "CYP2C9": "2.0"}, "otherPrescribingGuidance" : false, - "population" : "PHT use >3mos", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA164746820", - "name" : "fosphenytoin", - "version" : 9 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166122806", - "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 - }, - "text" : { - "id" : 1452061024, - "html" : "

No adjustments needed from typical dosing strategies. Subsequent doses should be adjusted according to therapeutic drug monitoring, response, and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN and patients should be carefully monitored according to a usual standard.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166298435", - "name" : "Recommendation PA166298435", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 981501930, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "CYP2C9: Normal phenytoin metabolism", - "HLA-B: n/a" - ], - "lookupKey" : {"HLA-B": "No Result", "CYP2C9": "2.0"}, - "otherPrescribingGuidance" : false, - "population" : "PHT use >3mos", + "population" : "PHT naive", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA164746820", - "name" : "fosphenytoin", - "version" : 9 + "id" : "PA450947", + "name" : "phenytoin", + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452061037, + "id" : 1452060961, "html" : "

No adjustments needed from typical dosing strategies. Subsequent doses should be adjusted according to therapeutic drug monitoring, response, and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN and patients should be carefully monitored according to a usual standard.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298382", - "name" : "Recommendation PA166298382", + "id" : "PA166298395", + "name" : "Recommendation PA166298395", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -53227,7 +53200,7 @@ "CYP2C9: Reduced phenytoin metabolism; Higher plasma concentrations will increase probability of toxicities.", "HLA-B: n/a" ], - "lookupKey" : {"HLA-B": "*15:02 negative", "CYP2C9": "1.0"}, + "lookupKey" : {"HLA-B": "No Result", "CYP2C9": "1.0"}, "otherPrescribingGuidance" : false, "population" : "PHT use >3mos", "relatedChemicals" : [ @@ -53235,71 +53208,27 @@ "objCls" : "Chemical", "id" : "PA450947", "name" : "phenytoin", - "version" : 14 + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452060984, + "id" : 1452060997, "html" : "

For first dose, use typical initial or loading dose. For subsequent doses, use approximately 25% less than typical maintenance dose. Subsequent doses should be adjusted according to therapeutic drug monitoring, response and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN, and patients should be carefully monitored according to a usual standard.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298440", - "name" : "Recommendation PA166298440", + "id" : "PA166298425", + "name" : "Recommendation PA166298425", "alternateDrugAvailable" : false, - "classification" : { - "id" : 981501929, - "description" : "Not Applicable", - "parents" : [], - "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", - "valid" : true, - "version" : 1 - }, - "dosingInformation" : false, - "implications" : [ - "CYP2C9: n/a", - "HLA-B: n/a" - ], - "lookupKey" : {"HLA-B": "No Result", "CYP2C9": "n/a"}, - "otherPrescribingGuidance" : false, - "population" : "PHT use >3mos", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA164746820", - "name" : "fosphenytoin", - "version" : 9 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166122806", - "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 - }, - "text" : { - "id" : 1452061042, - "html" : "

No recommendation

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166298409", - "name" : "Recommendation PA166298409", - "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, "parents" : [], @@ -53309,55 +53238,55 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ "CYP2C9: Reduced phenytoin metabolism; Higher plasma concentrations will increase probability of toxicities.", - "HLA-B: Increased risk of phenytoin-induced SJS/TEN" + "HLA-B: n/a" ], - "lookupKey" : {"HLA-B": "*15:02 positive", "CYP2C9": "1.0"}, + "lookupKey" : {"HLA-B": "*15:02 negative", "CYP2C9": "0.5"}, "otherPrescribingGuidance" : false, - "population" : "PHT naive", + "population" : "PHT use >3mos", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA164746820", "name" : "fosphenytoin", - "version" : 9 + "version" : 24 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452061011, - "html" : "

If patient is phenytoin-naive, do not use phenytoin/fosphenytoin. Avoid carbamazepine and oxcarbazepine.

\n

Other Considerations

\n

Other aromatic anticonvulsants, including eslicarbazepine, lamotrigine, and phenobarbital, have weaker evidence linking SJS/TEN with the HLA-B*15:02 allele; however, caution should still be used in choosing an alternative agent.

\n", + "id" : 1452061027, + "html" : "

For first dose, use typical initial or loading dose. For subsequent doses use approximately 50% less than typical maintenance dose. Subsequent doses should be adjusted according to therapeutic drug monitoring, response, and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN, and patients should be carefully monitored according to a usual standard.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298369", - "name" : "Recommendation PA166298369", - "alternateDrugAvailable" : true, + "id" : "PA166298360", + "name" : "Recommendation PA166298360", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2C9: Reduced phenytoin metabolism; Higher plasma concentrations will increase probability of toxicities.", - "HLA-B: Increased risk of phenytoin-induced SJS/TEN" + "CYP2C9: Slightly reduced phenytoin metabolism; however, this does not appear to translate into increased side effects.", + "HLA-B: n/a" ], - "lookupKey" : {"HLA-B": "*15:02 positive", "CYP2C9": "0.0"}, + "lookupKey" : {"HLA-B": "*15:02 negative", "CYP2C9": "1.5"}, "otherPrescribingGuidance" : false, "population" : "PHT naive", "relatedChemicals" : [ @@ -53365,69 +53294,69 @@ "objCls" : "Chemical", "id" : "PA450947", "name" : "phenytoin", - "version" : 14 + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452060971, - "html" : "

If patient is phenytoin-naive, do not use phenytoin/fosphenytoin. Avoid carbamazepine and oxcarbazepine.

\n

Other Considerations

\n

Other aromatic anticonvulsants, including eslicarbazepine, lamotrigine, and phenobarbital, have weaker evidence linking SJS/TEN with the HLA-B*15:02 allele; however, caution should still be used in choosing an alternative agent.

\n", + "id" : 1452060962, + "html" : "

No adjustments needed from typical dosing strategies. Subsequent doses should be adjusted according to therapeutic drug monitoring, response and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN and patients should be carefully monitored according to a usual standard.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298431", - "name" : "Recommendation PA166298431", + "id" : "PA166298361", + "name" : "Recommendation PA166298361", "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ "CYP2C9: Reduced phenytoin metabolism; Higher plasma concentrations will increase probability of toxicities.", - "HLA-B: Increased risk of phenytoin-induced SJS/TEN" + "HLA-B: n/a" ], - "lookupKey" : {"HLA-B": "*15:02 positive", "CYP2C9": "1.0"}, - "otherPrescribingGuidance" : true, - "population" : "PHT use >3mos", + "lookupKey" : {"HLA-B": "*15:02 negative", "CYP2C9": "1.0"}, + "otherPrescribingGuidance" : false, + "population" : "PHT naive", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA164746820", - "name" : "fosphenytoin", - "version" : 9 + "id" : "PA450947", + "name" : "phenytoin", + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452061033, - "html" : "

If the patient has previously used phenytoin continuously for longer than three months without incidence of cutaneous adverse reactions, cautiously consider use of phenytoin in the future. The latency period for drug-induced SJS/TEN is short with continuous dosing and adherence to therapy (4-28 days), and cases usually occur within three months of dosing.

\n

Other Considerations

\n

Previous tolerance of phenytoin is not indicative of tolerance to other aromatic anticonvulsants.

\n", + "id" : 1452060963, + "html" : "

For first dose, use typical initial or loading dose. For subsequent doses, use approximately 25% less than typical maintenance dose. Subsequent doses should be adjusted according to therapeutic drug monitoring, response and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN, and patients should be carefully monitored according to a usual standard.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298399", - "name" : "Recommendation PA166298399", + "id" : "PA166298362", + "name" : "Recommendation PA166298362", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -53438,39 +53367,39 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C9: n/a", + "CYP2C9: Reduced phenytoin metabolism; Higher plasma concentrations will increase probability of toxicities.", "HLA-B: n/a" ], - "lookupKey" : {"HLA-B": "*15:02 negative", "CYP2C9": "No Result"}, + "lookupKey" : {"HLA-B": "*15:02 negative", "CYP2C9": "0.5"}, "otherPrescribingGuidance" : false, - "population" : "PHT use >3mos", + "population" : "PHT naive", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450947", "name" : "phenytoin", - "version" : 14 + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452061001, - "html" : "

No adjustments needed from typical dosing strategies. Subsequent doses should be adjusted according to therapeutic drug monitoring, response, and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN and patients should be carefully monitored according to a usual standard.

\n", + "id" : 1452060964, + "html" : "

For first dose, use typical initial or loading dose. For subsequent doses use approximately 50% less than typical maintenance dose. Subsequent doses should be adjusted according to therapeutic drug monitoring, response, and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN, and patients should be carefully monitored according to a usual standard.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298417", - "name" : "Recommendation PA166298417", + "id" : "PA166298363", + "name" : "Recommendation PA166298363", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -53486,29 +53415,29 @@ "CYP2C9: Reduced phenytoin metabolism; Higher plasma concentrations will increase probability of toxicities.", "HLA-B: n/a" ], - "lookupKey" : {"HLA-B": "No Result", "CYP2C9": "0.5"}, + "lookupKey" : {"HLA-B": "*15:02 negative", "CYP2C9": "0.0"}, "otherPrescribingGuidance" : false, "population" : "PHT naive", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA164746820", - "name" : "fosphenytoin", - "version" : 9 + "id" : "PA450947", + "name" : "phenytoin", + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452061019, + "id" : 1452060965, "html" : "

For first dose, use typical initial or loading dose. For subsequent doses use approximately 50% less than typical maintenance dose. Subsequent doses should be adjusted according to therapeutic drug monitoring, response, and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN, and patients should be carefully monitored according to a usual standard.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -53538,27 +53467,27 @@ "objCls" : "Chemical", "id" : "PA450947", "name" : "phenytoin", - "version" : 14 + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { "id" : 1452060966, "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298377", - "name" : "Recommendation PA166298377", - "alternateDrugAvailable" : false, + "id" : "PA166298365", + "name" : "Recommendation PA166298365", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, "parents" : [], @@ -53570,10 +53499,10 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2C9: n/a", - "HLA-B: n/a" + "CYP2C9: Normal phenytoin metabolism", + "HLA-B: Increased risk of phenytoin-induced SJS/TEN" ], - "lookupKey" : {"HLA-B": "*15:02 negative", "CYP2C9": "No Result"}, + "lookupKey" : {"HLA-B": "*15:02 positive", "CYP2C9": "2.0"}, "otherPrescribingGuidance" : false, "population" : "PHT naive", "relatedChemicals" : [ @@ -53581,26 +53510,26 @@ "objCls" : "Chemical", "id" : "PA450947", "name" : "phenytoin", - "version" : 14 + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452060979, - "html" : "

No adjustments needed from typical dosing strategies. Subsequent doses should be adjusted according to therapeutic drug monitoring, response, and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN and patients should be carefully monitored according to a usual standard.

\n", + "id" : 1452060967, + "html" : "

If patient is phenytoin-naive, do not use phenytoin/fosphenytoin. Avoid carbamazepine and oxcarbazepine.

\n

Other Considerations

\n

Other aromatic anticonvulsants, including eslicarbazepine, lamotrigine, and phenobarbital, have weaker evidence linking SJS/TEN with the HLA-B*15:02 allele; however, caution should still be used in choosing an alternative agent.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298408", - "name" : "Recommendation PA166298408", + "id" : "PA166298366", + "name" : "Recommendation PA166298366", "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, @@ -53622,78 +53551,164 @@ "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA164746820", - "name" : "fosphenytoin", - "version" : 9 + "id" : "PA450947", + "name" : "phenytoin", + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452061010, + "id" : 1452060968, "html" : "

If patient is phenytoin-naive, do not use phenytoin/fosphenytoin. Avoid carbamazepine and oxcarbazepine.

\n

Other Considerations

\n

Other aromatic anticonvulsants, including eslicarbazepine, lamotrigine, and phenobarbital, have weaker evidence linking SJS/TEN with the HLA-B*15:02 allele; however, caution should still be used in choosing an alternative agent.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298395", - "name" : "Recommendation PA166298395", - "alternateDrugAvailable" : false, + "id" : "PA166298367", + "name" : "Recommendation PA166298367", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501931, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ "CYP2C9: Reduced phenytoin metabolism; Higher plasma concentrations will increase probability of toxicities.", - "HLA-B: n/a" + "HLA-B: Increased risk of phenytoin-induced SJS/TEN" ], - "lookupKey" : {"HLA-B": "No Result", "CYP2C9": "1.0"}, + "lookupKey" : {"HLA-B": "*15:02 positive", "CYP2C9": "1.0"}, "otherPrescribingGuidance" : false, - "population" : "PHT use >3mos", + "population" : "PHT naive", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450947", "name" : "phenytoin", - "version" : 14 + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452060997, - "html" : "

For first dose, use typical initial or loading dose. For subsequent doses, use approximately 25% less than typical maintenance dose. Subsequent doses should be adjusted according to therapeutic drug monitoring, response and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN, and patients should be carefully monitored according to a usual standard.

\n", + "id" : 1452060969, + "html" : "

If patient is phenytoin-naive, do not use phenytoin/fosphenytoin. Avoid carbamazepine and oxcarbazepine.

\n

Other Considerations

\n

Other aromatic anticonvulsants, including eslicarbazepine, lamotrigine, and phenobarbital, have weaker evidence linking SJS/TEN with the HLA-B*15:02 allele; however, caution should still be used in choosing an alternative agent.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298400", - "name" : "Recommendation PA166298400", - "alternateDrugAvailable" : false, + "id" : "PA166298368", + "name" : "Recommendation PA166298368", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : false, + "implications" : [ + "CYP2C9: Reduced phenytoin metabolism; Higher plasma concentrations will increase probability of toxicities.", + "HLA-B: Increased risk of phenytoin-induced SJS/TEN" + ], + "lookupKey" : {"HLA-B": "*15:02 positive", "CYP2C9": "0.5"}, + "otherPrescribingGuidance" : false, + "population" : "PHT naive", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA450947", + "name" : "phenytoin", + "version" : 49 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166122806", + "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", + "version" : 268 + }, + "text" : { + "id" : 1452060970, + "html" : "

If patient is phenytoin-naive, do not use phenytoin/fosphenytoin. Avoid carbamazepine and oxcarbazepine.

\n

Other Considerations

\n

Other aromatic anticonvulsants, including eslicarbazepine, lamotrigine, and phenobarbital, have weaker evidence linking SJS/TEN with the HLA-B*15:02 allele; however, caution should still be used in choosing an alternative agent.

\n", + "version" : 0 + }, + "version" : 1 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166298369", + "name" : "Recommendation PA166298369", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981501930, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : false, + "implications" : [ + "CYP2C9: Reduced phenytoin metabolism; Higher plasma concentrations will increase probability of toxicities.", + "HLA-B: Increased risk of phenytoin-induced SJS/TEN" + ], + "lookupKey" : {"HLA-B": "*15:02 positive", "CYP2C9": "0.0"}, + "otherPrescribingGuidance" : false, + "population" : "PHT naive", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA450947", + "name" : "phenytoin", + "version" : 49 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166122806", + "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", + "version" : 268 + }, + "text" : { + "id" : 1452060971, + "html" : "

If patient is phenytoin-naive, do not use phenytoin/fosphenytoin. Avoid carbamazepine and oxcarbazepine.

\n

Other Considerations

\n

Other aromatic anticonvulsants, including eslicarbazepine, lamotrigine, and phenobarbital, have weaker evidence linking SJS/TEN with the HLA-B*15:02 allele; however, caution should still be used in choosing an alternative agent.

\n", + "version" : 0 + }, + "version" : 1 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166298370", + "name" : "Recommendation PA166298370", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981501930, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, @@ -53702,34 +53717,34 @@ "CYP2C9: n/a", "HLA-B: Increased risk of phenytoin-induced SJS/TEN" ], - "lookupKey" : {"HLA-B": "*15:02 positive", "CYP2C9": "No Result"}, - "otherPrescribingGuidance" : true, - "population" : "PHT use >3mos", + "lookupKey" : {"HLA-B": "*15:02 positive", "CYP2C9": "n/a"}, + "otherPrescribingGuidance" : false, + "population" : "PHT naive", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450947", "name" : "phenytoin", - "version" : 14 + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452061002, - "html" : "

If the patient has previously used phenytoin continuously for longer than three months without incidence of cutaneous adverse reactions, cautiously consider use of phenytoin in the future. The latency period for drug-induced SJS/TEN is short with continuous dosing and adherence to therapy (4-28 days), and cases usually occur within three months of dosing.

\n

Other Considerations

\n

Previous tolerance of phenytoin is not indicative of tolerance to other aromatic anticonvulsants.

\n", + "id" : 1452060972, + "html" : "

If patient is phenytoin-naive, do not use phenytoin/fosphenytoin. Avoid carbamazepine and oxcarbazepine.

\n

Other Considerations

\n

Other aromatic anticonvulsants, including eslicarbazepine, lamotrigine, and phenobarbital, have weaker evidence linking SJS/TEN with the HLA-B*15:02 allele; however, caution should still be used in choosing an alternative agent.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298413", - "name" : "Recommendation PA166298413", + "id" : "PA166298371", + "name" : "Recommendation PA166298371", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -53751,28 +53766,28 @@ "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA164746820", - "name" : "fosphenytoin", - "version" : 9 + "id" : "PA450947", + "name" : "phenytoin", + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452061015, + "id" : 1452060973, "html" : "

No adjustments needed from typical dosing strategies. Subsequent doses should be adjusted according to therapeutic drug monitoring, response, and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN and patients should be carefully monitored according to a usual standard.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298360", - "name" : "Recommendation PA166298360", + "id" : "PA166298372", + "name" : "Recommendation PA166298372", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -53788,7 +53803,7 @@ "CYP2C9: Slightly reduced phenytoin metabolism; however, this does not appear to translate into increased side effects.", "HLA-B: n/a" ], - "lookupKey" : {"HLA-B": "*15:02 negative", "CYP2C9": "1.5"}, + "lookupKey" : {"HLA-B": "No Result", "CYP2C9": "1.5"}, "otherPrescribingGuidance" : false, "population" : "PHT naive", "relatedChemicals" : [ @@ -53796,33 +53811,33 @@ "objCls" : "Chemical", "id" : "PA450947", "name" : "phenytoin", - "version" : 14 + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452060962, + "id" : 1452060974, "html" : "

No adjustments needed from typical dosing strategies. Subsequent doses should be adjusted according to therapeutic drug monitoring, response and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN and patients should be carefully monitored according to a usual standard.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298426", - "name" : "Recommendation PA166298426", + "id" : "PA166298373", + "name" : "Recommendation PA166298373", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, @@ -53831,41 +53846,41 @@ "CYP2C9: Reduced phenytoin metabolism; Higher plasma concentrations will increase probability of toxicities.", "HLA-B: n/a" ], - "lookupKey" : {"HLA-B": "*15:02 negative", "CYP2C9": "0.0"}, + "lookupKey" : {"HLA-B": "No Result", "CYP2C9": "1.0"}, "otherPrescribingGuidance" : false, - "population" : "PHT use >3mos", + "population" : "PHT naive", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA164746820", - "name" : "fosphenytoin", - "version" : 9 + "id" : "PA450947", + "name" : "phenytoin", + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452061028, - "html" : "

For first dose, use typical initial or loading dose. For subsequent doses use approximately 50% less than typical maintenance dose. Subsequent doses should be adjusted according to therapeutic drug monitoring, response, and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN, and patients should be carefully monitored according to a usual standard.

\n", + "id" : 1452060975, + "html" : "

For first dose, use typical initial or loading dose. For subsequent doses, use approximately 25% less than typical maintenance dose. Subsequent doses should be adjusted according to therapeutic drug monitoring, response and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN, and patients should be carefully monitored according to a usual standard.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298373", - "name" : "Recommendation PA166298373", + "id" : "PA166298374", + "name" : "Recommendation PA166298374", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, @@ -53874,7 +53889,7 @@ "CYP2C9: Reduced phenytoin metabolism; Higher plasma concentrations will increase probability of toxicities.", "HLA-B: n/a" ], - "lookupKey" : {"HLA-B": "No Result", "CYP2C9": "1.0"}, + "lookupKey" : {"HLA-B": "No Result", "CYP2C9": "0.5"}, "otherPrescribingGuidance" : false, "population" : "PHT naive", "relatedChemicals" : [ @@ -53882,26 +53897,26 @@ "objCls" : "Chemical", "id" : "PA450947", "name" : "phenytoin", - "version" : 14 + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452060975, - "html" : "

For first dose, use typical initial or loading dose. For subsequent doses, use approximately 25% less than typical maintenance dose. Subsequent doses should be adjusted according to therapeutic drug monitoring, response and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN, and patients should be carefully monitored according to a usual standard.

\n", + "id" : 1452060976, + "html" : "

For first dose, use typical initial or loading dose. For subsequent doses use approximately 50% less than typical maintenance dose. Subsequent doses should be adjusted according to therapeutic drug monitoring, response, and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN, and patients should be carefully monitored according to a usual standard.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298439", - "name" : "Recommendation PA166298439", + "id" : "PA166298375", + "name" : "Recommendation PA166298375", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -53919,75 +53934,76 @@ ], "lookupKey" : {"HLA-B": "No Result", "CYP2C9": "0.0"}, "otherPrescribingGuidance" : false, - "population" : "PHT use >3mos", + "population" : "PHT naive", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA164746820", - "name" : "fosphenytoin", - "version" : 9 + "id" : "PA450947", + "name" : "phenytoin", + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452061041, + "id" : 1452060977, "html" : "

For first dose, use typical initial or loading dose. For subsequent doses use approximately 50% less than typical maintenance dose. Subsequent doses should be adjusted according to therapeutic drug monitoring, response, and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN, and patients should be carefully monitored according to a usual standard.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298386", - "name" : "Recommendation PA166298386", + "id" : "PA166298376", + "name" : "Recommendation PA166298376", "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, "dosingInformation" : false, "implications" : [ - "CYP2C9: Normal phenytoin metabolism", - "HLA-B: Increased risk of phenytoin-induced SJS/TEN" + "CYP2C9: n/a", + "HLA-B: n/a" ], - "lookupKey" : {"HLA-B": "*15:02 positive", "CYP2C9": "2.0"}, - "otherPrescribingGuidance" : true, - "population" : "PHT use >3mos", + "lookupKey" : {"HLA-B": "No Result", "CYP2C9": "n/a"}, + "otherPrescribingGuidance" : false, + "population" : "PHT naive", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450947", "name" : "phenytoin", - "version" : 14 + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452060988, - "html" : "

If the patient has previously used phenytoin continuously for longer than three months without incidence of cutaneous adverse reactions, cautiously consider use of phenytoin in the future. The latency period for drug-induced SJS/TEN is short with continuous dosing and adherence to therapy (4-28 days), and cases usually occur within three months of dosing.

\n

Other Considerations

\n

Previous tolerance of phenytoin is not indicative of tolerance to other aromatic anticonvulsants.

\n", + "id" : 1452060978, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298404", - "name" : "Recommendation PA166298404", + "id" : "PA166298377", + "name" : "Recommendation PA166298377", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -53998,168 +54014,168 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C9: Reduced phenytoin metabolism; Higher plasma concentrations will increase probability of toxicities.", + "CYP2C9: n/a", "HLA-B: n/a" ], - "lookupKey" : {"HLA-B": "*15:02 negative", "CYP2C9": "0.5"}, + "lookupKey" : {"HLA-B": "*15:02 negative", "CYP2C9": "No Result"}, "otherPrescribingGuidance" : false, "population" : "PHT naive", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA164746820", - "name" : "fosphenytoin", - "version" : 9 + "id" : "PA450947", + "name" : "phenytoin", + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452061006, - "html" : "

For first dose, use typical initial or loading dose. For subsequent doses use approximately 50% less than typical maintenance dose. Subsequent doses should be adjusted according to therapeutic drug monitoring, response, and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN, and patients should be carefully monitored according to a usual standard.

\n", + "id" : 1452060979, + "html" : "

No adjustments needed from typical dosing strategies. Subsequent doses should be adjusted according to therapeutic drug monitoring, response, and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN and patients should be carefully monitored according to a usual standard.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298432", - "name" : "Recommendation PA166298432", - "alternateDrugAvailable" : false, + "id" : "PA166298378", + "name" : "Recommendation PA166298378", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2C9: Reduced phenytoin metabolism; Higher plasma concentrations will increase probability of toxicities.", + "CYP2C9: n/a", "HLA-B: Increased risk of phenytoin-induced SJS/TEN" ], - "lookupKey" : {"HLA-B": "*15:02 positive", "CYP2C9": "0.5"}, - "otherPrescribingGuidance" : true, - "population" : "PHT use >3mos", + "lookupKey" : {"HLA-B": "*15:02 positive", "CYP2C9": "No Result"}, + "otherPrescribingGuidance" : false, + "population" : "PHT naive", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA164746820", - "name" : "fosphenytoin", - "version" : 9 + "id" : "PA450947", + "name" : "phenytoin", + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452061034, - "html" : "

If the patient has previously used phenytoin continuously for longer than three months without incidence of cutaneous adverse reactions, cautiously consider use of phenytoin in the future. The latency period for drug-induced SJS/TEN is short with continuous dosing and adherence to therapy (4-28 days), and cases usually occur within three months of dosing.

\n

Other Considerations

\n

Previous tolerance of phenytoin is not indicative of tolerance to other aromatic anticonvulsants.

\n", + "id" : 1452060980, + "html" : "

If patient is phenytoin-naive, do not use phenytoin/fosphenytoin. Avoid carbamazepine and oxcarbazepine.

\n

Other Considerations

\n

Other aromatic anticonvulsants, including eslicarbazepine, lamotrigine, and phenobarbital, have weaker evidence linking SJS/TEN with the HLA-B*15:02 allele; however, caution should still be used in choosing an alternative agent.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298392", - "name" : "Recommendation PA166298392", + "id" : "PA166298379", + "name" : "Recommendation PA166298379", "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2C9: n/a", - "HLA-B: Increased risk of phenytoin-induced SJS/TEN" + "CYP2C9: Normal phenytoin metabolism", + "HLA-B: n/a" ], - "lookupKey" : {"HLA-B": "*15:02 positive", "CYP2C9": "n/a"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"HLA-B": "*15:02 negative", "CYP2C9": "2.0"}, + "otherPrescribingGuidance" : false, "population" : "PHT use >3mos", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450947", "name" : "phenytoin", - "version" : 14 + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452060994, - "html" : "

If the patient has previously used phenytoin continuously for longer than three months without incidence of cutaneous adverse reactions, cautiously consider use of phenytoin in the future. The latency period for drug-induced SJS/TEN is short with continuous dosing and adherence to therapy (4-28 days), and cases usually occur within three months of dosing.

\n

Other Considerations

\n

Previous tolerance of phenytoin is not indicative of tolerance to other aromatic anticonvulsants.

\n", + "id" : 1452060981, + "html" : "

No adjustments needed from typical dosing strategies. Subsequent doses should be adjusted according to therapeutic drug monitoring, response, and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN and patients should be carefully monitored according to a usual standard.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298410", - "name" : "Recommendation PA166298410", - "alternateDrugAvailable" : true, + "id" : "PA166298381", + "name" : "Recommendation PA166298381", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2C9: Reduced phenytoin metabolism; Higher plasma concentrations will increase probability of toxicities.", - "HLA-B: Increased risk of phenytoin-induced SJS/TEN" + "CYP2C9: Slightly reduced phenytoin metabolism; however, this does not appear to translate into increased side effects.", + "HLA-B: n/a" ], - "lookupKey" : {"HLA-B": "*15:02 positive", "CYP2C9": "0.5"}, + "lookupKey" : {"HLA-B": "*15:02 negative", "CYP2C9": "1.5"}, "otherPrescribingGuidance" : false, - "population" : "PHT naive", + "population" : "PHT use >3mos", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA164746820", - "name" : "fosphenytoin", - "version" : 9 + "id" : "PA450947", + "name" : "phenytoin", + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452061012, - "html" : "

If patient is phenytoin-naive, do not use phenytoin/fosphenytoin. Avoid carbamazepine and oxcarbazepine.

\n

Other Considerations

\n

Other aromatic anticonvulsants, including eslicarbazepine, lamotrigine, and phenobarbital, have weaker evidence linking SJS/TEN with the HLA-B*15:02 allele; however, caution should still be used in choosing an alternative agent.

\n", + "id" : 1452060983, + "html" : "

No adjustments needed from typical dosing strategies. Subsequent doses should be adjusted according to therapeutic drug monitoring, response and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN and patients should be carefully monitored according to a usual standard.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298423", - "name" : "Recommendation PA166298423", + "id" : "PA166298382", + "name" : "Recommendation PA166298382", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -54170,40 +54186,40 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C9: Slightly reduced phenytoin metabolism; however, this does not appear to translate into increased side effects.", + "CYP2C9: Reduced phenytoin metabolism; Higher plasma concentrations will increase probability of toxicities.", "HLA-B: n/a" ], - "lookupKey" : {"HLA-B": "*15:02 negative", "CYP2C9": "1.5"}, + "lookupKey" : {"HLA-B": "*15:02 negative", "CYP2C9": "1.0"}, "otherPrescribingGuidance" : false, "population" : "PHT use >3mos", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA164746820", - "name" : "fosphenytoin", - "version" : 9 + "id" : "PA450947", + "name" : "phenytoin", + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452061025, - "html" : "

No adjustments needed from typical dosing strategies. Subsequent doses should be adjusted according to therapeutic drug monitoring, response and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN and patients should be carefully monitored according to a usual standard.

\n", + "id" : 1452060984, + "html" : "

For first dose, use typical initial or loading dose. For subsequent doses, use approximately 25% less than typical maintenance dose. Subsequent doses should be adjusted according to therapeutic drug monitoring, response and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN, and patients should be carefully monitored according to a usual standard.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298370", - "name" : "Recommendation PA166298370", - "alternateDrugAvailable" : true, + "id" : "PA166298383", + "name" : "Recommendation PA166298383", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, "parents" : [], @@ -54213,39 +54229,39 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C9: n/a", - "HLA-B: Increased risk of phenytoin-induced SJS/TEN" + "CYP2C9: Reduced phenytoin metabolism; Higher plasma concentrations will increase probability of toxicities.", + "HLA-B: n/a" ], - "lookupKey" : {"HLA-B": "*15:02 positive", "CYP2C9": "n/a"}, + "lookupKey" : {"HLA-B": "*15:02 negative", "CYP2C9": "0.5"}, "otherPrescribingGuidance" : false, - "population" : "PHT naive", + "population" : "PHT use >3mos", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450947", "name" : "phenytoin", - "version" : 14 + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452060972, - "html" : "

If patient is phenytoin-naive, do not use phenytoin/fosphenytoin. Avoid carbamazepine and oxcarbazepine.

\n

Other Considerations

\n

Other aromatic anticonvulsants, including eslicarbazepine, lamotrigine, and phenobarbital, have weaker evidence linking SJS/TEN with the HLA-B*15:02 allele; however, caution should still be used in choosing an alternative agent.

\n", + "id" : 1452060985, + "html" : "

For first dose, use typical initial or loading dose. For subsequent doses use approximately 50% less than typical maintenance dose. Subsequent doses should be adjusted according to therapeutic drug monitoring, response, and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN, and patients should be carefully monitored according to a usual standard.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298379", - "name" : "Recommendation PA166298379", + "id" : "PA166298384", + "name" : "Recommendation PA166298384", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -54256,12 +54272,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C9: Normal phenytoin metabolism", + "CYP2C9: Reduced phenytoin metabolism; Higher plasma concentrations will increase probability of toxicities.", "HLA-B: n/a" ], - "lookupKey" : {"HLA-B": "*15:02 negative", "CYP2C9": "2.0"}, + "lookupKey" : {"HLA-B": "*15:02 negative", "CYP2C9": "0.0"}, "otherPrescribingGuidance" : false, "population" : "PHT use >3mos", "relatedChemicals" : [ @@ -54269,69 +54285,70 @@ "objCls" : "Chemical", "id" : "PA450947", "name" : "phenytoin", - "version" : 14 + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452060981, - "html" : "

No adjustments needed from typical dosing strategies. Subsequent doses should be adjusted according to therapeutic drug monitoring, response, and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN and patients should be carefully monitored according to a usual standard.

\n", + "id" : 1452060986, + "html" : "

For first dose, use typical initial or loading dose. For subsequent doses use approximately 50% less than typical maintenance dose. Subsequent doses should be adjusted according to therapeutic drug monitoring, response, and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN, and patients should be carefully monitored according to a usual standard.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298441", - "name" : "Recommendation PA166298441", + "id" : "PA166298385", + "name" : "Recommendation PA166298385", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, "dosingInformation" : false, "implications" : [ "CYP2C9: n/a", "HLA-B: n/a" ], - "lookupKey" : {"HLA-B": "*15:02 negative", "CYP2C9": "No Result"}, + "lookupKey" : {"HLA-B": "*15:02 negative", "CYP2C9": "n/a"}, "otherPrescribingGuidance" : false, "population" : "PHT use >3mos", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA164746820", - "name" : "fosphenytoin", - "version" : 9 + "id" : "PA450947", + "name" : "phenytoin", + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452061043, - "html" : "

No adjustments needed from typical dosing strategies. Subsequent doses should be adjusted according to therapeutic drug monitoring, response, and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN and patients should be carefully monitored according to a usual standard.

\n", + "id" : 1452060987, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298387", - "name" : "Recommendation PA166298387", + "id" : "PA166298386", + "name" : "Recommendation PA166298386", "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, @@ -54344,10 +54361,10 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2C9: Slightly reduced phenytoin metabolism; however, this does not appear to translate into increased side effects.", + "CYP2C9: Normal phenytoin metabolism", "HLA-B: Increased risk of phenytoin-induced SJS/TEN" ], - "lookupKey" : {"HLA-B": "*15:02 positive", "CYP2C9": "1.5"}, + "lookupKey" : {"HLA-B": "*15:02 positive", "CYP2C9": "2.0"}, "otherPrescribingGuidance" : true, "population" : "PHT use >3mos", "relatedChemicals" : [ @@ -54355,322 +54372,322 @@ "objCls" : "Chemical", "id" : "PA450947", "name" : "phenytoin", - "version" : 14 + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452060989, + "id" : 1452060988, "html" : "

If the patient has previously used phenytoin continuously for longer than three months without incidence of cutaneous adverse reactions, cautiously consider use of phenytoin in the future. The latency period for drug-induced SJS/TEN is short with continuous dosing and adherence to therapy (4-28 days), and cases usually occur within three months of dosing.

\n

Other Considerations

\n

Previous tolerance of phenytoin is not indicative of tolerance to other aromatic anticonvulsants.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298405", - "name" : "Recommendation PA166298405", + "id" : "PA166298387", + "name" : "Recommendation PA166298387", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C9: Reduced phenytoin metabolism; Higher plasma concentrations will increase probability of toxicities.", - "HLA-B: n/a" + "CYP2C9: Slightly reduced phenytoin metabolism; however, this does not appear to translate into increased side effects.", + "HLA-B: Increased risk of phenytoin-induced SJS/TEN" ], - "lookupKey" : {"HLA-B": "*15:02 negative", "CYP2C9": "0.0"}, - "otherPrescribingGuidance" : false, - "population" : "PHT naive", + "lookupKey" : {"HLA-B": "*15:02 positive", "CYP2C9": "1.5"}, + "otherPrescribingGuidance" : true, + "population" : "PHT use >3mos", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA164746820", - "name" : "fosphenytoin", - "version" : 9 + "id" : "PA450947", + "name" : "phenytoin", + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452061007, - "html" : "

For first dose, use typical initial or loading dose. For subsequent doses use approximately 50% less than typical maintenance dose. Subsequent doses should be adjusted according to therapeutic drug monitoring, response, and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN, and patients should be carefully monitored according to a usual standard.

\n", + "id" : 1452060989, + "html" : "

If the patient has previously used phenytoin continuously for longer than three months without incidence of cutaneous adverse reactions, cautiously consider use of phenytoin in the future. The latency period for drug-induced SJS/TEN is short with continuous dosing and adherence to therapy (4-28 days), and cases usually occur within three months of dosing.

\n

Other Considerations

\n

Previous tolerance of phenytoin is not indicative of tolerance to other aromatic anticonvulsants.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298418", - "name" : "Recommendation PA166298418", + "id" : "PA166298388", + "name" : "Recommendation PA166298388", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ "CYP2C9: Reduced phenytoin metabolism; Higher plasma concentrations will increase probability of toxicities.", - "HLA-B: n/a" + "HLA-B: Increased risk of phenytoin-induced SJS/TEN" ], - "lookupKey" : {"HLA-B": "No Result", "CYP2C9": "0.0"}, - "otherPrescribingGuidance" : false, - "population" : "PHT naive", + "lookupKey" : {"HLA-B": "*15:02 positive", "CYP2C9": "1.0"}, + "otherPrescribingGuidance" : true, + "population" : "PHT use >3mos", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA164746820", - "name" : "fosphenytoin", - "version" : 9 + "id" : "PA450947", + "name" : "phenytoin", + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452061020, - "html" : "

For first dose, use typical initial or loading dose. For subsequent doses use approximately 50% less than typical maintenance dose. Subsequent doses should be adjusted according to therapeutic drug monitoring, response, and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN, and patients should be carefully monitored according to a usual standard.

\n", + "id" : 1452060990, + "html" : "

If the patient has previously used phenytoin continuously for longer than three months without incidence of cutaneous adverse reactions, cautiously consider use of phenytoin in the future. The latency period for drug-induced SJS/TEN is short with continuous dosing and adherence to therapy (4-28 days), and cases usually occur within three months of dosing.

\n

Other Considerations

\n

Previous tolerance of phenytoin is not indicative of tolerance to other aromatic anticonvulsants.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298365", - "name" : "Recommendation PA166298365", - "alternateDrugAvailable" : true, + "id" : "PA166298389", + "name" : "Recommendation PA166298389", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2C9: Normal phenytoin metabolism", + "CYP2C9: Reduced phenytoin metabolism; Higher plasma concentrations will increase probability of toxicities.", "HLA-B: Increased risk of phenytoin-induced SJS/TEN" ], - "lookupKey" : {"HLA-B": "*15:02 positive", "CYP2C9": "2.0"}, - "otherPrescribingGuidance" : false, - "population" : "PHT naive", + "lookupKey" : {"HLA-B": "*15:02 positive", "CYP2C9": "0.5"}, + "otherPrescribingGuidance" : true, + "population" : "PHT use >3mos", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450947", "name" : "phenytoin", - "version" : 14 + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452060967, - "html" : "

If patient is phenytoin-naive, do not use phenytoin/fosphenytoin. Avoid carbamazepine and oxcarbazepine.

\n

Other Considerations

\n

Other aromatic anticonvulsants, including eslicarbazepine, lamotrigine, and phenobarbital, have weaker evidence linking SJS/TEN with the HLA-B*15:02 allele; however, caution should still be used in choosing an alternative agent.

\n", + "id" : 1452060991, + "html" : "

If the patient has previously used phenytoin continuously for longer than three months without incidence of cutaneous adverse reactions, cautiously consider use of phenytoin in the future. The latency period for drug-induced SJS/TEN is short with continuous dosing and adherence to therapy (4-28 days), and cases usually occur within three months of dosing.

\n

Other Considerations

\n

Previous tolerance of phenytoin is not indicative of tolerance to other aromatic anticonvulsants.

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If patient is phenytoin-naive, do not use phenytoin/fosphenytoin. Avoid carbamazepine and oxcarbazepine.

\n

Other Considerations

\n

Other aromatic anticonvulsants, including eslicarbazepine, lamotrigine, and phenobarbital, have weaker evidence linking SJS/TEN with the HLA-B*15:02 allele; however, caution should still be used in choosing an alternative agent.

\n", + "id" : 1452060992, + "html" : "

If the patient has previously used phenytoin continuously for longer than three months without incidence of cutaneous adverse reactions, cautiously consider use of phenytoin in the future. The latency period for drug-induced SJS/TEN is short with continuous dosing and adherence to therapy (4-28 days), and cases usually occur within three months of dosing.

\n

Other Considerations

\n

Previous tolerance of phenytoin is not indicative of tolerance to other aromatic anticonvulsants.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298383", - "name" : "Recommendation PA166298383", + "id" : "PA166298392", + "name" : "Recommendation PA166298392", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C9: Reduced phenytoin metabolism; Higher plasma concentrations will increase probability of toxicities.", - "HLA-B: n/a" + "CYP2C9: n/a", + "HLA-B: Increased risk of phenytoin-induced SJS/TEN" ], - "lookupKey" : {"HLA-B": "*15:02 negative", "CYP2C9": "0.5"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"HLA-B": "*15:02 positive", "CYP2C9": "n/a"}, + "otherPrescribingGuidance" : true, "population" : "PHT use >3mos", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450947", "name" : "phenytoin", - "version" : 14 + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452060985, - "html" : "

For first dose, use typical initial or loading dose. For subsequent doses use approximately 50% less than typical maintenance dose. Subsequent doses should be adjusted according to therapeutic drug monitoring, response, and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN, and patients should be carefully monitored according to a usual standard.

\n", + "id" : 1452060994, + "html" : "

If the patient has previously used phenytoin continuously for longer than three months without incidence of cutaneous adverse reactions, cautiously consider use of phenytoin in the future. The latency period for drug-induced SJS/TEN is short with continuous dosing and adherence to therapy (4-28 days), and cases usually occur within three months of dosing.

\n

Other Considerations

\n

Previous tolerance of phenytoin is not indicative of tolerance to other aromatic anticonvulsants.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298436", - "name" : "Recommendation PA166298436", + "id" : "PA166298393", + "name" : "Recommendation PA166298393", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2C9: Slightly reduced phenytoin metabolism; however, this does not appear to translate into increased side effects.", + "CYP2C9: Normal phenytoin metabolism", "HLA-B: n/a" ], - "lookupKey" : {"HLA-B": "No Result", "CYP2C9": "1.5"}, + "lookupKey" : {"HLA-B": "No Result", "CYP2C9": "2.0"}, "otherPrescribingGuidance" : false, "population" : "PHT use >3mos", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA164746820", - "name" : "fosphenytoin", - "version" : 9 + "id" : "PA450947", + "name" : "phenytoin", + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452061038, - "html" : "

No adjustments needed from typical dosing strategies. Subsequent doses should be adjusted according to therapeutic drug monitoring, response and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN and patients should be carefully monitored according to a usual standard.

\n", + "id" : 1452060995, + "html" : "

No adjustments needed from typical dosing strategies. Subsequent doses should be adjusted according to therapeutic drug monitoring, response, and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN and patients should be carefully monitored according to a usual standard.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298401", - "name" : "Recommendation PA166298401", + "id" : "PA166298394", + "name" : "Recommendation PA166298394", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2C9: Normal phenytoin metabolism", + "CYP2C9: Slightly reduced phenytoin metabolism; however, this does not appear to translate into increased side effects.", "HLA-B: n/a" ], - "lookupKey" : {"HLA-B": "*15:02 negative", "CYP2C9": "2.0"}, + "lookupKey" : {"HLA-B": "No Result", "CYP2C9": "1.5"}, "otherPrescribingGuidance" : false, - "population" : "PHT naive", + "population" : "PHT use >3mos", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA164746820", - "name" : "fosphenytoin", - "version" : 9 + "id" : "PA450947", + "name" : "phenytoin", + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452061003, - "html" : "

No adjustments needed from typical dosing strategies. Subsequent doses should be adjusted according to therapeutic drug monitoring, response, and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN and patients should be carefully monitored according to a usual standard.

\n", + "id" : 1452060996, + "html" : "

No adjustments needed from typical dosing strategies. Subsequent doses should be adjusted according to therapeutic drug monitoring, response and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN and patients should be carefully monitored according to a usual standard.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -54699,33 +54716,33 @@ "objCls" : "Chemical", "id" : "PA450947", "name" : "phenytoin", - "version" : 14 + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { "id" : 1452060998, "html" : "

For first dose, use typical initial or loading dose. For subsequent doses use approximately 50% less than typical maintenance dose. Subsequent doses should be adjusted according to therapeutic drug monitoring, response, and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN, and patients should be carefully monitored according to a usual standard.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298361", - "name" : "Recommendation PA166298361", + "id" : "PA166298397", + "name" : "Recommendation PA166298397", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, @@ -54734,164 +54751,164 @@ "CYP2C9: Reduced phenytoin metabolism; Higher plasma concentrations will increase probability of toxicities.", "HLA-B: n/a" ], - "lookupKey" : {"HLA-B": "*15:02 negative", "CYP2C9": "1.0"}, + "lookupKey" : {"HLA-B": "No Result", "CYP2C9": "0.0"}, "otherPrescribingGuidance" : false, - "population" : "PHT naive", + "population" : "PHT use >3mos", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450947", "name" : "phenytoin", - "version" : 14 + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452060963, - "html" : "

For first dose, use typical initial or loading dose. For subsequent doses, use approximately 25% less than typical maintenance dose. Subsequent doses should be adjusted according to therapeutic drug monitoring, response and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN, and patients should be carefully monitored according to a usual standard.

\n", + "id" : 1452060999, + "html" : "

For first dose, use typical initial or loading dose. For subsequent doses use approximately 50% less than typical maintenance dose. Subsequent doses should be adjusted according to therapeutic drug monitoring, response, and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN, and patients should be carefully monitored according to a usual standard.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298414", - "name" : "Recommendation PA166298414", + "id" : "PA166298398", + "name" : "Recommendation PA166298398", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, "dosingInformation" : false, "implications" : [ - "CYP2C9: Slightly reduced phenytoin metabolism; however, this does not appear to translate into increased side effects.", + "CYP2C9: n/a", "HLA-B: n/a" ], - "lookupKey" : {"HLA-B": "No Result", "CYP2C9": "1.5"}, + "lookupKey" : {"HLA-B": "No Result", "CYP2C9": "n/a"}, "otherPrescribingGuidance" : false, - "population" : "PHT naive", + "population" : "PHT use >3mos", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA164746820", - "name" : "fosphenytoin", - "version" : 9 + "id" : "PA450947", + "name" : "phenytoin", + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452061016, - "html" : "

No adjustments needed from typical dosing strategies. Subsequent doses should be adjusted according to therapeutic drug monitoring, response and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN and patients should be carefully monitored according to a usual standard.

\n", + "id" : 1452061000, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298427", - "name" : "Recommendation PA166298427", + "id" : "PA166298399", + "name" : "Recommendation PA166298399", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, - "version" : 1 + "version" : 0 }, "dosingInformation" : false, "implications" : [ "CYP2C9: n/a", "HLA-B: n/a" ], - "lookupKey" : {"HLA-B": "*15:02 negative", "CYP2C9": "n/a"}, + "lookupKey" : {"HLA-B": "*15:02 negative", "CYP2C9": "No Result"}, "otherPrescribingGuidance" : false, "population" : "PHT use >3mos", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA164746820", - "name" : "fosphenytoin", - "version" : 9 + "id" : "PA450947", + "name" : "phenytoin", + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452061029, - "html" : "

No recommendation

\n", + "id" : 1452061001, + "html" : "

No adjustments needed from typical dosing strategies. Subsequent doses should be adjusted according to therapeutic drug monitoring, response, and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN and patients should be carefully monitored according to a usual standard.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298374", - "name" : "Recommendation PA166298374", + "id" : "PA166298400", + "name" : "Recommendation PA166298400", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C9: Reduced phenytoin metabolism; Higher plasma concentrations will increase probability of toxicities.", - "HLA-B: n/a" + "CYP2C9: n/a", + "HLA-B: Increased risk of phenytoin-induced SJS/TEN" ], - "lookupKey" : {"HLA-B": "No Result", "CYP2C9": "0.5"}, - "otherPrescribingGuidance" : false, - "population" : "PHT naive", + "lookupKey" : {"HLA-B": "*15:02 positive", "CYP2C9": "No Result"}, + "otherPrescribingGuidance" : true, + "population" : "PHT use >3mos", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450947", "name" : "phenytoin", - "version" : 14 + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452060976, - "html" : "

For first dose, use typical initial or loading dose. For subsequent doses use approximately 50% less than typical maintenance dose. Subsequent doses should be adjusted according to therapeutic drug monitoring, response, and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN, and patients should be carefully monitored according to a usual standard.

\n", + "id" : 1452061002, + "html" : "

If the patient has previously used phenytoin continuously for longer than three months without incidence of cutaneous adverse reactions, cautiously consider use of phenytoin in the future. The latency period for drug-induced SJS/TEN is short with continuous dosing and adherence to therapy (4-28 days), and cases usually occur within three months of dosing.

\n

Other Considerations

\n

Previous tolerance of phenytoin is not indicative of tolerance to other aromatic anticonvulsants.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298420", - "name" : "Recommendation PA166298420", + "id" : "PA166298401", + "name" : "Recommendation PA166298401", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -54904,10 +54921,10 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2C9: n/a", + "CYP2C9: Normal phenytoin metabolism", "HLA-B: n/a" ], - "lookupKey" : {"HLA-B": "*15:02 negative", "CYP2C9": "No Result"}, + "lookupKey" : {"HLA-B": "*15:02 negative", "CYP2C9": "2.0"}, "otherPrescribingGuidance" : false, "population" : "PHT naive", "relatedChemicals" : [ @@ -54915,113 +54932,113 @@ "objCls" : "Chemical", "id" : "PA164746820", "name" : "fosphenytoin", - "version" : 9 + "version" : 24 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452061022, + "id" : 1452061003, "html" : "

No adjustments needed from typical dosing strategies. Subsequent doses should be adjusted according to therapeutic drug monitoring, response, and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN and patients should be carefully monitored according to a usual standard.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298433", - "name" : "Recommendation PA166298433", + "id" : "PA166298402", + "name" : "Recommendation PA166298402", "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2C9: Reduced phenytoin metabolism; Higher plasma concentrations will increase probability of toxicities.", - "HLA-B: Increased risk of phenytoin-induced SJS/TEN" + "CYP2C9: Slightly reduced phenytoin metabolism; however, this does not appear to translate into increased side effects.", + "HLA-B: n/a" ], - "lookupKey" : {"HLA-B": "*15:02 positive", "CYP2C9": "0.0"}, - "otherPrescribingGuidance" : true, - "population" : "PHT use >3mos", + "lookupKey" : {"HLA-B": "*15:02 negative", "CYP2C9": "1.5"}, + "otherPrescribingGuidance" : false, + "population" : "PHT naive", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA164746820", "name" : "fosphenytoin", - "version" : 9 + "version" : 24 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452061035, - "html" : "

If the patient has previously used phenytoin continuously for longer than three months without incidence of cutaneous adverse reactions, cautiously consider use of phenytoin in the future. The latency period for drug-induced SJS/TEN is short with continuous dosing and adherence to therapy (4-28 days), and cases usually occur within three months of dosing.

\n

Other Considerations

\n

Previous tolerance of phenytoin is not indicative of tolerance to other aromatic anticonvulsants.

\n", + "id" : 1452061004, + "html" : "

No adjustments needed from typical dosing strategies. Subsequent doses should be adjusted according to therapeutic drug monitoring, response and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN and patients should be carefully monitored according to a usual standard.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298393", - "name" : "Recommendation PA166298393", + "id" : "PA166298403", + "name" : "Recommendation PA166298403", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C9: Normal phenytoin metabolism", + "CYP2C9: Reduced phenytoin metabolism; Higher plasma concentrations will increase probability of toxicities.", "HLA-B: n/a" ], - "lookupKey" : {"HLA-B": "No Result", "CYP2C9": "2.0"}, + "lookupKey" : {"HLA-B": "*15:02 negative", "CYP2C9": "1.0"}, "otherPrescribingGuidance" : false, - "population" : "PHT use >3mos", + "population" : "PHT naive", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA450947", - "name" : "phenytoin", - "version" : 14 + "id" : "PA164746820", + "name" : "fosphenytoin", + "version" : 24 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452060995, - "html" : "

No adjustments needed from typical dosing strategies. Subsequent doses should be adjusted according to therapeutic drug monitoring, response, and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN and patients should be carefully monitored according to a usual standard.

\n", + "id" : 1452061005, + "html" : "

For first dose, use typical initial or loading dose. For subsequent doses, use approximately 25% less than typical maintenance dose. Subsequent doses should be adjusted according to therapeutic drug monitoring, response and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN, and patients should be carefully monitored according to a usual standard.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298411", - "name" : "Recommendation PA166298411", - "alternateDrugAvailable" : true, + "id" : "PA166298404", + "name" : "Recommendation PA166298404", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, "parents" : [], @@ -55031,12 +55048,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ "CYP2C9: Reduced phenytoin metabolism; Higher plasma concentrations will increase probability of toxicities.", - "HLA-B: Increased risk of phenytoin-induced SJS/TEN" + "HLA-B: n/a" ], - "lookupKey" : {"HLA-B": "*15:02 positive", "CYP2C9": "0.0"}, + "lookupKey" : {"HLA-B": "*15:02 negative", "CYP2C9": "0.5"}, "otherPrescribingGuidance" : false, "population" : "PHT naive", "relatedChemicals" : [ @@ -55044,27 +55061,27 @@ "objCls" : "Chemical", "id" : "PA164746820", "name" : "fosphenytoin", - "version" : 9 + "version" : 24 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452061013, - "html" : "

If patient is phenytoin-naive, do not use phenytoin/fosphenytoin. Avoid carbamazepine and oxcarbazepine.

\n

Other Considerations

\n

Other aromatic anticonvulsants, including eslicarbazepine, lamotrigine, and phenobarbital, have weaker evidence linking SJS/TEN with the HLA-B*15:02 allele; however, caution should still be used in choosing an alternative agent.

\n", + "id" : 1452061006, + "html" : "

For first dose, use typical initial or loading dose. For subsequent doses use approximately 50% less than typical maintenance dose. Subsequent doses should be adjusted according to therapeutic drug monitoring, response, and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN, and patients should be carefully monitored according to a usual standard.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298367", - "name" : "Recommendation PA166298367", - "alternateDrugAvailable" : true, + "id" : "PA166298405", + "name" : "Recommendation PA166298405", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, "parents" : [], @@ -55074,83 +55091,84 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ "CYP2C9: Reduced phenytoin metabolism; Higher plasma concentrations will increase probability of toxicities.", - "HLA-B: Increased risk of phenytoin-induced SJS/TEN" + "HLA-B: n/a" ], - "lookupKey" : {"HLA-B": "*15:02 positive", "CYP2C9": "1.0"}, + "lookupKey" : {"HLA-B": "*15:02 negative", "CYP2C9": "0.0"}, "otherPrescribingGuidance" : false, "population" : "PHT naive", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA450947", - "name" : "phenytoin", - "version" : 14 + "id" : "PA164746820", + "name" : "fosphenytoin", + "version" : 24 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452060969, - "html" : "

If patient is phenytoin-naive, do not use phenytoin/fosphenytoin. Avoid carbamazepine and oxcarbazepine.

\n

Other Considerations

\n

Other aromatic anticonvulsants, including eslicarbazepine, lamotrigine, and phenobarbital, have weaker evidence linking SJS/TEN with the HLA-B*15:02 allele; however, caution should still be used in choosing an alternative agent.

\n", + "id" : 1452061007, + "html" : "

For first dose, use typical initial or loading dose. For subsequent doses use approximately 50% less than typical maintenance dose. Subsequent doses should be adjusted according to therapeutic drug monitoring, response, and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN, and patients should be carefully monitored according to a usual standard.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298442", - "name" : "Recommendation PA166298442", + "id" : "PA166298406", + "name" : "Recommendation PA166298406", "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, "dosingInformation" : false, "implications" : [ "CYP2C9: n/a", - "HLA-B: Increased risk of phenytoin-induced SJS/TEN" + "HLA-B: n/a" ], - "lookupKey" : {"HLA-B": "*15:02 positive", "CYP2C9": "No Result"}, - "otherPrescribingGuidance" : true, - "population" : "PHT use >3mos", + "lookupKey" : {"HLA-B": "*15:02 negative", "CYP2C9": "n/a"}, + "otherPrescribingGuidance" : false, + "population" : "PHT naive", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA164746820", "name" : "fosphenytoin", - "version" : 9 + "version" : 24 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452061044, - "html" : "

If the patient has previously used phenytoin continuously for longer than three months without incidence of cutaneous adverse reactions, cautiously consider use of phenytoin in the future. The latency period for drug-induced SJS/TEN is short with continuous dosing and adherence to therapy (4-28 days), and cases usually occur within three months of dosing.

\n

Other Considerations

\n

Previous tolerance of phenytoin is not indicative of tolerance to other aromatic anticonvulsants.

\n", + "id" : 1452061008, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298375", - "name" : "Recommendation PA166298375", - "alternateDrugAvailable" : false, + "id" : "PA166298407", + "name" : "Recommendation PA166298407", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, "parents" : [], @@ -55160,99 +55178,98 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C9: Reduced phenytoin metabolism; Higher plasma concentrations will increase probability of toxicities.", - "HLA-B: n/a" + "CYP2C9: Normal phenytoin metabolism", + "HLA-B: Increased risk of phenytoin-induced SJS/TEN" ], - "lookupKey" : {"HLA-B": "No Result", "CYP2C9": "0.0"}, + "lookupKey" : {"HLA-B": "*15:02 positive", "CYP2C9": "2.0"}, "otherPrescribingGuidance" : false, "population" : "PHT naive", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA450947", - "name" : "phenytoin", - "version" : 14 + "id" : "PA164746820", + "name" : "fosphenytoin", + "version" : 24 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452060977, - "html" : "

For first dose, use typical initial or loading dose. For subsequent doses use approximately 50% less than typical maintenance dose. Subsequent doses should be adjusted according to therapeutic drug monitoring, response, and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN, and patients should be carefully monitored according to a usual standard.

\n", + "id" : 1452061009, + "html" : "

If patient is phenytoin-naive, do not use phenytoin/fosphenytoin. Avoid carbamazepine and oxcarbazepine.

\n

Other Considerations

\n

Other aromatic anticonvulsants, including eslicarbazepine, lamotrigine, and phenobarbital, have weaker evidence linking SJS/TEN with the HLA-B*15:02 allele; however, caution should still be used in choosing an alternative agent.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298388", - "name" : "Recommendation PA166298388", - "alternateDrugAvailable" : false, + "id" : "PA166298408", + "name" : "Recommendation PA166298408", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2C9: Reduced phenytoin metabolism; Higher plasma concentrations will increase probability of toxicities.", + "CYP2C9: Slightly reduced phenytoin metabolism; however, this does not appear to translate into increased side effects.", "HLA-B: Increased risk of phenytoin-induced SJS/TEN" ], - "lookupKey" : {"HLA-B": "*15:02 positive", "CYP2C9": "1.0"}, - "otherPrescribingGuidance" : true, - "population" : "PHT use >3mos", + "lookupKey" : {"HLA-B": "*15:02 positive", "CYP2C9": "1.5"}, + "otherPrescribingGuidance" : false, + "population" : "PHT naive", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA450947", - "name" : "phenytoin", - "version" : 14 + "id" : "PA164746820", + "name" : "fosphenytoin", + "version" : 24 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452060990, - "html" : "

If the patient has previously used phenytoin continuously for longer than three months without incidence of cutaneous adverse reactions, cautiously consider use of phenytoin in the future. The latency period for drug-induced SJS/TEN is short with continuous dosing and adherence to therapy (4-28 days), and cases usually occur within three months of dosing.

\n

Other Considerations

\n

Previous tolerance of phenytoin is not indicative of tolerance to other aromatic anticonvulsants.

\n", + "id" : 1452061010, + "html" : "

If patient is phenytoin-naive, do not use phenytoin/fosphenytoin. Avoid carbamazepine and oxcarbazepine.

\n

Other Considerations

\n

Other aromatic anticonvulsants, including eslicarbazepine, lamotrigine, and phenobarbital, have weaker evidence linking SJS/TEN with the HLA-B*15:02 allele; however, caution should still be used in choosing an alternative agent.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298406", - "name" : "Recommendation PA166298406", - "alternateDrugAvailable" : false, + "id" : "PA166298409", + "name" : "Recommendation PA166298409", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, - "version" : 1 + "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2C9: n/a", - "HLA-B: n/a" + "CYP2C9: Reduced phenytoin metabolism; Higher plasma concentrations will increase probability of toxicities.", + "HLA-B: Increased risk of phenytoin-induced SJS/TEN" ], - "lookupKey" : {"HLA-B": "*15:02 negative", "CYP2C9": "n/a"}, + "lookupKey" : {"HLA-B": "*15:02 positive", "CYP2C9": "1.0"}, "otherPrescribingGuidance" : false, "population" : "PHT naive", "relatedChemicals" : [ @@ -55260,43 +55277,42 @@ "objCls" : "Chemical", "id" : "PA164746820", "name" : "fosphenytoin", - "version" : 9 + "version" : 24 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452061008, - "html" : "

No recommendation

\n", + "id" : 1452061011, + "html" : "

If patient is phenytoin-naive, do not use phenytoin/fosphenytoin. Avoid carbamazepine and oxcarbazepine.

\n

Other Considerations

\n

Other aromatic anticonvulsants, including eslicarbazepine, lamotrigine, and phenobarbital, have weaker evidence linking SJS/TEN with the HLA-B*15:02 allele; however, caution should still be used in choosing an alternative agent.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298419", - "name" : "Recommendation PA166298419", - "alternateDrugAvailable" : false, + "id" : "PA166298410", + "name" : "Recommendation PA166298410", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, - "version" : 1 + "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2C9: n/a", - "HLA-B: n/a" + "CYP2C9: Reduced phenytoin metabolism; Higher plasma concentrations will increase probability of toxicities.", + "HLA-B: Increased risk of phenytoin-induced SJS/TEN" ], - "lookupKey" : {"HLA-B": "No Result", "CYP2C9": "n/a"}, + "lookupKey" : {"HLA-B": "*15:02 positive", "CYP2C9": "0.5"}, "otherPrescribingGuidance" : false, "population" : "PHT naive", "relatedChemicals" : [ @@ -55304,26 +55320,26 @@ "objCls" : "Chemical", "id" : "PA164746820", "name" : "fosphenytoin", - "version" : 9 + "version" : 24 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452061021, - "html" : "

No recommendation

\n", + "id" : 1452061012, + "html" : "

If patient is phenytoin-naive, do not use phenytoin/fosphenytoin. Avoid carbamazepine and oxcarbazepine.

\n

Other Considerations

\n

Other aromatic anticonvulsants, including eslicarbazepine, lamotrigine, and phenobarbital, have weaker evidence linking SJS/TEN with the HLA-B*15:02 allele; however, caution should still be used in choosing an alternative agent.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298366", - "name" : "Recommendation PA166298366", + "id" : "PA166298411", + "name" : "Recommendation PA166298411", "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, @@ -55336,80 +55352,80 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2C9: Slightly reduced phenytoin metabolism; however, this does not appear to translate into increased side effects.", + "CYP2C9: Reduced phenytoin metabolism; Higher plasma concentrations will increase probability of toxicities.", "HLA-B: Increased risk of phenytoin-induced SJS/TEN" ], - "lookupKey" : {"HLA-B": "*15:02 positive", "CYP2C9": "1.5"}, + "lookupKey" : {"HLA-B": "*15:02 positive", "CYP2C9": "0.0"}, "otherPrescribingGuidance" : false, "population" : "PHT naive", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA450947", - "name" : "phenytoin", - "version" : 14 + "id" : "PA164746820", + "name" : "fosphenytoin", + "version" : 24 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452060968, + "id" : 1452061013, "html" : "

If patient is phenytoin-naive, do not use phenytoin/fosphenytoin. Avoid carbamazepine and oxcarbazepine.

\n

Other Considerations

\n

Other aromatic anticonvulsants, including eslicarbazepine, lamotrigine, and phenobarbital, have weaker evidence linking SJS/TEN with the HLA-B*15:02 allele; however, caution should still be used in choosing an alternative agent.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298424", - "name" : "Recommendation PA166298424", - "alternateDrugAvailable" : false, + "id" : "PA166298412", + "name" : "Recommendation PA166298412", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501931, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C9: Reduced phenytoin metabolism; Higher plasma concentrations will increase probability of toxicities.", - "HLA-B: n/a" + "CYP2C9: n/a", + "HLA-B: Increased risk of phenytoin-induced SJS/TEN" ], - "lookupKey" : {"HLA-B": "*15:02 negative", "CYP2C9": "1.0"}, + "lookupKey" : {"HLA-B": "*15:02 positive", "CYP2C9": "n/a"}, "otherPrescribingGuidance" : false, - "population" : "PHT use >3mos", + "population" : "PHT naive", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA164746820", "name" : "fosphenytoin", - "version" : 9 + "version" : 24 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452061026, - "html" : "

For first dose, use typical initial or loading dose. For subsequent doses, use approximately 25% less than typical maintenance dose. Subsequent doses should be adjusted according to therapeutic drug monitoring, response and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN, and patients should be carefully monitored according to a usual standard.

\n", + "id" : 1452061014, + "html" : "

If patient is phenytoin-naive, do not use phenytoin/fosphenytoin. Avoid carbamazepine and oxcarbazepine.

\n

Other Considerations

\n

Other aromatic anticonvulsants, including eslicarbazepine, lamotrigine, and phenobarbital, have weaker evidence linking SJS/TEN with the HLA-B*15:02 allele; however, caution should still be used in choosing an alternative agent.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298371", - "name" : "Recommendation PA166298371", + "id" : "PA166298413", + "name" : "Recommendation PA166298413", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -55431,28 +55447,28 @@ "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA450947", - "name" : "phenytoin", - "version" : 14 + "id" : "PA164746820", + "name" : "fosphenytoin", + "version" : 24 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452060973, + "id" : 1452061015, "html" : "

No adjustments needed from typical dosing strategies. Subsequent doses should be adjusted according to therapeutic drug monitoring, response, and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN and patients should be carefully monitored according to a usual standard.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298437", - "name" : "Recommendation PA166298437", + "id" : "PA166298414", + "name" : "Recommendation PA166298414", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -55463,46 +55479,46 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C9: Reduced phenytoin metabolism; Higher plasma concentrations will increase probability of toxicities.", + "CYP2C9: Slightly reduced phenytoin metabolism; however, this does not appear to translate into increased side effects.", "HLA-B: n/a" ], - "lookupKey" : {"HLA-B": "No Result", "CYP2C9": "1.0"}, + "lookupKey" : {"HLA-B": "No Result", "CYP2C9": "1.5"}, "otherPrescribingGuidance" : false, - "population" : "PHT use >3mos", + "population" : "PHT naive", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA164746820", "name" : "fosphenytoin", - "version" : 9 + "version" : 24 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452061039, - "html" : "

For first dose, use typical initial or loading dose. For subsequent doses, use approximately 25% less than typical maintenance dose. Subsequent doses should be adjusted according to therapeutic drug monitoring, response and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN, and patients should be carefully monitored according to a usual standard.

\n", + "id" : 1452061016, + "html" : "

No adjustments needed from typical dosing strategies. Subsequent doses should be adjusted according to therapeutic drug monitoring, response and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN and patients should be carefully monitored according to a usual standard.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298384", - "name" : "Recommendation PA166298384", + "id" : "PA166298416", + "name" : "Recommendation PA166298416", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, @@ -55511,50 +55527,50 @@ "CYP2C9: Reduced phenytoin metabolism; Higher plasma concentrations will increase probability of toxicities.", "HLA-B: n/a" ], - "lookupKey" : {"HLA-B": "*15:02 negative", "CYP2C9": "0.0"}, + "lookupKey" : {"HLA-B": "No Result", "CYP2C9": "1.0"}, "otherPrescribingGuidance" : false, - "population" : "PHT use >3mos", + "population" : "PHT naive", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA450947", - "name" : "phenytoin", - "version" : 14 + "id" : "PA164746820", + "name" : "fosphenytoin", + "version" : 24 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452060986, - "html" : "

For first dose, use typical initial or loading dose. For subsequent doses use approximately 50% less than typical maintenance dose. Subsequent doses should be adjusted according to therapeutic drug monitoring, response, and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN, and patients should be carefully monitored according to a usual standard.

\n", + "id" : 1452061018, + "html" : "

For first dose, use typical initial or loading dose. For subsequent doses, use approximately 25% less than typical maintenance dose. Subsequent doses should be adjusted according to therapeutic drug monitoring, response and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN, and patients should be carefully monitored according to a usual standard.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298402", - "name" : "Recommendation PA166298402", + "id" : "PA166298417", + "name" : "Recommendation PA166298417", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C9: Slightly reduced phenytoin metabolism; however, this does not appear to translate into increased side effects.", + "CYP2C9: Reduced phenytoin metabolism; Higher plasma concentrations will increase probability of toxicities.", "HLA-B: n/a" ], - "lookupKey" : {"HLA-B": "*15:02 negative", "CYP2C9": "1.5"}, + "lookupKey" : {"HLA-B": "No Result", "CYP2C9": "0.5"}, "otherPrescribingGuidance" : false, "population" : "PHT naive", "relatedChemicals" : [ @@ -55562,26 +55578,26 @@ "objCls" : "Chemical", "id" : "PA164746820", "name" : "fosphenytoin", - "version" : 9 + "version" : 24 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452061004, - "html" : "

No adjustments needed from typical dosing strategies. Subsequent doses should be adjusted according to therapeutic drug monitoring, response and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN and patients should be carefully monitored according to a usual standard.

\n", + "id" : 1452061019, + "html" : "

For first dose, use typical initial or loading dose. For subsequent doses use approximately 50% less than typical maintenance dose. Subsequent doses should be adjusted according to therapeutic drug monitoring, response, and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN, and patients should be carefully monitored according to a usual standard.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298397", - "name" : "Recommendation PA166298397", + "id" : "PA166298418", + "name" : "Recommendation PA166298418", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -55599,75 +55615,76 @@ ], "lookupKey" : {"HLA-B": "No Result", "CYP2C9": "0.0"}, "otherPrescribingGuidance" : false, - "population" : "PHT use >3mos", + "population" : "PHT naive", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA450947", - "name" : "phenytoin", - "version" : 14 + "id" : "PA164746820", + "name" : "fosphenytoin", + "version" : 24 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452060999, + "id" : 1452061020, "html" : "

For first dose, use typical initial or loading dose. For subsequent doses use approximately 50% less than typical maintenance dose. Subsequent doses should be adjusted according to therapeutic drug monitoring, response, and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN, and patients should be carefully monitored according to a usual standard.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298362", - "name" : "Recommendation PA166298362", + "id" : "PA166298419", + "name" : "Recommendation PA166298419", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C9: Reduced phenytoin metabolism; Higher plasma concentrations will increase probability of toxicities.", + "CYP2C9: n/a", "HLA-B: n/a" ], - "lookupKey" : {"HLA-B": "*15:02 negative", "CYP2C9": "0.5"}, + "lookupKey" : {"HLA-B": "No Result", "CYP2C9": "n/a"}, "otherPrescribingGuidance" : false, "population" : "PHT naive", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA450947", - "name" : "phenytoin", - "version" : 14 + "id" : "PA164746820", + "name" : "fosphenytoin", + "version" : 24 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452060964, - "html" : "

For first dose, use typical initial or loading dose. For subsequent doses use approximately 50% less than typical maintenance dose. Subsequent doses should be adjusted according to therapeutic drug monitoring, response, and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN, and patients should be carefully monitored according to a usual standard.

\n", + "id" : 1452061021, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298359", - "name" : "Recommendation PA166298359", + "id" : "PA166298420", + "name" : "Recommendation PA166298420", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -55680,32 +55697,32 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2C9: Normal phenytoin metabolism", + "CYP2C9: n/a", "HLA-B: n/a" ], - "lookupKey" : {"HLA-B": "*15:02 negative", "CYP2C9": "2.0"}, + "lookupKey" : {"HLA-B": "*15:02 negative", "CYP2C9": "No Result"}, "otherPrescribingGuidance" : false, "population" : "PHT naive", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA450947", - "name" : "phenytoin", - "version" : 14 + "id" : "PA164746820", + "name" : "fosphenytoin", + "version" : 24 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452060961, + "id" : 1452061022, "html" : "

No adjustments needed from typical dosing strategies. Subsequent doses should be adjusted according to therapeutic drug monitoring, response, and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN and patients should be carefully monitored according to a usual standard.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -55734,69 +55751,69 @@ "objCls" : "Chemical", "id" : "PA164746820", "name" : "fosphenytoin", - "version" : 9 + "version" : 24 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { "id" : 1452061023, "html" : "

If patient is phenytoin-naive, do not use phenytoin/fosphenytoin. Avoid carbamazepine and oxcarbazepine.

\n

Other Considerations

\n

Other aromatic anticonvulsants, including eslicarbazepine, lamotrigine, and phenobarbital, have weaker evidence linking SJS/TEN with the HLA-B*15:02 allele; however, caution should still be used in choosing an alternative agent.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298434", - "name" : "Recommendation PA166298434", + "id" : "PA166298422", + "name" : "Recommendation PA166298422", "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2C9: n/a", - "HLA-B: Increased risk of phenytoin-induced SJS/TEN" + "CYP2C9: Normal phenytoin metabolism", + "HLA-B: n/a" ], - "lookupKey" : {"HLA-B": "*15:02 positive", "CYP2C9": "n/a"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"HLA-B": "*15:02 negative", "CYP2C9": "2.0"}, + "otherPrescribingGuidance" : false, "population" : "PHT use >3mos", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA164746820", "name" : "fosphenytoin", - "version" : 9 + "version" : 24 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452061036, - "html" : "

If the patient has previously used phenytoin continuously for longer than three months without incidence of cutaneous adverse reactions, cautiously consider use of phenytoin in the future. The latency period for drug-induced SJS/TEN is short with continuous dosing and adherence to therapy (4-28 days), and cases usually occur within three months of dosing.

\n

Other Considerations

\n

Previous tolerance of phenytoin is not indicative of tolerance to other aromatic anticonvulsants.

\n", + "id" : 1452061024, + "html" : "

No adjustments needed from typical dosing strategies. Subsequent doses should be adjusted according to therapeutic drug monitoring, response, and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN and patients should be carefully monitored according to a usual standard.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298381", - "name" : "Recommendation PA166298381", + "id" : "PA166298423", + "name" : "Recommendation PA166298423", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -55818,28 +55835,28 @@ "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA450947", - "name" : "phenytoin", - "version" : 14 + "id" : "PA164746820", + "name" : "fosphenytoin", + "version" : 24 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452060983, + "id" : 1452061025, "html" : "

No adjustments needed from typical dosing strategies. Subsequent doses should be adjusted according to therapeutic drug monitoring, response and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN and patients should be carefully monitored according to a usual standard.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298394", - "name" : "Recommendation PA166298394", + "id" : "PA166298424", + "name" : "Recommendation PA166298424", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -55850,40 +55867,40 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C9: Slightly reduced phenytoin metabolism; however, this does not appear to translate into increased side effects.", + "CYP2C9: Reduced phenytoin metabolism; Higher plasma concentrations will increase probability of toxicities.", "HLA-B: n/a" ], - "lookupKey" : {"HLA-B": "No Result", "CYP2C9": "1.5"}, + "lookupKey" : {"HLA-B": "*15:02 negative", "CYP2C9": "1.0"}, "otherPrescribingGuidance" : false, "population" : "PHT use >3mos", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA450947", - "name" : "phenytoin", - "version" : 14 + "id" : "PA164746820", + "name" : "fosphenytoin", + "version" : 24 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452060996, - "html" : "

No adjustments needed from typical dosing strategies. Subsequent doses should be adjusted according to therapeutic drug monitoring, response and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN and patients should be carefully monitored according to a usual standard.

\n", + "id" : 1452061026, + "html" : "

For first dose, use typical initial or loading dose. For subsequent doses, use approximately 25% less than typical maintenance dose. Subsequent doses should be adjusted according to therapeutic drug monitoring, response and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN, and patients should be carefully monitored according to a usual standard.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298368", - "name" : "Recommendation PA166298368", - "alternateDrugAvailable" : true, + "id" : "PA166298426", + "name" : "Recommendation PA166298426", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, "parents" : [], @@ -55893,34 +55910,121 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ "CYP2C9: Reduced phenytoin metabolism; Higher plasma concentrations will increase probability of toxicities.", - "HLA-B: Increased risk of phenytoin-induced SJS/TEN" + "HLA-B: n/a" ], - "lookupKey" : {"HLA-B": "*15:02 positive", "CYP2C9": "0.5"}, + "lookupKey" : {"HLA-B": "*15:02 negative", "CYP2C9": "0.0"}, "otherPrescribingGuidance" : false, - "population" : "PHT naive", + "population" : "PHT use >3mos", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA450947", - "name" : "phenytoin", - "version" : 14 + "id" : "PA164746820", + "name" : "fosphenytoin", + "version" : 24 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452060970, - "html" : "

If patient is phenytoin-naive, do not use phenytoin/fosphenytoin. Avoid carbamazepine and oxcarbazepine.

\n

Other Considerations

\n

Other aromatic anticonvulsants, including eslicarbazepine, lamotrigine, and phenobarbital, have weaker evidence linking SJS/TEN with the HLA-B*15:02 allele; however, caution should still be used in choosing an alternative agent.

\n", + "id" : 1452061028, + "html" : "

For first dose, use typical initial or loading dose. For subsequent doses use approximately 50% less than typical maintenance dose. Subsequent doses should be adjusted according to therapeutic drug monitoring, response, and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN, and patients should be carefully monitored according to a usual standard.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166298427", + "name" : "Recommendation PA166298427", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501929, + "description" : "Not Applicable", + "parents" : [], + "resource" : "Guideline Strength", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", + "valid" : true, + "version" : 1 + }, + "dosingInformation" : false, + "implications" : [ + "CYP2C9: n/a", + "HLA-B: n/a" + ], + "lookupKey" : {"HLA-B": "*15:02 negative", "CYP2C9": "n/a"}, + "otherPrescribingGuidance" : false, + "population" : "PHT use >3mos", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA164746820", + "name" : "fosphenytoin", + "version" : 24 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166122806", + "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", + "version" : 268 + }, + "text" : { + "id" : 1452061029, + "html" : "

No recommendation

\n", + "version" : 0 + }, + "version" : 1 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166298429", + "name" : "Recommendation PA166298429", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 981565059, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : false, + "implications" : [ + "CYP2C9: Normal phenytoin metabolism", + "HLA-B: Increased risk of phenytoin-induced SJS/TEN" + ], + "lookupKey" : {"HLA-B": "*15:02 positive", "CYP2C9": "2.0"}, + "otherPrescribingGuidance" : true, + "population" : "PHT use >3mos", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA164746820", + "name" : "fosphenytoin", + "version" : 24 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166122806", + "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", + "version" : 268 + }, + "text" : { + "id" : 1452061031, + "html" : "

If the patient has previously used phenytoin continuously for longer than three months without incidence of cutaneous adverse reactions, cautiously consider use of phenytoin in the future. The latency period for drug-induced SJS/TEN is short with continuous dosing and adherence to therapy (4-28 days), and cases usually occur within three months of dosing.

\n

Other Considerations

\n

Previous tolerance of phenytoin is not indicative of tolerance to other aromatic anticonvulsants.

\n", + "version" : 0 + }, + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -55949,26 +56053,26 @@ "objCls" : "Chemical", "id" : "PA164746820", "name" : "fosphenytoin", - "version" : 9 + "version" : 24 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { "id" : 1452061032, "html" : "

If the patient has previously used phenytoin continuously for longer than three months without incidence of cutaneous adverse reactions, cautiously consider use of phenytoin in the future. The latency period for drug-induced SJS/TEN is short with continuous dosing and adherence to therapy (4-28 days), and cases usually occur within three months of dosing.

\n

Other Considerations

\n

Previous tolerance of phenytoin is not indicative of tolerance to other aromatic anticonvulsants.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298390", - "name" : "Recommendation PA166298390", + "id" : "PA166298431", + "name" : "Recommendation PA166298431", "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, @@ -55984,77 +56088,77 @@ "CYP2C9: Reduced phenytoin metabolism; Higher plasma concentrations will increase probability of toxicities.", "HLA-B: Increased risk of phenytoin-induced SJS/TEN" ], - "lookupKey" : {"HLA-B": "*15:02 positive", "CYP2C9": "0.0"}, + "lookupKey" : {"HLA-B": "*15:02 positive", "CYP2C9": "1.0"}, "otherPrescribingGuidance" : true, "population" : "PHT use >3mos", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA450947", - "name" : "phenytoin", - "version" : 14 + "id" : "PA164746820", + "name" : "fosphenytoin", + "version" : 24 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452060992, + "id" : 1452061033, "html" : "

If the patient has previously used phenytoin continuously for longer than three months without incidence of cutaneous adverse reactions, cautiously consider use of phenytoin in the future. The latency period for drug-induced SJS/TEN is short with continuous dosing and adherence to therapy (4-28 days), and cases usually occur within three months of dosing.

\n

Other Considerations

\n

Previous tolerance of phenytoin is not indicative of tolerance to other aromatic anticonvulsants.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298363", - "name" : "Recommendation PA166298363", + "id" : "PA166298432", + "name" : "Recommendation PA166298432", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ "CYP2C9: Reduced phenytoin metabolism; Higher plasma concentrations will increase probability of toxicities.", - "HLA-B: n/a" + "HLA-B: Increased risk of phenytoin-induced SJS/TEN" ], - "lookupKey" : {"HLA-B": "*15:02 negative", "CYP2C9": "0.0"}, - "otherPrescribingGuidance" : false, - "population" : "PHT naive", + "lookupKey" : {"HLA-B": "*15:02 positive", "CYP2C9": "0.5"}, + "otherPrescribingGuidance" : true, + "population" : "PHT use >3mos", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA450947", - "name" : "phenytoin", - "version" : 14 + "id" : "PA164746820", + "name" : "fosphenytoin", + "version" : 24 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452060965, - "html" : "

For first dose, use typical initial or loading dose. For subsequent doses use approximately 50% less than typical maintenance dose. Subsequent doses should be adjusted according to therapeutic drug monitoring, response, and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN, and patients should be carefully monitored according to a usual standard.

\n", + "id" : 1452061034, + "html" : "

If the patient has previously used phenytoin continuously for longer than three months without incidence of cutaneous adverse reactions, cautiously consider use of phenytoin in the future. The latency period for drug-induced SJS/TEN is short with continuous dosing and adherence to therapy (4-28 days), and cases usually occur within three months of dosing.

\n

Other Considerations

\n

Previous tolerance of phenytoin is not indicative of tolerance to other aromatic anticonvulsants.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298429", - "name" : "Recommendation PA166298429", + "id" : "PA166298433", + "name" : "Recommendation PA166298433", "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, @@ -56067,10 +56171,10 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2C9: Normal phenytoin metabolism", + "CYP2C9: Reduced phenytoin metabolism; Higher plasma concentrations will increase probability of toxicities.", "HLA-B: Increased risk of phenytoin-induced SJS/TEN" ], - "lookupKey" : {"HLA-B": "*15:02 positive", "CYP2C9": "2.0"}, + "lookupKey" : {"HLA-B": "*15:02 positive", "CYP2C9": "0.0"}, "otherPrescribingGuidance" : true, "population" : "PHT use >3mos", "relatedChemicals" : [ @@ -56078,70 +56182,26 @@ "objCls" : "Chemical", "id" : "PA164746820", "name" : "fosphenytoin", - "version" : 9 + "version" : 24 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452061031, + "id" : 1452061035, "html" : "

If the patient has previously used phenytoin continuously for longer than three months without incidence of cutaneous adverse reactions, cautiously consider use of phenytoin in the future. The latency period for drug-induced SJS/TEN is short with continuous dosing and adherence to therapy (4-28 days), and cases usually occur within three months of dosing.

\n

Other Considerations

\n

Previous tolerance of phenytoin is not indicative of tolerance to other aromatic anticonvulsants.

\n", "version" : 0 }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166298376", - "name" : "Recommendation PA166298376", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 981501929, - "description" : "Not Applicable", - "parents" : [], - "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", - "valid" : true, - "version" : 1 - }, - "dosingInformation" : false, - "implications" : [ - "CYP2C9: n/a", - "HLA-B: n/a" - ], - "lookupKey" : {"HLA-B": "No Result", "CYP2C9": "n/a"}, - "otherPrescribingGuidance" : false, - "population" : "PHT naive", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA450947", - "name" : "phenytoin", - "version" : 14 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166122806", - "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 - }, - "text" : { - "id" : 1452060978, - "html" : "

No recommendation

\n", - "version" : 0 - }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298389", - "name" : "Recommendation PA166298389", + "id" : "PA166298434", + "name" : "Recommendation PA166298434", "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, @@ -56154,38 +56214,38 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2C9: Reduced phenytoin metabolism; Higher plasma concentrations will increase probability of toxicities.", + "CYP2C9: n/a", "HLA-B: Increased risk of phenytoin-induced SJS/TEN" ], - "lookupKey" : {"HLA-B": "*15:02 positive", "CYP2C9": "0.5"}, + "lookupKey" : {"HLA-B": "*15:02 positive", "CYP2C9": "n/a"}, "otherPrescribingGuidance" : true, "population" : "PHT use >3mos", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA450947", - "name" : "phenytoin", - "version" : 14 + "id" : "PA164746820", + "name" : "fosphenytoin", + "version" : 24 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452060991, + "id" : 1452061036, "html" : "

If the patient has previously used phenytoin continuously for longer than three months without incidence of cutaneous adverse reactions, cautiously consider use of phenytoin in the future. The latency period for drug-induced SJS/TEN is short with continuous dosing and adherence to therapy (4-28 days), and cases usually occur within three months of dosing.

\n

Other Considerations

\n

Previous tolerance of phenytoin is not indicative of tolerance to other aromatic anticonvulsants.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298407", - "name" : "Recommendation PA166298407", - "alternateDrugAvailable" : true, + "id" : "PA166298435", + "name" : "Recommendation PA166298435", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, "parents" : [], @@ -56198,79 +56258,79 @@ "dosingInformation" : false, "implications" : [ "CYP2C9: Normal phenytoin metabolism", - "HLA-B: Increased risk of phenytoin-induced SJS/TEN" + "HLA-B: n/a" ], - "lookupKey" : {"HLA-B": "*15:02 positive", "CYP2C9": "2.0"}, + "lookupKey" : {"HLA-B": "No Result", "CYP2C9": "2.0"}, "otherPrescribingGuidance" : false, - "population" : "PHT naive", + "population" : "PHT use >3mos", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA164746820", "name" : "fosphenytoin", - "version" : 9 + "version" : 24 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452061009, - "html" : "

If patient is phenytoin-naive, do not use phenytoin/fosphenytoin. Avoid carbamazepine and oxcarbazepine.

\n

Other Considerations

\n

Other aromatic anticonvulsants, including eslicarbazepine, lamotrigine, and phenobarbital, have weaker evidence linking SJS/TEN with the HLA-B*15:02 allele; however, caution should still be used in choosing an alternative agent.

\n", + "id" : 1452061037, + "html" : "

No adjustments needed from typical dosing strategies. Subsequent doses should be adjusted according to therapeutic drug monitoring, response, and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN and patients should be carefully monitored according to a usual standard.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298412", - "name" : "Recommendation PA166298412", - "alternateDrugAvailable" : true, + "id" : "PA166298436", + "name" : "Recommendation PA166298436", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2C9: n/a", - "HLA-B: Increased risk of phenytoin-induced SJS/TEN" + "CYP2C9: Slightly reduced phenytoin metabolism; however, this does not appear to translate into increased side effects.", + "HLA-B: n/a" ], - "lookupKey" : {"HLA-B": "*15:02 positive", "CYP2C9": "n/a"}, + "lookupKey" : {"HLA-B": "No Result", "CYP2C9": "1.5"}, "otherPrescribingGuidance" : false, - "population" : "PHT naive", + "population" : "PHT use >3mos", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA164746820", "name" : "fosphenytoin", - "version" : 9 + "version" : 24 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452061014, - "html" : "

If patient is phenytoin-naive, do not use phenytoin/fosphenytoin. Avoid carbamazepine and oxcarbazepine.

\n

Other Considerations

\n

Other aromatic anticonvulsants, including eslicarbazepine, lamotrigine, and phenobarbital, have weaker evidence linking SJS/TEN with the HLA-B*15:02 allele; however, caution should still be used in choosing an alternative agent.

\n", + "id" : 1452061038, + "html" : "

No adjustments needed from typical dosing strategies. Subsequent doses should be adjusted according to therapeutic drug monitoring, response and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN and patients should be carefully monitored according to a usual standard.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298372", - "name" : "Recommendation PA166298372", + "id" : "PA166298437", + "name" : "Recommendation PA166298437", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -56281,39 +56341,39 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C9: Slightly reduced phenytoin metabolism; however, this does not appear to translate into increased side effects.", + "CYP2C9: Reduced phenytoin metabolism; Higher plasma concentrations will increase probability of toxicities.", "HLA-B: n/a" ], - "lookupKey" : {"HLA-B": "No Result", "CYP2C9": "1.5"}, + "lookupKey" : {"HLA-B": "No Result", "CYP2C9": "1.0"}, "otherPrescribingGuidance" : false, - "population" : "PHT naive", + "population" : "PHT use >3mos", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA450947", - "name" : "phenytoin", - "version" : 14 + "id" : "PA164746820", + "name" : "fosphenytoin", + "version" : 24 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452060974, - "html" : "

No adjustments needed from typical dosing strategies. Subsequent doses should be adjusted according to therapeutic drug monitoring, response and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN and patients should be carefully monitored according to a usual standard.

\n", + "id" : 1452061039, + "html" : "

For first dose, use typical initial or loading dose. For subsequent doses, use approximately 25% less than typical maintenance dose. Subsequent doses should be adjusted according to therapeutic drug monitoring, response and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN, and patients should be carefully monitored according to a usual standard.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298425", - "name" : "Recommendation PA166298425", + "id" : "PA166298438", + "name" : "Recommendation PA166298438", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -56329,7 +56389,7 @@ "CYP2C9: Reduced phenytoin metabolism; Higher plasma concentrations will increase probability of toxicities.", "HLA-B: n/a" ], - "lookupKey" : {"HLA-B": "*15:02 negative", "CYP2C9": "0.5"}, + "lookupKey" : {"HLA-B": "No Result", "CYP2C9": "0.5"}, "otherPrescribingGuidance" : false, "population" : "PHT use >3mos", "relatedChemicals" : [ @@ -56337,26 +56397,26 @@ "objCls" : "Chemical", "id" : "PA164746820", "name" : "fosphenytoin", - "version" : 9 + "version" : 24 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452061027, + "id" : 1452061040, "html" : "

For first dose, use typical initial or loading dose. For subsequent doses use approximately 50% less than typical maintenance dose. Subsequent doses should be adjusted according to therapeutic drug monitoring, response, and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN, and patients should be carefully monitored according to a usual standard.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298438", - "name" : "Recommendation PA166298438", + "id" : "PA166298439", + "name" : "Recommendation PA166298439", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -56372,7 +56432,7 @@ "CYP2C9: Reduced phenytoin metabolism; Higher plasma concentrations will increase probability of toxicities.", "HLA-B: n/a" ], - "lookupKey" : {"HLA-B": "No Result", "CYP2C9": "0.5"}, + "lookupKey" : {"HLA-B": "No Result", "CYP2C9": "0.0"}, "otherPrescribingGuidance" : false, "population" : "PHT use >3mos", "relatedChemicals" : [ @@ -56380,26 +56440,26 @@ "objCls" : "Chemical", "id" : "PA164746820", "name" : "fosphenytoin", - "version" : 9 + "version" : 24 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452061040, + "id" : 1452061041, "html" : "

For first dose, use typical initial or loading dose. For subsequent doses use approximately 50% less than typical maintenance dose. Subsequent doses should be adjusted according to therapeutic drug monitoring, response, and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN, and patients should be carefully monitored according to a usual standard.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298385", - "name" : "Recommendation PA166298385", + "id" : "PA166298440", + "name" : "Recommendation PA166298440", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -56416,159 +56476,115 @@ "CYP2C9: n/a", "HLA-B: n/a" ], - "lookupKey" : {"HLA-B": "*15:02 negative", "CYP2C9": "n/a"}, + "lookupKey" : {"HLA-B": "No Result", "CYP2C9": "n/a"}, "otherPrescribingGuidance" : false, "population" : "PHT use >3mos", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA450947", - "name" : "phenytoin", - "version" : 14 + "id" : "PA164746820", + "name" : "fosphenytoin", + "version" : 24 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452060987, + "id" : 1452061042, "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298403", - "name" : "Recommendation PA166298403", + "id" : "PA166298441", + "name" : "Recommendation PA166298441", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C9: Reduced phenytoin metabolism; Higher plasma concentrations will increase probability of toxicities.", + "CYP2C9: n/a", "HLA-B: n/a" ], - "lookupKey" : {"HLA-B": "*15:02 negative", "CYP2C9": "1.0"}, + "lookupKey" : {"HLA-B": "*15:02 negative", "CYP2C9": "No Result"}, "otherPrescribingGuidance" : false, - "population" : "PHT naive", + "population" : "PHT use >3mos", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA164746820", "name" : "fosphenytoin", - "version" : 9 + "version" : 24 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452061005, - "html" : "

For first dose, use typical initial or loading dose. For subsequent doses, use approximately 25% less than typical maintenance dose. Subsequent doses should be adjusted according to therapeutic drug monitoring, response and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN, and patients should be carefully monitored according to a usual standard.

\n", + "id" : 1452061043, + "html" : "

No adjustments needed from typical dosing strategies. Subsequent doses should be adjusted according to therapeutic drug monitoring, response, and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN and patients should be carefully monitored according to a usual standard.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298398", - "name" : "Recommendation PA166298398", + "id" : "PA166298442", + "name" : "Recommendation PA166298442", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, - "version" : 1 + "version" : 0 }, "dosingInformation" : false, "implications" : [ "CYP2C9: n/a", - "HLA-B: n/a" + "HLA-B: Increased risk of phenytoin-induced SJS/TEN" ], - "lookupKey" : {"HLA-B": "No Result", "CYP2C9": "n/a"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"HLA-B": "*15:02 positive", "CYP2C9": "No Result"}, + "otherPrescribingGuidance" : true, "population" : "PHT use >3mos", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA450947", - "name" : "phenytoin", - "version" : 14 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166122806", - "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 - }, - "text" : { - "id" : 1452061000, - "html" : "

No recommendation

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166298416", - "name" : "Recommendation PA166298416", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 981501931, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : true, - "implications" : [ - "CYP2C9: Reduced phenytoin metabolism; Higher plasma concentrations will increase probability of toxicities.", - "HLA-B: n/a" - ], - "lookupKey" : {"HLA-B": "No Result", "CYP2C9": "1.0"}, - "otherPrescribingGuidance" : false, - "population" : "PHT naive", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA164746820", "name" : "fosphenytoin", - "version" : 9 + "version" : 24 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166122806", "name" : "Annotation of CPIC Guideline for fosphenytoin, phenytoin and CYP2C9, HLA-B", - "version" : 51 + "version" : 268 }, "text" : { - "id" : 1452061018, - "html" : "

For first dose, use typical initial or loading dose. For subsequent doses, use approximately 25% less than typical maintenance dose. Subsequent doses should be adjusted according to therapeutic drug monitoring, response and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN, and patients should be carefully monitored according to a usual standard.

\n", + "id" : 1452061044, + "html" : "

If the patient has previously used phenytoin continuously for longer than three months without incidence of cutaneous adverse reactions, cautiously consider use of phenytoin in the future. The latency period for drug-induced SJS/TEN is short with continuous dosing and adherence to therapy (4-28 days), and cases usually occur within three months of dosing.

\n

Other Considerations

\n

Previous tolerance of phenytoin is not indicative of tolerance to other aromatic anticonvulsants.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166122806" @@ -56726,7 +56742,7 @@ "objCls" : "Chemical", "id" : "PA449900", "name" : "hydrocodone", - "version" : 11 + "version" : 36 } ], "relatedGenes" : [ @@ -56735,7 +56751,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "CPIC", @@ -56751,20 +56767,20 @@ "version" : 2 }, "userId" : "rachel", - "version" : 7 + "version" : 61 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166297958", - "name" : "Recommendation PA166297958", + "id" : "PA166297457", + "name" : "Recommendation PA166297457", "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, @@ -56772,34 +56788,34 @@ "implications" : [ "CYP2D6: Minimal evidence for pharmacokinetic or clinical effect." ], - "lookupKey" : {"CYP2D6": "0.75"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"CYP2D6": "≥3.0"}, + "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449900", "name" : "hydrocodone", - "version" : 11 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166228121", "name" : "Annotation of CPIC Guideline for hydrocodone and CYP2D6", - "version" : 7 + "version" : 61 }, "text" : { - "id" : 1452060560, - "html" : "

Use hydrocodone label recommended age- or weight-specific dosing. If no response and opioid use is warranted, consider non-codeine or non-tramadol opioid.

\n", + "id" : 1452060059, + "html" : "

No recommendation for hydrocodone therapy because of minimal evidence regarding adverse events or analgesia.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297927", - "name" : "Recommendation PA166297927", + "id" : "PA166297468", + "name" : "Recommendation PA166297468", "alternateDrugAvailable" : false, "classification" : { "id" : 1448526251, @@ -56812,9 +56828,9 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2D6: n/a" + "CYP2D6: Minimal evidence for pharmacokinetic or clinical effect." ], - "lookupKey" : {"CYP2D6": "n/a"}, + "lookupKey" : {"CYP2D6": "≥3.25"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -56822,41 +56838,41 @@ "objCls" : "Chemical", "id" : "PA449900", "name" : "hydrocodone", - "version" : 11 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166228121", "name" : "Annotation of CPIC Guideline for hydrocodone and CYP2D6", - "version" : 7 + "version" : 61 }, "text" : { - "id" : 1452060529, - "html" : "

No recommendation

\n", + "id" : 1452060070, + "html" : "

No recommendation for hydrocodone therapy because of minimal evidence regarding adverse events or analgesia.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297223", - "name" : "Recommendation PA166297223", + "id" : "PA166297507", + "name" : "Recommendation PA166297507", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Normal hydromorphone formation" + "CYP2D6: Minimal evidence for pharmacokinetic or clinical effect." ], - "lookupKey" : {"CYP2D6": "1.25"}, + "lookupKey" : {"CYP2D6": "≥3.5"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -56864,68 +56880,56 @@ "objCls" : "Chemical", "id" : "PA449900", "name" : "hydrocodone", - "version" : 11 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166228121", "name" : "Annotation of CPIC Guideline for hydrocodone and CYP2D6", - "version" : 7 + "version" : 61 }, "text" : { - "id" : 1452059825, - "html" : "

Use hydrocodone label recommended age- or weight-specific dosing.

\n", + "id" : 1452060109, + "html" : "

No recommendation for hydrocodone therapy because of minimal evidence regarding adverse events or analgesia.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297078", - "name" : "Recommendation PA166297078", + "id" : "PA166301324", + "name" : "Recommendation Annotation PA166301324", "alternateDrugAvailable" : false, - "classification" : { - "id" : 1448526251, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", - "valid" : true, - "version" : 0 - }, "dosingInformation" : false, - "implications" : [ - "CYP2D6: Minimal evidence for pharmacokinetic or clinical effect." - ], - "lookupKey" : {"CYP2D6": "2.5"}, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations"}, "otherPrescribingGuidance" : false, - "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449900", "name" : "hydrocodone", - "version" : 11 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166228121", "name" : "Annotation of CPIC Guideline for hydrocodone and CYP2D6", - "version" : 7 + "version" : 61 }, "text" : { - "id" : 1452059680, - "html" : "

No recommendation for hydrocodone therapy because of minimal evidence regarding adverse events or analgesia.

\n", + "id" : 1452095643, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297457", - "name" : "Recommendation PA166297457", + "id" : "PA166297078", + "name" : "Recommendation PA166297078", "alternateDrugAvailable" : false, "classification" : { "id" : 1448526251, @@ -56940,7 +56944,7 @@ "implications" : [ "CYP2D6: Minimal evidence for pharmacokinetic or clinical effect." ], - "lookupKey" : {"CYP2D6": "≥3.0"}, + "lookupKey" : {"CYP2D6": "2.5"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -56948,33 +56952,33 @@ "objCls" : "Chemical", "id" : "PA449900", "name" : "hydrocodone", - "version" : 11 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166228121", "name" : "Annotation of CPIC Guideline for hydrocodone and CYP2D6", - "version" : 7 + "version" : 61 }, "text" : { - "id" : 1452060059, + "id" : 1452059680, "html" : "

No recommendation for hydrocodone therapy because of minimal evidence regarding adverse events or analgesia.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297686", - "name" : "Recommendation PA166297686", + "id" : "PA166297162", + "name" : "Recommendation PA166297162", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, @@ -56982,91 +56986,91 @@ "implications" : [ "CYP2D6: Minimal evidence for pharmacokinetic or clinical effect." ], - "lookupKey" : {"CYP2D6": "≥3.75"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"CYP2D6": "1.0"}, + "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449900", "name" : "hydrocodone", - "version" : 11 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166228121", "name" : "Annotation of CPIC Guideline for hydrocodone and CYP2D6", - "version" : 7 + "version" : 61 }, "text" : { - "id" : 1452060288, - "html" : "

No recommendation for hydrocodone therapy because of minimal evidence regarding adverse events or analgesia.

\n", + "id" : 1452059764, + "html" : "

Use hydrocodone label recommended age- or weight-specific dosing. If no response and opioid use is warranted, consider non-codeine or non-tramadol opioid.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297162", - "name" : "Recommendation PA166297162", + "id" : "PA166297223", + "name" : "Recommendation PA166297223", "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Minimal evidence for pharmacokinetic or clinical effect." + "CYP2D6: Normal hydromorphone formation" ], - "lookupKey" : {"CYP2D6": "1.0"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"CYP2D6": "1.25"}, + "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449900", "name" : "hydrocodone", - "version" : 11 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166228121", "name" : "Annotation of CPIC Guideline for hydrocodone and CYP2D6", - "version" : 7 + "version" : 61 }, "text" : { - "id" : 1452059764, - "html" : "

Use hydrocodone label recommended age- or weight-specific dosing. If no response and opioid use is warranted, consider non-codeine or non-tramadol opioid.

\n", + "id" : 1452059825, + "html" : "

Use hydrocodone label recommended age- or weight-specific dosing.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297391", - "name" : "Recommendation PA166297391", + "id" : "PA166297239", + "name" : "Recommendation PA166297239", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Minimal evidence for pharmacokinetic or clinical effect." + "CYP2D6: Normal hydromorphone formation" ], - "lookupKey" : {"CYP2D6": "4.0"}, + "lookupKey" : {"CYP2D6": "1.5"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -57074,71 +57078,83 @@ "objCls" : "Chemical", "id" : "PA449900", "name" : "hydrocodone", - "version" : 11 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166228121", "name" : "Annotation of CPIC Guideline for hydrocodone and CYP2D6", - "version" : 7 + "version" : 61 }, "text" : { - "id" : 1452059993, - "html" : "

No recommendation for hydrocodone therapy because of minimal evidence regarding adverse events or analgesia.

\n", + "id" : 1452059841, + "html" : "

Use hydrocodone label recommended age- or weight-specific dosing.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301324", - "name" : "Recommendation Annotation PA166301324", + "id" : "PA166297256", + "name" : "Recommendation PA166297256", "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501930, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", + "valid" : true, + "version" : 0 + }, "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations"}, + "implications" : [ + "CYP2D6: Normal hydromorphone formation" + ], + "lookupKey" : {"CYP2D6": "1.75"}, "otherPrescribingGuidance" : false, + "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449900", "name" : "hydrocodone", - "version" : 11 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166228121", "name" : "Annotation of CPIC Guideline for hydrocodone and CYP2D6", - "version" : 7 + "version" : 61 }, "text" : { - "id" : 1452095643, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "id" : 1452059858, + "html" : "

Use hydrocodone label recommended age- or weight-specific dosing.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297360", - "name" : "Recommendation PA166297360", + "id" : "PA166297270", + "name" : "Recommendation PA166297270", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Minimal evidence for pharmacokinetic or clinical effect." + "CYP2D6: Normal hydromorphone formation" ], - "lookupKey" : {"CYP2D6": "3.0"}, + "lookupKey" : {"CYP2D6": "2.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -57146,68 +57162,68 @@ "objCls" : "Chemical", "id" : "PA449900", "name" : "hydrocodone", - "version" : 11 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166228121", "name" : "Annotation of CPIC Guideline for hydrocodone and CYP2D6", - "version" : 7 + "version" : 61 }, "text" : { - "id" : 1452059962, - "html" : "

No recommendation for hydrocodone therapy because of minimal evidence regarding adverse events or analgesia.

\n", + "id" : 1452059872, + "html" : "

Use hydrocodone label recommended age- or weight-specific dosing.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297938", - "name" : "Recommendation PA166297938", + "id" : "PA166297278", + "name" : "Recommendation PA166297278", "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Minimal evidence for pharmacokinetic or clinical effect." + "CYP2D6: Normal hydromorphone formation" ], - "lookupKey" : {"CYP2D6": "0.25"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"CYP2D6": "2.25"}, + "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449900", "name" : "hydrocodone", - "version" : 11 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166228121", "name" : "Annotation of CPIC Guideline for hydrocodone and CYP2D6", - "version" : 7 + "version" : 61 }, "text" : { - "id" : 1452060540, - "html" : "

Use hydrocodone label recommended age- or weight-specific dosing. If no response and opioid use is warranted, consider non-codeine or non-tramadol opioid.

\n", + "id" : 1452059880, + "html" : "

Use hydrocodone label recommended age- or weight-specific dosing.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297692", - "name" : "Recommendation PA166297692", + "id" : "PA166297367", + "name" : "Recommendation PA166297367", "alternateDrugAvailable" : false, "classification" : { "id" : 1448526251, @@ -57222,7 +57238,7 @@ "implications" : [ "CYP2D6: Minimal evidence for pharmacokinetic or clinical effect." ], - "lookupKey" : {"CYP2D6": "≥5.0"}, + "lookupKey" : {"CYP2D6": "2.75"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -57230,41 +57246,41 @@ "objCls" : "Chemical", "id" : "PA449900", "name" : "hydrocodone", - "version" : 11 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166228121", "name" : "Annotation of CPIC Guideline for hydrocodone and CYP2D6", - "version" : 7 + "version" : 61 }, "text" : { - "id" : 1452060294, + "id" : 1452059969, "html" : "

No recommendation for hydrocodone therapy because of minimal evidence regarding adverse events or analgesia.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297256", - "name" : "Recommendation PA166297256", + "id" : "PA166297360", + "name" : "Recommendation PA166297360", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Normal hydromorphone formation" + "CYP2D6: Minimal evidence for pharmacokinetic or clinical effect." ], - "lookupKey" : {"CYP2D6": "1.75"}, + "lookupKey" : {"CYP2D6": "3.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -57272,41 +57288,41 @@ "objCls" : "Chemical", "id" : "PA449900", "name" : "hydrocodone", - "version" : 11 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166228121", "name" : "Annotation of CPIC Guideline for hydrocodone and CYP2D6", - "version" : 7 + "version" : 61 }, "text" : { - "id" : 1452059858, - "html" : "

Use hydrocodone label recommended age- or weight-specific dosing.

\n", + "id" : 1452059962, + "html" : "

No recommendation for hydrocodone therapy because of minimal evidence regarding adverse events or analgesia.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297278", - "name" : "Recommendation PA166297278", + "id" : "PA166297391", + "name" : "Recommendation PA166297391", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Normal hydromorphone formation" + "CYP2D6: Minimal evidence for pharmacokinetic or clinical effect." ], - "lookupKey" : {"CYP2D6": "2.25"}, + "lookupKey" : {"CYP2D6": "4.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -57314,26 +57330,26 @@ "objCls" : "Chemical", "id" : "PA449900", "name" : "hydrocodone", - "version" : 11 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166228121", "name" : "Annotation of CPIC Guideline for hydrocodone and CYP2D6", - "version" : 7 + "version" : 61 }, "text" : { - "id" : 1452059880, - "html" : "

Use hydrocodone label recommended age- or weight-specific dosing.

\n", + "id" : 1452059993, + "html" : "

No recommendation for hydrocodone therapy because of minimal evidence regarding adverse events or analgesia.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297507", - "name" : "Recommendation PA166297507", + "id" : "PA166297679", + "name" : "Recommendation PA166297679", "alternateDrugAvailable" : false, "classification" : { "id" : 1448526251, @@ -57348,7 +57364,7 @@ "implications" : [ "CYP2D6: Minimal evidence for pharmacokinetic or clinical effect." ], - "lookupKey" : {"CYP2D6": "≥3.5"}, + "lookupKey" : {"CYP2D6": "≥4.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -57356,26 +57372,26 @@ "objCls" : "Chemical", "id" : "PA449900", "name" : "hydrocodone", - "version" : 11 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166228121", "name" : "Annotation of CPIC Guideline for hydrocodone and CYP2D6", - "version" : 7 + "version" : 61 }, "text" : { - "id" : 1452060109, + "id" : 1452060281, "html" : "

No recommendation for hydrocodone therapy because of minimal evidence regarding adverse events or analgesia.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297468", - "name" : "Recommendation PA166297468", + "id" : "PA166297692", + "name" : "Recommendation PA166297692", "alternateDrugAvailable" : false, "classification" : { "id" : 1448526251, @@ -57390,7 +57406,7 @@ "implications" : [ "CYP2D6: Minimal evidence for pharmacokinetic or clinical effect." ], - "lookupKey" : {"CYP2D6": "≥3.25"}, + "lookupKey" : {"CYP2D6": "≥5.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -57398,41 +57414,41 @@ "objCls" : "Chemical", "id" : "PA449900", "name" : "hydrocodone", - "version" : 11 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166228121", "name" : "Annotation of CPIC Guideline for hydrocodone and CYP2D6", - "version" : 7 + "version" : 61 }, "text" : { - "id" : 1452060070, + "id" : 1452060294, "html" : "

No recommendation for hydrocodone therapy because of minimal evidence regarding adverse events or analgesia.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297270", - "name" : "Recommendation PA166297270", + "id" : "PA166297711", + "name" : "Recommendation PA166297711", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Normal hydromorphone formation" + "CYP2D6: Minimal evidence for pharmacokinetic or clinical effect." ], - "lookupKey" : {"CYP2D6": "2.0"}, + "lookupKey" : {"CYP2D6": "≥6.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -57440,33 +57456,33 @@ "objCls" : "Chemical", "id" : "PA449900", "name" : "hydrocodone", - "version" : 11 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166228121", "name" : "Annotation of CPIC Guideline for hydrocodone and CYP2D6", - "version" : 7 + "version" : 61 }, "text" : { - "id" : 1452059872, - "html" : "

Use hydrocodone label recommended age- or weight-specific dosing.

\n", + "id" : 1452060313, + "html" : "

No recommendation for hydrocodone therapy because of minimal evidence regarding adverse events or analgesia.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297948", - "name" : "Recommendation PA166297948", + "id" : "PA166297686", + "name" : "Recommendation PA166297686", "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, @@ -57474,76 +57490,76 @@ "implications" : [ "CYP2D6: Minimal evidence for pharmacokinetic or clinical effect." ], - "lookupKey" : {"CYP2D6": "0.5"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"CYP2D6": "≥3.75"}, + "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449900", "name" : "hydrocodone", - "version" : 11 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166228121", "name" : "Annotation of CPIC Guideline for hydrocodone and CYP2D6", - "version" : 7 + "version" : 61 }, "text" : { - "id" : 1452060550, - "html" : "

Use hydrocodone label recommended age- or weight-specific dosing. If no response and opioid use is warranted, consider non-codeine or non-tramadol opioid.

\n", + "id" : 1452060288, + "html" : "

No recommendation for hydrocodone therapy because of minimal evidence regarding adverse events or analgesia.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297239", - "name" : "Recommendation PA166297239", + "id" : "PA166297789", + "name" : "Recommendation PA166297789", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Normal hydromorphone formation" + "CYP2D6: Decreased metabolism of hydrocodone to active metabolite, hydromorphone, but there is insufficient evidence to determine if these effects on pharmacokinetics translate into decreased analgesia or side effects." ], - "lookupKey" : {"CYP2D6": "1.5"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"CYP2D6": "0.0"}, + "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449900", "name" : "hydrocodone", - "version" : 11 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166228121", "name" : "Annotation of CPIC Guideline for hydrocodone and CYP2D6", - "version" : 7 + "version" : 61 }, "text" : { - "id" : 1452059841, - "html" : "

Use hydrocodone label recommended age- or weight-specific dosing.

\n", + "id" : 1452060391, + "html" : "

Use hydrocodone label recommended age- or weight-specific dosing. If no response and opioid use is warranted, consider non-codeine and non-tramadol opioid.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297679", - "name" : "Recommendation PA166297679", + "id" : "PA166297927", + "name" : "Recommendation PA166297927", "alternateDrugAvailable" : false, "classification" : { "id" : 1448526251, @@ -57556,9 +57572,9 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Minimal evidence for pharmacokinetic or clinical effect." + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "≥4.0"}, + "lookupKey" : {"CYP2D6": "n/a"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -57566,26 +57582,26 @@ "objCls" : "Chemical", "id" : "PA449900", "name" : "hydrocodone", - "version" : 11 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166228121", "name" : "Annotation of CPIC Guideline for hydrocodone and CYP2D6", - "version" : 7 + "version" : 61 }, "text" : { - "id" : 1452060281, - "html" : "

No recommendation for hydrocodone therapy because of minimal evidence regarding adverse events or analgesia.

\n", + "id" : 1452060529, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297789", - "name" : "Recommendation PA166297789", + "id" : "PA166297938", + "name" : "Recommendation PA166297938", "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, @@ -57598,9 +57614,9 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Decreased metabolism of hydrocodone to active metabolite, hydromorphone, but there is insufficient evidence to determine if these effects on pharmacokinetics translate into decreased analgesia or side effects." + "CYP2D6: Minimal evidence for pharmacokinetic or clinical effect." ], - "lookupKey" : {"CYP2D6": "0.0"}, + "lookupKey" : {"CYP2D6": "0.25"}, "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ @@ -57608,33 +57624,33 @@ "objCls" : "Chemical", "id" : "PA449900", "name" : "hydrocodone", - "version" : 11 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166228121", "name" : "Annotation of CPIC Guideline for hydrocodone and CYP2D6", - "version" : 7 + "version" : 61 }, "text" : { - "id" : 1452060391, - "html" : "

Use hydrocodone label recommended age- or weight-specific dosing. If no response and opioid use is warranted, consider non-codeine and non-tramadol opioid.

\n", + "id" : 1452060540, + "html" : "

Use hydrocodone label recommended age- or weight-specific dosing. If no response and opioid use is warranted, consider non-codeine or non-tramadol opioid.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297711", - "name" : "Recommendation PA166297711", + "id" : "PA166297948", + "name" : "Recommendation PA166297948", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, @@ -57642,41 +57658,41 @@ "implications" : [ "CYP2D6: Minimal evidence for pharmacokinetic or clinical effect." ], - "lookupKey" : {"CYP2D6": "≥6.0"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"CYP2D6": "0.5"}, + "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449900", "name" : "hydrocodone", - "version" : 11 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166228121", "name" : "Annotation of CPIC Guideline for hydrocodone and CYP2D6", - "version" : 7 + "version" : 61 }, "text" : { - "id" : 1452060313, - "html" : "

No recommendation for hydrocodone therapy because of minimal evidence regarding adverse events or analgesia.

\n", + "id" : 1452060550, + "html" : "

Use hydrocodone label recommended age- or weight-specific dosing. If no response and opioid use is warranted, consider non-codeine or non-tramadol opioid.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297367", - "name" : "Recommendation PA166297367", + "id" : "PA166297958", + "name" : "Recommendation PA166297958", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, @@ -57684,29 +57700,29 @@ "implications" : [ "CYP2D6: Minimal evidence for pharmacokinetic or clinical effect." ], - "lookupKey" : {"CYP2D6": "2.75"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"CYP2D6": "0.75"}, + "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449900", "name" : "hydrocodone", - "version" : 11 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166228121", "name" : "Annotation of CPIC Guideline for hydrocodone and CYP2D6", - "version" : 7 + "version" : 61 }, "text" : { - "id" : 1452059969, - "html" : "

No recommendation for hydrocodone therapy because of minimal evidence regarding adverse events or analgesia.

\n", + "id" : 1452060560, + "html" : "

Use hydrocodone label recommended age- or weight-specific dosing. If no response and opioid use is warranted, consider non-codeine or non-tramadol opioid.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166228121" @@ -57947,7 +57963,7 @@ "pediatricMarkdown" : { "id" : 1451266660, "html" : "

Guideline excerpt: "There are scarce studies focusing solely on CYP2D6 or CYP2C19 genotype and association with pharmacokinetic parameters or treatment outcomes of TCAs in pediatric patients. CYP2D6 activity is fully mature by early childhood, but CYP2C19 activity may be increased in children relative to adults. Although further genomic ontogeny studies are needed, there is a lack of evidence suggesting that this guideline cannot be extrapolated to pediatric patients."

\n", - "version" : 0 + "version" : 1 }, "recommendation" : true, "relatedAlleles" : [], @@ -57956,7 +57972,7 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "relatedGenes" : [ @@ -57965,21 +57981,21 @@ "id" : "PA124", "symbol" : "CYP2C19", "name" : "cytochrome P450 family 2 subfamily C member 19", - "version" : 7210 + "version" : 7266 }, { "objCls" : "Gene", "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "CPIC", "summaryMarkdown" : { "id" : 1447982030, "html" : "

Tricyclic antidepressants have comparable pharmacokinetic properties, it may be reasonable to apply the CPIC Dosing Guideline for amitriptyline and CYP2C19, CYP2D6 to other tricyclics including imipramine. The CPIC Dosing Guideline update for amitriptyline recommends an alternative drug for CYP2D6 ultrarapid or poor metabolizers and CYP2C19 ultrarapid, rapid or poor metabolizers. If amitriptyline is warranted, consider a 50% dose reduction in CYP2D6 or CYP2C19 poor metabolizers. For CYP2D6 intermediate metabolizers, a 25% dose reduction should be considered.

\n", - "version" : 1 + "version" : 4 }, "terms" : [], "textMarkdown" : { @@ -57988,13 +58004,13 @@ "version" : 1 }, "userId" : "whaleyr", - "version" : 48 + "version" : 136 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166298118", - "name" : "Recommendation PA166298118", + "id" : "PA166298120", + "name" : "Recommendation PA166298120", "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, @@ -58007,10 +58023,10 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: n/a" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -58018,27 +58034,27 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060720, - "html" : "

No recommendation

\n", + "id" : 1452060722, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298065", - "name" : "Recommendation PA166298065", - "alternateDrugAvailable" : true, + "id" : "PA166298168", + "name" : "Recommendation PA166298168", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -58050,10 +58066,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: n/a", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -58061,242 +58077,177 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060667, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452060770, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298105", - "name" : "Recommendation PA166298105", + "id" : "PA166301401", + "name" : "Recommendation Annotation PA166301401", "alternateDrugAvailable" : false, - "classification" : { - "id" : 981501930, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", - "valid" : true, - "version" : 0 - }, "dosingInformation" : false, - "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Normal metabolism of TCAs" - ], - "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Indeterminate"}, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, - "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060707, - "html" : "

No recommendation

\n", + "id" : 1452095740, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298052", - "name" : "Recommendation PA166298052", - "alternateDrugAvailable" : true, - "classification" : { - "id" : 981565059, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : true, - "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" - ], - "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Rapid Metabolizer"}, + "id" : "PA166301402", + "name" : "Recommendation Annotation PA166301402", + "alternateDrugAvailable" : false, + "dosingInformation" : false, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, - "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060654, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452095741, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298162", - "name" : "Recommendation PA166298162", - "alternateDrugAvailable" : true, - "classification" : { - "id" : 981565059, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : true, - "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" - ], - "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Likely Poor Metabolizer"}, + "id" : "PA166301403", + "name" : "Recommendation Annotation PA166301403", + "alternateDrugAvailable" : false, + "dosingInformation" : false, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, - "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060764, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452095742, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298043", - "name" : "Recommendation PA166298043", - "alternateDrugAvailable" : true, - "classification" : { - "id" : 981565059, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : true, - "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" - ], - "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Poor Metabolizer"}, + "id" : "PA166301404", + "name" : "Recommendation Annotation PA166301404", + "alternateDrugAvailable" : false, + "dosingInformation" : false, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, - "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060645, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452095743, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298175", - "name" : "Recommendation PA166298175", + "id" : "PA166301405", + "name" : "Recommendation Annotation PA166301405", "alternateDrugAvailable" : false, - "classification" : { - "id" : 981501930, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", - "valid" : true, - "version" : 0 - }, "dosingInformation" : false, - "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Normal metabolism of TCAs" - ], - "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "No Result"}, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, - "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060777, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452095744, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297980", - "name" : "Recommendation PA166297980", - "alternateDrugAvailable" : false, + "id" : "PA166297976", + "name" : "Recommendation PA166297976", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -58309,9 +58260,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -58319,26 +58270,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060582, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060578, + "html" : "

Avoid imipramine use. If a imipramine is warranted, consider a 50% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298109", - "name" : "Recommendation PA166298109", + "id" : "PA166297983", + "name" : "Recommendation PA166297983", "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, @@ -58354,7 +58305,7 @@ "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -58362,27 +58313,27 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060711, + "id" : 1452060585, "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298078", - "name" : "Recommendation PA166298078", - "alternateDrugAvailable" : true, + "id" : "PA166297981", + "name" : "Recommendation PA166297981", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -58392,12 +58343,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -58405,57 +58356,70 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060680, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060583, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301422", - "name" : "Recommendation Annotation PA166301422", + "id" : "PA166297980", + "name" : "Recommendation PA166297980", "alternateDrugAvailable" : false, - "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Poor Metabolizer"}, + "classification" : { + "id" : 981565059, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + ], + "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, + "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452095761, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "id" : 1452060582, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298030", - "name" : "Recommendation PA166298030", - "alternateDrugAvailable" : true, + "id" : "PA166297979", + "name" : "Recommendation PA166297979", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -58467,10 +58431,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -58478,27 +58442,27 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060632, - "html" : "

Avoid imipramine use. If imipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060581, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298140", - "name" : "Recommendation PA166298140", - "alternateDrugAvailable" : true, + "id" : "PA166297978", + "name" : "Recommendation PA166297978", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -58510,10 +58474,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -58521,27 +58485,27 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060742, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060580, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298017", - "name" : "Recommendation PA166298017", - "alternateDrugAvailable" : true, + "id" : "PA166297977", + "name" : "Recommendation PA166297977", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -58553,10 +58517,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -58564,26 +58528,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060619, - "html" : "

Avoid imipramine use; If imipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", + "id" : 1452060579, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298061", - "name" : "Recommendation PA166298061", + "id" : "PA166297987", + "name" : "Recommendation PA166297987", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -58596,10 +58560,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -58607,27 +58571,27 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060663, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452060589, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298101", - "name" : "Recommendation PA166298101", - "alternateDrugAvailable" : false, + "id" : "PA166297988", + "name" : "Recommendation PA166297988", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -58639,10 +58603,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -58650,26 +58614,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060703, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452060590, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298149", - "name" : "Recommendation PA166298149", + "id" : "PA166297990", + "name" : "Recommendation PA166297990", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -58682,10 +58646,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -58693,27 +58657,27 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060751, - "html" : "

Avoid imipramine use. If imipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060592, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298004", - "name" : "Recommendation PA166298004", - "alternateDrugAvailable" : false, + "id" : "PA166297991", + "name" : "Recommendation PA166297991", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -58725,10 +58689,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -58736,26 +58700,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060606, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452060593, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298096", - "name" : "Recommendation PA166298096", + "id" : "PA166297993", + "name" : "Recommendation PA166297993", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -58768,10 +58732,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -58779,26 +58743,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060698, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452060595, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297993", - "name" : "Recommendation PA166297993", + "id" : "PA166297994", + "name" : "Recommendation PA166297994", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -58814,7 +58778,7 @@ "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -58822,17 +58786,17 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060595, + "id" : 1452060596, "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, @@ -58840,8 +58804,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298114", - "name" : "Recommendation PA166298114", + "id" : "PA166297995", + "name" : "Recommendation PA166297995", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -58854,10 +58818,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -58865,18 +58829,18 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060716, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060597, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 @@ -58908,14 +58872,14 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { "id" : 1452060599, @@ -58926,8 +58890,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298087", - "name" : "Recommendation PA166298087", + "id" : "PA166297998", + "name" : "Recommendation PA166297998", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -58940,10 +58904,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -58951,42 +58915,42 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060689, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452060600, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298171", - "name" : "Recommendation PA166298171", - "alternateDrugAvailable" : false, + "id" : "PA166298001", + "name" : "Recommendation PA166298001", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -58994,42 +58958,42 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060773, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060603, + "html" : "

Avoid imipramine use. If a imipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298008", - "name" : "Recommendation PA166298008", - "alternateDrugAvailable" : false, + "id" : "PA166298011", + "name" : "Recommendation PA166298011", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Normal metabolism of TCAs" + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -59037,27 +59001,27 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060610, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060613, + "html" : "

Avoid imipramine use; If imipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297984", - "name" : "Recommendation PA166297984", - "alternateDrugAvailable" : false, + "id" : "PA166298012", + "name" : "Recommendation PA166298012", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -59067,12 +59031,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -59080,26 +59044,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060586, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060614, + "html" : "

Avoid imipramine use; If imipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298127", - "name" : "Recommendation PA166298127", + "id" : "PA166298014", + "name" : "Recommendation PA166298014", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -59112,10 +59076,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: Normal metabolism of tertiary amines", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -59123,26 +59087,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060729, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060616, + "html" : "

Avoid imipramine use; If imipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298074", - "name" : "Recommendation PA166298074", + "id" : "PA166298015", + "name" : "Recommendation PA166298015", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -59155,10 +59119,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -59166,26 +59130,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060676, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060617, + "html" : "

Avoid imipramine use; If imipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298184", - "name" : "Recommendation PA166298184", + "id" : "PA166298016", + "name" : "Recommendation PA166298016", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -59198,10 +59162,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Normal metabolism of tertiary amines", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -59209,26 +59173,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060786, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060618, + "html" : "

Avoid imipramine use; If imipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298025", - "name" : "Recommendation PA166298025", + "id" : "PA166298017", + "name" : "Recommendation PA166298017", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -59241,10 +59205,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -59252,26 +59216,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060627, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060619, + "html" : "

Avoid imipramine use; If imipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298157", - "name" : "Recommendation PA166298157", + "id" : "PA166298018", + "name" : "Recommendation PA166298018", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -59284,10 +59248,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Normal metabolism of tertiary amines", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -59295,26 +59259,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060759, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060620, + "html" : "

Avoid imipramine use; If imipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297998", - "name" : "Recommendation PA166297998", + "id" : "PA166298020", + "name" : "Recommendation PA166298020", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -59327,10 +59291,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: Normal metabolism of tertiary amines", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -59338,26 +59302,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060600, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060622, + "html" : "

Avoid imipramine use; If imipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298012", - "name" : "Recommendation PA166298012", + "id" : "PA166298021", + "name" : "Recommendation PA166298021", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -59373,7 +59337,7 @@ "CYP2C19: Normal metabolism of tertiary amines", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -59381,17 +59345,17 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060614, + "id" : 1452060623, "html" : "

Avoid imipramine use; If imipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", "version" : 0 }, @@ -59399,9 +59363,9 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298122", - "name" : "Recommendation PA166298122", - "alternateDrugAvailable" : false, + "id" : "PA166298024", + "name" : "Recommendation PA166298024", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -59413,10 +59377,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -59424,27 +59388,27 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060724, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060626, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297985", - "name" : "Recommendation PA166297985", - "alternateDrugAvailable" : false, + "id" : "PA166298025", + "name" : "Recommendation PA166298025", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -59454,12 +59418,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -59467,27 +59431,27 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060587, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060627, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298003", - "name" : "Recommendation PA166298003", - "alternateDrugAvailable" : false, + "id" : "PA166298026", + "name" : "Recommendation PA166298026", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -59499,10 +59463,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -59510,26 +59474,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060605, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452060628, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297989", - "name" : "Recommendation PA166297989", + "id" : "PA166298027", + "name" : "Recommendation PA166298027", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -59542,10 +59506,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -59553,26 +59517,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060591, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060629, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298095", - "name" : "Recommendation PA166298095", + "id" : "PA166298028", + "name" : "Recommendation PA166298028", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -59585,10 +59549,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -59596,26 +59560,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060697, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452060630, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298135", - "name" : "Recommendation PA166298135", + "id" : "PA166298029", + "name" : "Recommendation PA166298029", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -59628,10 +59592,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -59639,26 +59603,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060737, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060631, + "html" : "

Avoid imipramine use. If imipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298038", - "name" : "Recommendation PA166298038", + "id" : "PA166298030", + "name" : "Recommendation PA166298030", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -59672,9 +59636,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -59682,26 +59646,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060640, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060632, + "html" : "

Avoid imipramine use. If imipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297976", - "name" : "Recommendation PA166297976", + "id" : "PA166298031", + "name" : "Recommendation PA166298031", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -59714,10 +59678,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -59725,26 +59689,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060578, - "html" : "

Avoid imipramine use. If a imipramine is warranted, consider a 50% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060633, + "html" : "

Avoid imipramine use. If imipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298082", - "name" : "Recommendation PA166298082", + "id" : "PA166298032", + "name" : "Recommendation PA166298032", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -59757,10 +59721,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -59768,27 +59732,27 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060684, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060634, + "html" : "

Avoid imipramine use. If imipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298100", - "name" : "Recommendation PA166298100", - "alternateDrugAvailable" : false, + "id" : "PA166298033", + "name" : "Recommendation PA166298033", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -59800,10 +59764,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -59811,26 +59775,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060702, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452060635, + "html" : "

Avoid imipramine use. If imipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298069", - "name" : "Recommendation PA166298069", + "id" : "PA166298034", + "name" : "Recommendation PA166298034", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -59843,10 +59807,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -59854,26 +59818,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060671, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452060636, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298021", - "name" : "Recommendation PA166298021", + "id" : "PA166298036", + "name" : "Recommendation PA166298036", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -59886,10 +59850,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -59897,26 +59861,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060623, - "html" : "

Avoid imipramine use; If imipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", + "id" : 1452060638, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298153", - "name" : "Recommendation PA166298153", + "id" : "PA166298038", + "name" : "Recommendation PA166298038", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -59932,7 +59896,7 @@ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -59940,17 +59904,17 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060755, + "id" : 1452060640, "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, @@ -59958,8 +59922,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298056", - "name" : "Recommendation PA166298056", + "id" : "PA166298039", + "name" : "Recommendation PA166298039", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -59972,10 +59936,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -59983,56 +59947,69 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060658, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060641, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301404", - "name" : "Recommendation Annotation PA166301404", - "alternateDrugAvailable" : false, - "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Likely Poor Metabolizer"}, + "id" : "PA166298040", + "name" : "Recommendation PA166298040", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981565059, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + ], + "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, + "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452095743, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "id" : 1452060642, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298166", - "name" : "Recommendation PA166298166", + "id" : "PA166298041", + "name" : "Recommendation PA166298041", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -60045,10 +60022,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -60056,26 +60033,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060768, - "html" : "

Avoid tricyclic use due to potential for side effects. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452060643, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298047", - "name" : "Recommendation PA166298047", + "id" : "PA166298042", + "name" : "Recommendation PA166298042", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -60089,9 +60066,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: n/a" + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -60099,26 +60076,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060649, - "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. For tertiary amines, consider a 50% reduction of the recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060644, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298091", - "name" : "Recommendation PA166298091", + "id" : "PA166298044", + "name" : "Recommendation PA166298044", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -60131,10 +60108,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -60142,26 +60119,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060693, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452060646, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298131", - "name" : "Recommendation PA166298131", + "id" : "PA166297996", + "name" : "Recommendation PA166297996", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -60177,7 +60154,7 @@ "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -60185,26 +60162,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060733, + "id" : 1452060598, "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298179", - "name" : "Recommendation PA166298179", + "id" : "PA166298013", + "name" : "Recommendation PA166298013", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -60217,10 +60194,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Normal metabolism of tertiary amines", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -60228,26 +60205,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060781, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060615, + "html" : "

Avoid imipramine use; If imipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298034", - "name" : "Recommendation PA166298034", + "id" : "PA166298019", + "name" : "Recommendation PA166298019", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -60260,10 +60237,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Normal metabolism of tertiary amines", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -60271,26 +60248,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060636, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060621, + "html" : "

Avoid imipramine use; If imipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298144", - "name" : "Recommendation PA166298144", + "id" : "PA166298037", + "name" : "Recommendation PA166298037", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -60304,9 +60281,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -60314,26 +60291,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060746, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060639, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298053", - "name" : "Recommendation PA166298053", + "id" : "PA166298043", + "name" : "Recommendation PA166298043", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -60346,10 +60323,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -60357,42 +60334,42 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060655, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060645, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298185", - "name" : "Recommendation PA166298185", - "alternateDrugAvailable" : true, + "id" : "PA166298022", + "name" : "Recommendation PA166298022", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -60400,27 +60377,27 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060787, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060624, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297990", - "name" : "Recommendation PA166297990", - "alternateDrugAvailable" : true, + "id" : "PA166297999", + "name" : "Recommendation PA166297999", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -60430,12 +60407,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -60443,42 +60420,42 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060592, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060601, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298119", - "name" : "Recommendation PA166298119", + "id" : "PA166298023", + "name" : "Recommendation PA166298023", "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Normal metabolism of tertiary amines", "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -60486,27 +60463,27 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060721, - "html" : "

No recommendation

\n", + "id" : 1452060625, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298088", - "name" : "Recommendation PA166298088", - "alternateDrugAvailable" : true, + "id" : "PA166298000", + "name" : "Recommendation PA166298000", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -60516,12 +60493,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -60529,42 +60506,42 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060690, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452060602, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298040", - "name" : "Recommendation PA166298040", - "alternateDrugAvailable" : true, + "id" : "PA166298010", + "name" : "Recommendation PA166298010", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -60572,27 +60549,27 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060642, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060612, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298150", - "name" : "Recommendation PA166298150", - "alternateDrugAvailable" : true, + "id" : "PA166298035", + "name" : "Recommendation PA166298035", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -60602,12 +60579,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -60615,42 +60592,42 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060752, - "html" : "

Avoid imipramine use. If imipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060637, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298009", - "name" : "Recommendation PA166298009", + "id" : "PA166297986", + "name" : "Recommendation PA166297986", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -60658,26 +60635,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060611, + "id" : 1452060588, "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298106", - "name" : "Recommendation PA166298106", + "id" : "PA166298009", + "name" : "Recommendation PA166298009", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -60690,10 +60667,10 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Normal metabolism of tertiary amines", "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -60701,27 +60678,27 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060708, - "html" : "

No recommendation

\n", + "id" : 1452060611, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298079", - "name" : "Recommendation PA166298079", - "alternateDrugAvailable" : true, + "id" : "PA166297985", + "name" : "Recommendation PA166297985", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -60731,12 +60708,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -60744,42 +60721,42 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060681, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060587, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298031", - "name" : "Recommendation PA166298031", - "alternateDrugAvailable" : true, + "id" : "PA166298008", + "name" : "Recommendation PA166298008", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Normal metabolism of tertiary amines", "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -60787,27 +60764,27 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060633, - "html" : "

Avoid imipramine use. If imipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060610, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298163", - "name" : "Recommendation PA166298163", - "alternateDrugAvailable" : true, + "id" : "PA166297984", + "name" : "Recommendation PA166297984", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -60817,12 +60794,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -60830,42 +60807,42 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060765, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060586, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298066", - "name" : "Recommendation PA166298066", - "alternateDrugAvailable" : true, + "id" : "PA166298007", + "name" : "Recommendation PA166298007", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -60873,42 +60850,42 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060668, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452060609, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298176", - "name" : "Recommendation PA166298176", - "alternateDrugAvailable" : true, + "id" : "PA166298006", + "name" : "Recommendation PA166298006", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -60916,21 +60893,21 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060778, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060608, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -60959,57 +60936,70 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { "id" : 1452060607, "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301421", - "name" : "Recommendation Annotation PA166301421", + "id" : "PA166298004", + "name" : "Recommendation PA166298004", "alternateDrugAvailable" : false, - "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Normal Metabolizer"}, + "classification" : { + "id" : 981565059, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + ], + "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, + "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452095760, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "id" : 1452060606, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298097", - "name" : "Recommendation PA166298097", - "alternateDrugAvailable" : true, + "id" : "PA166298003", + "name" : "Recommendation PA166298003", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -61021,10 +61011,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: n/a" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -61032,26 +61022,69 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060699, - "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. If a tertiary amine is warranted, utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060605, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298181", - "name" : "Recommendation PA166298181", + "id" : "PA166298002", + "name" : "Recommendation PA166298002", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 981565059, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + ], + "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Normal Metabolizer"}, + "otherPrescribingGuidance" : false, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA449969", + "name" : "imipramine", + "version" : 46 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104999", + "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", + "version" : 136 + }, + "text" : { + "id" : 1452060604, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "version" : 0 + }, + "version" : 1 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166298045", + "name" : "Recommendation PA166298045", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -61064,10 +61097,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -61075,26 +61108,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060783, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060647, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298137", - "name" : "Recommendation PA166298137", + "id" : "PA166298046", + "name" : "Recommendation PA166298046", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -61107,10 +61140,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -61118,26 +61151,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060739, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060648, + "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. For tertiary amines, consider a 50% reduction of the recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297994", - "name" : "Recommendation PA166297994", + "id" : "PA166298047", + "name" : "Recommendation PA166298047", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -61150,10 +61183,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -61161,26 +61194,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060596, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060649, + "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. For tertiary amines, consider a 50% reduction of the recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298084", - "name" : "Recommendation PA166298084", + "id" : "PA166298048", + "name" : "Recommendation PA166298048", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -61194,9 +61227,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -61204,27 +61237,27 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060686, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060650, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297981", - "name" : "Recommendation PA166297981", - "alternateDrugAvailable" : false, + "id" : "PA166298049", + "name" : "Recommendation PA166298049", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -61234,12 +61267,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -61247,27 +61280,27 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060583, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060651, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298102", - "name" : "Recommendation PA166298102", - "alternateDrugAvailable" : false, + "id" : "PA166298050", + "name" : "Recommendation PA166298050", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -61279,10 +61312,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -61290,26 +61323,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060704, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452060652, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298075", - "name" : "Recommendation PA166298075", + "id" : "PA166298051", + "name" : "Recommendation PA166298051", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -61325,7 +61358,7 @@ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -61333,17 +61366,17 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060677, + "id" : 1452060653, "html" : "

Consider alternative drug not metabolized by CYP2C19; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, @@ -61351,8 +61384,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298115", - "name" : "Recommendation PA166298115", + "id" : "PA166298052", + "name" : "Recommendation PA166298052", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -61365,10 +61398,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -61376,26 +61409,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060717, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060654, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298018", - "name" : "Recommendation PA166298018", + "id" : "PA166298053", + "name" : "Recommendation PA166298053", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -61408,10 +61441,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", + "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -61419,26 +61452,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060620, - "html" : "

Avoid imipramine use; If imipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", + "id" : 1452060655, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298062", - "name" : "Recommendation PA166298062", + "id" : "PA166298054", + "name" : "Recommendation PA166298054", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -61452,9 +61485,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -61462,42 +61495,42 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060664, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452060656, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298172", - "name" : "Recommendation PA166298172", - "alternateDrugAvailable" : false, + "id" : "PA166298055", + "name" : "Recommendation PA166298055", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -61505,26 +61538,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060774, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060657, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298128", - "name" : "Recommendation PA166298128", + "id" : "PA166298056", + "name" : "Recommendation PA166298056", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -61537,10 +61570,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -61548,27 +61581,27 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060730, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060658, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297999", - "name" : "Recommendation PA166297999", - "alternateDrugAvailable" : false, + "id" : "PA166298057", + "name" : "Recommendation PA166298057", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -61578,12 +61611,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: n/a" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -61591,26 +61624,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060601, - "html" : "

No recommendation

\n", + "id" : 1452060659, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298013", - "name" : "Recommendation PA166298013", + "id" : "PA166298058", + "name" : "Recommendation PA166298058", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -61623,10 +61656,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -61634,26 +61667,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060615, - "html" : "

Avoid imipramine use; If imipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", + "id" : 1452060660, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298145", - "name" : "Recommendation PA166298145", + "id" : "PA166298059", + "name" : "Recommendation PA166298059", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -61666,10 +61699,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -61677,26 +61710,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060747, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060661, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298048", - "name" : "Recommendation PA166298048", + "id" : "PA166298060", + "name" : "Recommendation PA166298060", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -61709,10 +61742,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: n/a", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -61720,27 +61753,27 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060650, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060662, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297986", - "name" : "Recommendation PA166297986", - "alternateDrugAvailable" : false, + "id" : "PA166298061", + "name" : "Recommendation PA166298061", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -61750,12 +61783,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -61763,27 +61796,27 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060588, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060663, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298000", - "name" : "Recommendation PA166298000", - "alternateDrugAvailable" : false, + "id" : "PA166298063", + "name" : "Recommendation PA166298063", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -61793,12 +61826,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: n/a" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -61806,26 +61839,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060602, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060665, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298092", - "name" : "Recommendation PA166298092", + "id" : "PA166298064", + "name" : "Recommendation PA166298064", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -61841,7 +61874,7 @@ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -61849,17 +61882,17 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060694, + "id" : 1452060666, "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, @@ -61867,8 +61900,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298158", - "name" : "Recommendation PA166298158", + "id" : "PA166298065", + "name" : "Recommendation PA166298065", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -61881,10 +61914,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -61892,26 +61925,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060760, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060667, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298110", - "name" : "Recommendation PA166298110", + "id" : "PA166298066", + "name" : "Recommendation PA166298066", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -61924,10 +61957,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -61935,27 +61968,27 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060712, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060668, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297977", - "name" : "Recommendation PA166297977", - "alternateDrugAvailable" : false, + "id" : "PA166298067", + "name" : "Recommendation PA166298067", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -61967,10 +62000,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -61978,26 +62011,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060579, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060669, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298039", - "name" : "Recommendation PA166298039", + "id" : "PA166298069", + "name" : "Recommendation PA166298069", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -62010,10 +62043,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -62021,26 +62054,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060641, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060671, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298083", - "name" : "Recommendation PA166298083", + "id" : "PA166298070", + "name" : "Recommendation PA166298070", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -62054,9 +62087,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -62064,27 +62097,27 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060685, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060672, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298123", - "name" : "Recommendation PA166298123", - "alternateDrugAvailable" : false, + "id" : "PA166298071", + "name" : "Recommendation PA166298071", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -62096,10 +62129,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -62107,26 +62140,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060725, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060673, + "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. If a tertiary amine is warranted, utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298026", - "name" : "Recommendation PA166298026", + "id" : "PA166298072", + "name" : "Recommendation PA166298072", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -62139,10 +62172,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -62150,26 +62183,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060628, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060674, + "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. If a tertiary amine is warranted, utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298070", - "name" : "Recommendation PA166298070", + "id" : "PA166298074", + "name" : "Recommendation PA166298074", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -62183,9 +62216,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -62193,26 +62226,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060672, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452060676, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298180", - "name" : "Recommendation PA166298180", + "id" : "PA166298075", + "name" : "Recommendation PA166298075", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -62225,10 +62258,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -62236,26 +62269,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060782, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060677, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298136", - "name" : "Recommendation PA166298136", + "id" : "PA166298076", + "name" : "Recommendation PA166298076", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -62268,10 +62301,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -62279,26 +62312,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060738, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060678, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298057", - "name" : "Recommendation PA166298057", + "id" : "PA166298077", + "name" : "Recommendation PA166298077", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -62312,9 +62345,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -62322,26 +62355,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060659, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060679, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298141", - "name" : "Recommendation PA166298141", + "id" : "PA166298078", + "name" : "Recommendation PA166298078", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -62354,10 +62387,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -62365,26 +62398,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060743, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060680, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298044", - "name" : "Recommendation PA166298044", + "id" : "PA166298080", + "name" : "Recommendation PA166298080", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -62397,10 +62430,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -62408,26 +62441,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060646, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060682, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298154", - "name" : "Recommendation PA166298154", + "id" : "PA166298081", + "name" : "Recommendation PA166298081", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -62440,10 +62473,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -62451,27 +62484,27 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060756, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060683, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298035", - "name" : "Recommendation PA166298035", - "alternateDrugAvailable" : false, + "id" : "PA166298082", + "name" : "Recommendation PA166298082", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -62481,12 +62514,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -62494,57 +62527,70 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060637, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060684, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301403", - "name" : "Recommendation Annotation PA166301403", - "alternateDrugAvailable" : false, - "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Likely Intermediate Metabolizer"}, + "id" : "PA166298083", + "name" : "Recommendation PA166298083", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981565059, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" + ], + "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, + "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452095742, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "id" : 1452060685, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298167", - "name" : "Recommendation PA166298167", - "alternateDrugAvailable" : false, + "id" : "PA166298084", + "name" : "Recommendation PA166298084", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -62556,10 +62602,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -62567,42 +62613,42 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060769, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452060686, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298022", - "name" : "Recommendation PA166298022", - "alternateDrugAvailable" : false, + "id" : "PA166298085", + "name" : "Recommendation PA166298085", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: n/a" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -62610,26 +62656,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060624, - "html" : "

No recommendation

\n", + "id" : 1452060687, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298132", - "name" : "Recommendation PA166298132", + "id" : "PA166298087", + "name" : "Recommendation PA166298087", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -62642,10 +62688,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -62653,18 +62699,18 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060734, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060689, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 @@ -62696,14 +62742,14 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { "id" : 1452060691, @@ -62714,8 +62760,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298041", - "name" : "Recommendation PA166298041", + "id" : "PA166298090", + "name" : "Recommendation PA166298090", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -62728,10 +62774,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -62739,42 +62785,42 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060643, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060692, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298173", - "name" : "Recommendation PA166298173", - "alternateDrugAvailable" : false, + "id" : "PA166298091", + "name" : "Recommendation PA166298091", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -62782,42 +62828,42 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060775, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060693, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298107", - "name" : "Recommendation PA166298107", - "alternateDrugAvailable" : false, + "id" : "PA166298092", + "name" : "Recommendation PA166298092", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -62825,56 +62871,69 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060709, - "html" : "

No recommendation

\n", + "id" : 1452060694, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301424", - "name" : "Recommendation Annotation PA166301424", - "alternateDrugAvailable" : false, - "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Rapid Metabolizer"}, + "id" : "PA166298093", + "name" : "Recommendation PA166298093", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981565059, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + ], + "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, + "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452095763, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "id" : 1452060695, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298076", - "name" : "Recommendation PA166298076", + "id" : "PA166298095", + "name" : "Recommendation PA166298095", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -62888,9 +62947,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -62898,27 +62957,27 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060678, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060697, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298186", - "name" : "Recommendation PA166298186", - "alternateDrugAvailable" : false, + "id" : "PA166298096", + "name" : "Recommendation PA166298096", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -62928,12 +62987,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: n/a" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -62941,26 +63000,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060788, - "html" : "

No recommendation

\n", + "id" : 1452060698, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298067", - "name" : "Recommendation PA166298067", + "id" : "PA166298097", + "name" : "Recommendation PA166298097", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -62974,9 +63033,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -62984,26 +63043,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060669, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452060699, + "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. If a tertiary amine is warranted, utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298151", - "name" : "Recommendation PA166298151", + "id" : "PA166298098", + "name" : "Recommendation PA166298098", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -63016,10 +63075,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -63027,26 +63086,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060753, - "html" : "

Avoid imipramine use. If imipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060700, + "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. If a tertiary amine is warranted, utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298054", - "name" : "Recommendation PA166298054", + "id" : "PA166298099", + "name" : "Recommendation PA166298099", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -63059,10 +63118,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: n/a", + "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -63070,26 +63129,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060656, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060701, + "html" : "

Avoid tricyclic use due to potential for side effects. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298164", - "name" : "Recommendation PA166298164", + "id" : "PA166298062", + "name" : "Recommendation PA166298062", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -63102,10 +63161,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: n/a" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -63113,26 +63172,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060766, - "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. For tertiary amines, consider a 50% reduction of the recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060664, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297991", - "name" : "Recommendation PA166297991", + "id" : "PA166298068", + "name" : "Recommendation PA166298068", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -63145,10 +63204,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -63156,26 +63215,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060593, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060670, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298085", - "name" : "Recommendation PA166298085", + "id" : "PA166298079", + "name" : "Recommendation PA166298079", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -63188,10 +63247,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -63199,27 +63258,27 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060687, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452060681, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298125", - "name" : "Recommendation PA166298125", - "alternateDrugAvailable" : false, + "id" : "PA166298094", + "name" : "Recommendation PA166298094", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -63231,10 +63290,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -63242,42 +63301,42 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060727, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060696, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298028", - "name" : "Recommendation PA166298028", - "alternateDrugAvailable" : true, + "id" : "PA166298106", + "name" : "Recommendation PA166298106", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: n/a", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -63285,27 +63344,27 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060630, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060708, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298072", - "name" : "Recommendation PA166298072", - "alternateDrugAvailable" : true, + "id" : "PA166298086", + "name" : "Recommendation PA166298086", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -63315,12 +63374,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: n/a" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -63328,42 +63387,42 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060674, - "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. If a tertiary amine is warranted, utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060688, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298182", - "name" : "Recommendation PA166298182", - "alternateDrugAvailable" : true, + "id" : "PA166298105", + "name" : "Recommendation PA166298105", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -63371,42 +63430,42 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060784, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060707, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298138", - "name" : "Recommendation PA166298138", + "id" : "PA166298104", + "name" : "Recommendation PA166298104", "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: n/a" + "CYP2C19: n/a", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -63414,27 +63473,27 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060740, + "id" : 1452060706, "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298063", - "name" : "Recommendation PA166298063", - "alternateDrugAvailable" : true, + "id" : "PA166298103", + "name" : "Recommendation PA166298103", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -63446,10 +63505,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: n/a", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -63457,26 +63516,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060665, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452060705, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298103", - "name" : "Recommendation PA166298103", + "id" : "PA166298102", + "name" : "Recommendation PA166298102", "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, @@ -63492,7 +63551,7 @@ "CYP2C19: n/a", "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -63500,27 +63559,27 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060705, + "id" : 1452060704, "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298129", - "name" : "Recommendation PA166298129", - "alternateDrugAvailable" : true, + "id" : "PA166298101", + "name" : "Recommendation PA166298101", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -63532,10 +63591,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: n/a", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -63543,42 +63602,42 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060731, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060703, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298006", - "name" : "Recommendation PA166298006", + "id" : "PA166298100", + "name" : "Recommendation PA166298100", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: n/a", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -63586,26 +63645,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060608, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060702, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298098", - "name" : "Recommendation PA166298098", + "id" : "PA166298110", + "name" : "Recommendation PA166298110", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -63618,10 +63677,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: n/a" + "CYP2C19: n/a", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -63629,26 +63688,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060700, - "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. If a tertiary amine is warranted, utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060712, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298050", - "name" : "Recommendation PA166298050", + "id" : "PA166298111", + "name" : "Recommendation PA166298111", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -63661,10 +63720,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: n/a", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -63672,26 +63731,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060652, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060713, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298160", - "name" : "Recommendation PA166298160", + "id" : "PA166298112", + "name" : "Recommendation PA166298112", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -63704,10 +63763,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -63715,26 +63774,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060762, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060714, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298019", - "name" : "Recommendation PA166298019", + "id" : "PA166298113", + "name" : "Recommendation PA166298113", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -63747,10 +63806,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", + "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -63758,26 +63817,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060621, - "html" : "

Avoid imipramine use; If imipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", + "id" : 1452060715, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297995", - "name" : "Recommendation PA166297995", + "id" : "PA166298114", + "name" : "Recommendation PA166298114", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -63790,10 +63849,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -63801,18 +63860,18 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060597, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060716, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 @@ -63844,14 +63903,14 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { "id" : 1452060718, @@ -63862,8 +63921,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298049", - "name" : "Recommendation PA166298049", + "id" : "PA166298117", + "name" : "Recommendation PA166298117", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -63876,10 +63935,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: n/a", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -63887,26 +63946,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060651, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060719, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298001", - "name" : "Recommendation PA166298001", + "id" : "PA166298121", + "name" : "Recommendation PA166298121", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -63919,10 +63978,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -63930,26 +63989,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060603, - "html" : "

Avoid imipramine use. If a imipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452060723, + "html" : "

Avoid imipramine use. If a imipramine is warranted, consider a 50% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297987", - "name" : "Recommendation PA166297987", + "id" : "PA166298127", + "name" : "Recommendation PA166298127", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -63965,7 +64024,7 @@ "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -63973,17 +64032,17 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060589, + "id" : 1452060729, "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, @@ -63991,8 +64050,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298093", - "name" : "Recommendation PA166298093", + "id" : "PA166298128", + "name" : "Recommendation PA166298128", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -64005,10 +64064,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -64016,26 +64075,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060695, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452060730, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298133", - "name" : "Recommendation PA166298133", + "id" : "PA166298130", + "name" : "Recommendation PA166298130", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -64051,7 +64110,7 @@ "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -64059,17 +64118,17 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060735, + "id" : 1452060732, "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, @@ -64077,8 +64136,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298036", - "name" : "Recommendation PA166298036", + "id" : "PA166298131", + "name" : "Recommendation PA166298131", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -64091,10 +64150,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -64102,26 +64161,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060638, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060733, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298080", - "name" : "Recommendation PA166298080", + "id" : "PA166298132", + "name" : "Recommendation PA166298132", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -64134,10 +64193,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -64145,26 +64204,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060682, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060734, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298146", - "name" : "Recommendation PA166298146", + "id" : "PA166298133", + "name" : "Recommendation PA166298133", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -64177,10 +64236,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -64188,26 +64247,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060748, - "html" : "

Avoid imipramine use. If imipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060735, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298027", - "name" : "Recommendation PA166298027", + "id" : "PA166298134", + "name" : "Recommendation PA166298134", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -64220,10 +64279,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -64231,26 +64290,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060629, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060736, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298071", - "name" : "Recommendation PA166298071", + "id" : "PA166298136", + "name" : "Recommendation PA166298136", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -64263,10 +64322,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: n/a" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -64274,26 +64333,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060673, - "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. If a tertiary amine is warranted, utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060738, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298159", - "name" : "Recommendation PA166298159", + "id" : "PA166298137", + "name" : "Recommendation PA166298137", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -64306,10 +64365,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -64317,26 +64376,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060761, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060739, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298111", - "name" : "Recommendation PA166298111", + "id" : "PA166298140", + "name" : "Recommendation PA166298140", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -64349,10 +64408,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -64360,26 +64419,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060713, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060742, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298014", - "name" : "Recommendation PA166298014", + "id" : "PA166298141", + "name" : "Recommendation PA166298141", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -64392,10 +64451,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -64403,27 +64462,27 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060616, - "html" : "

Avoid imipramine use; If imipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", + "id" : 1452060743, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298124", - "name" : "Recommendation PA166298124", - "alternateDrugAvailable" : false, + "id" : "PA166298143", + "name" : "Recommendation PA166298143", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -64435,10 +64494,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -64446,26 +64505,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060726, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060745, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298045", - "name" : "Recommendation PA166298045", + "id" : "PA166298144", + "name" : "Recommendation PA166298144", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -64479,9 +64538,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -64489,26 +64548,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060647, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060746, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298177", - "name" : "Recommendation PA166298177", + "id" : "PA166298145", + "name" : "Recommendation PA166298145", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -64521,10 +64580,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -64532,27 +64591,27 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060779, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060747, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297978", - "name" : "Recommendation PA166297978", - "alternateDrugAvailable" : false, + "id" : "PA166298146", + "name" : "Recommendation PA166298146", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -64564,10 +64623,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -64575,26 +64634,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060580, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060748, + "html" : "

Avoid imipramine use. If imipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298032", - "name" : "Recommendation PA166298032", + "id" : "PA166298147", + "name" : "Recommendation PA166298147", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -64610,7 +64669,7 @@ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -64618,17 +64677,17 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060634, + "id" : 1452060749, "html" : "

Avoid imipramine use. If imipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, @@ -64636,8 +64695,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298142", - "name" : "Recommendation PA166298142", + "id" : "PA166298149", + "name" : "Recommendation PA166298149", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -64650,53 +64709,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" - ], - "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "No Result"}, - "otherPrescribingGuidance" : false, - "population" : "general", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA449969", - "name" : "imipramine", - "version" : 15 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166104999", - "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 - }, - "text" : { - "id" : 1452060744, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166298023", - "name" : "Recommendation PA166298023", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 981501930, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: n/a" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -64704,56 +64720,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060625, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166301402", - "name" : "Recommendation Annotation PA166301402", - "alternateDrugAvailable" : false, - "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Intermediate Metabolizer"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA449969", - "name" : "imipramine", - "version" : 15 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166104999", - "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 - }, - "text" : { - "id" : 1452095741, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "id" : 1452060751, + "html" : "

Avoid imipramine use. If imipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298058", - "name" : "Recommendation PA166298058", + "id" : "PA166298150", + "name" : "Recommendation PA166298150", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -64766,53 +64752,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" - ], - "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Rapid Metabolizer"}, - "otherPrescribingGuidance" : false, - "population" : "general", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA449969", - "name" : "imipramine", - "version" : 15 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166104999", - "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 - }, - "text" : { - "id" : 1452060660, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166298010", - "name" : "Recommendation PA166298010", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 981501930, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -64820,27 +64763,27 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060612, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060752, + "html" : "

Avoid imipramine use. If imipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298120", - "name" : "Recommendation PA166298120", - "alternateDrugAvailable" : false, + "id" : "PA166298151", + "name" : "Recommendation PA166298151", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -64850,12 +64793,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -64863,27 +64806,27 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060722, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060753, + "html" : "

Avoid imipramine use. If imipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298168", - "name" : "Recommendation PA166298168", - "alternateDrugAvailable" : false, + "id" : "PA166298152", + "name" : "Recommendation PA166298152", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -64895,10 +64838,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -64906,56 +64849,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060770, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166301401", - "name" : "Recommendation Annotation PA166301401", - "alternateDrugAvailable" : false, - "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Indeterminate"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA449969", - "name" : "imipramine", - "version" : 15 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166104999", - "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 - }, - "text" : { - "id" : 1452095740, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "id" : 1452060754, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298077", - "name" : "Recommendation PA166298077", + "id" : "PA166298153", + "name" : "Recommendation PA166298153", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -64968,10 +64881,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -64979,26 +64892,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060679, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060755, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298161", - "name" : "Recommendation PA166298161", + "id" : "PA166298156", + "name" : "Recommendation PA166298156", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -65014,7 +64927,7 @@ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -65022,17 +64935,17 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060763, + "id" : 1452060758, "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, @@ -65040,8 +64953,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298117", - "name" : "Recommendation PA166298117", + "id" : "PA166298157", + "name" : "Recommendation PA166298157", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -65054,10 +64967,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -65065,26 +64978,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060719, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060759, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298064", - "name" : "Recommendation PA166298064", + "id" : "PA166298158", + "name" : "Recommendation PA166298158", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -65097,10 +65010,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -65108,42 +65021,42 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060666, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452060760, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298174", - "name" : "Recommendation PA166298174", - "alternateDrugAvailable" : false, + "id" : "PA166298159", + "name" : "Recommendation PA166298159", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -65151,42 +65064,42 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060776, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060761, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298108", - "name" : "Recommendation PA166298108", - "alternateDrugAvailable" : false, + "id" : "PA166298160", + "name" : "Recommendation PA166298160", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -65194,26 +65107,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060710, - "html" : "

No recommendation

\n", + "id" : 1452060762, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298055", - "name" : "Recommendation PA166298055", + "id" : "PA166298162", + "name" : "Recommendation PA166298162", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -65226,10 +65139,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -65237,56 +65150,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166104999", - "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 - }, - "text" : { - "id" : 1452060657, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166301423", - "name" : "Recommendation Annotation PA166301423", - "alternateDrugAvailable" : false, - "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Ultrarapid Metabolizer"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA449969", - "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452095762, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "id" : 1452060764, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298042", - "name" : "Recommendation PA166298042", + "id" : "PA166298163", + "name" : "Recommendation PA166298163", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -65302,7 +65185,7 @@ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -65310,17 +65193,17 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060644, + "id" : 1452060765, "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, @@ -65328,8 +65211,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298152", - "name" : "Recommendation PA166298152", + "id" : "PA166298164", + "name" : "Recommendation PA166298164", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -65343,9 +65226,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -65353,26 +65236,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060754, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060766, + "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. For tertiary amines, consider a 50% reduction of the recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298029", - "name" : "Recommendation PA166298029", + "id" : "PA166298165", + "name" : "Recommendation PA166298165", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -65386,9 +65269,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -65396,26 +65279,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060631, - "html" : "

Avoid imipramine use. If imipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060767, + "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. For tertiary amines, consider a 50% reduction of the recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298113", - "name" : "Recommendation PA166298113", + "id" : "PA166298166", + "name" : "Recommendation PA166298166", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -65429,9 +65312,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -65439,26 +65322,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060715, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060768, + "html" : "

Avoid tricyclic use due to potential for side effects. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298016", - "name" : "Recommendation PA166298016", + "id" : "PA166298115", + "name" : "Recommendation PA166298115", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -65471,10 +65354,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", + "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -65482,26 +65365,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060618, - "html" : "

Avoid imipramine use; If imipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", + "id" : 1452060717, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298060", - "name" : "Recommendation PA166298060", + "id" : "PA166298129", + "name" : "Recommendation PA166298129", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -65514,10 +65397,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -65525,27 +65408,27 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060662, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060731, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298170", - "name" : "Recommendation PA166298170", - "alternateDrugAvailable" : false, + "id" : "PA166298135", + "name" : "Recommendation PA166298135", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -65557,10 +65440,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -65568,27 +65451,27 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060772, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452060737, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298126", - "name" : "Recommendation PA166298126", - "alternateDrugAvailable" : false, + "id" : "PA166298142", + "name" : "Recommendation PA166298142", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -65598,12 +65481,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: n/a", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -65611,42 +65494,42 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060728, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060744, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298007", - "name" : "Recommendation PA166298007", - "alternateDrugAvailable" : false, + "id" : "PA166298154", + "name" : "Recommendation PA166298154", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -65654,26 +65537,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060609, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060756, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298099", - "name" : "Recommendation PA166298099", + "id" : "PA166298161", + "name" : "Recommendation PA166298161", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -65686,10 +65569,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -65697,27 +65580,27 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060701, - "html" : "

Avoid tricyclic use due to potential for side effects. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452060763, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298051", - "name" : "Recommendation PA166298051", - "alternateDrugAvailable" : true, + "id" : "PA166298138", + "name" : "Recommendation PA166298138", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -65727,12 +65610,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -65740,27 +65623,27 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060653, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060740, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298183", - "name" : "Recommendation PA166298183", - "alternateDrugAvailable" : true, + "id" : "PA166298118", + "name" : "Recommendation PA166298118", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -65770,12 +65653,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -65783,21 +65666,21 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060785, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060720, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -65826,27 +65709,27 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { "id" : 1452060741, "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297996", - "name" : "Recommendation PA166297996", - "alternateDrugAvailable" : true, + "id" : "PA166298119", + "name" : "Recommendation PA166298119", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -65856,12 +65739,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: n/a", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -65869,42 +65752,42 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060598, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060721, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298086", - "name" : "Recommendation PA166298086", + "id" : "PA166298108", + "name" : "Recommendation PA166298108", "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: n/a", "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -65912,42 +65795,42 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060688, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060710, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297983", - "name" : "Recommendation PA166297983", + "id" : "PA166298107", + "name" : "Recommendation PA166298107", "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: n/a", "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -65955,42 +65838,42 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060585, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060709, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298104", - "name" : "Recommendation PA166298104", + "id" : "PA166298109", + "name" : "Recommendation PA166298109", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -65998,27 +65881,27 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060706, - "html" : "

No recommendation

\n", + "id" : 1452060711, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298037", - "name" : "Recommendation PA166298037", - "alternateDrugAvailable" : true, + "id" : "PA166298126", + "name" : "Recommendation PA166298126", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -66028,12 +65911,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -66041,27 +65924,27 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060639, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060728, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298081", - "name" : "Recommendation PA166298081", - "alternateDrugAvailable" : true, + "id" : "PA166298125", + "name" : "Recommendation PA166298125", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -66073,10 +65956,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -66084,26 +65967,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060683, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060727, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298169", - "name" : "Recommendation PA166298169", + "id" : "PA166298124", + "name" : "Recommendation PA166298124", "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, @@ -66116,10 +65999,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -66127,27 +66010,27 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060771, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452060726, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298121", - "name" : "Recommendation PA166298121", - "alternateDrugAvailable" : true, + "id" : "PA166298123", + "name" : "Recommendation PA166298123", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -66160,9 +66043,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -66170,27 +66053,27 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060723, - "html" : "

Avoid imipramine use. If a imipramine is warranted, consider a 50% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060725, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298024", - "name" : "Recommendation PA166298024", - "alternateDrugAvailable" : true, + "id" : "PA166298122", + "name" : "Recommendation PA166298122", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -66202,10 +66085,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -66213,26 +66096,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060626, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060724, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298134", - "name" : "Recommendation PA166298134", + "id" : "PA166298176", + "name" : "Recommendation PA166298176", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -66245,10 +66128,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -66256,26 +66139,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060736, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060778, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298015", - "name" : "Recommendation PA166298015", + "id" : "PA166298177", + "name" : "Recommendation PA166298177", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -66288,10 +66171,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", + "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -66299,26 +66182,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060617, - "html" : "

Avoid imipramine use; If imipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", + "id" : 1452060779, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298147", - "name" : "Recommendation PA166298147", + "id" : "PA166298178", + "name" : "Recommendation PA166298178", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -66331,10 +66214,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: n/a", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -66342,26 +66225,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060749, - "html" : "

Avoid imipramine use. If imipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060780, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297988", - "name" : "Recommendation PA166297988", + "id" : "PA166298179", + "name" : "Recommendation PA166298179", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -66374,10 +66257,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -66385,27 +66268,27 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060590, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060781, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298002", - "name" : "Recommendation PA166298002", - "alternateDrugAvailable" : false, + "id" : "PA166298180", + "name" : "Recommendation PA166298180", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -66417,10 +66300,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: n/a", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -66428,26 +66311,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060604, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452060782, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298094", - "name" : "Recommendation PA166298094", + "id" : "PA166298181", + "name" : "Recommendation PA166298181", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -66460,10 +66343,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -66471,26 +66354,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060696, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452060783, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298112", - "name" : "Recommendation PA166298112", + "id" : "PA166298182", + "name" : "Recommendation PA166298182", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -66506,7 +66389,7 @@ "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -66514,17 +66397,17 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060714, + "id" : 1452060784, "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, @@ -66532,38 +66415,51 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301405", - "name" : "Recommendation Annotation PA166301405", - "alternateDrugAvailable" : false, - "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "No Result"}, + "id" : "PA166298184", + "name" : "Recommendation PA166298184", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981565059, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "CYP2C19: n/a", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + ], + "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, + "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452095744, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "id" : 1452060786, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298033", - "name" : "Recommendation PA166298033", + "id" : "PA166298185", + "name" : "Recommendation PA166298185", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -66576,10 +66472,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: n/a", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -66587,26 +66483,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060635, - "html" : "

Avoid imipramine use. If imipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060787, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297979", - "name" : "Recommendation PA166297979", + "id" : "PA166298186", + "name" : "Recommendation PA166298186", "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, @@ -66617,12 +66513,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: n/a", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -66630,26 +66526,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060581, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060788, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298165", - "name" : "Recommendation PA166298165", + "id" : "PA166298183", + "name" : "Recommendation PA166298183", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -66662,10 +66558,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: n/a" + "CYP2C19: n/a", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -66673,42 +66569,42 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060767, - "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. For tertiary amines, consider a 50% reduction of the recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060785, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298068", - "name" : "Recommendation PA166298068", - "alternateDrugAvailable" : true, + "id" : "PA166298175", + "name" : "Recommendation PA166298175", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: n/a", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -66716,42 +66612,42 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060670, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452060777, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298020", - "name" : "Recommendation PA166298020", - "alternateDrugAvailable" : true, + "id" : "PA166298174", + "name" : "Recommendation PA166298174", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: n/a", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -66759,42 +66655,42 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060622, - "html" : "

Avoid imipramine use; If imipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", + "id" : 1452060776, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298130", - "name" : "Recommendation PA166298130", - "alternateDrugAvailable" : true, + "id" : "PA166298173", + "name" : "Recommendation PA166298173", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: n/a", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -66802,42 +66698,42 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060732, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060775, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298178", - "name" : "Recommendation PA166298178", - "alternateDrugAvailable" : true, + "id" : "PA166298172", + "name" : "Recommendation PA166298172", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -66845,42 +66741,42 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060780, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452060774, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298059", - "name" : "Recommendation PA166298059", - "alternateDrugAvailable" : true, + "id" : "PA166298171", + "name" : "Recommendation PA166298171", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: n/a", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -66888,27 +66784,27 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060661, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452060773, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298011", - "name" : "Recommendation PA166298011", - "alternateDrugAvailable" : true, + "id" : "PA166298170", + "name" : "Recommendation PA166298170", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -66920,10 +66816,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: n/a", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -66931,27 +66827,27 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060613, - "html" : "

Avoid imipramine use; If imipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", + "id" : 1452060772, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298143", - "name" : "Recommendation PA166298143", - "alternateDrugAvailable" : true, + "id" : "PA166298169", + "name" : "Recommendation PA166298169", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -66963,10 +66859,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: n/a", "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -66974,27 +66870,27 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060745, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060771, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298046", - "name" : "Recommendation PA166298046", - "alternateDrugAvailable" : true, + "id" : "PA166298167", + "name" : "Recommendation PA166298167", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -67006,10 +66902,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: n/a" + "CYP2C19: n/a", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -67017,26 +66913,146 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060648, - "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. For tertiary amines, consider a 50% reduction of the recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060769, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "version" : 0 + }, + "version" : 1 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166301421", + "name" : "Recommendation Annotation PA166301421", + "alternateDrugAvailable" : false, + "dosingInformation" : false, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Normal Metabolizer"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA449969", + "name" : "imipramine", + "version" : 46 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104999", + "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", + "version" : 136 + }, + "text" : { + "id" : 1452095760, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298090", - "name" : "Recommendation PA166298090", + "id" : "PA166301422", + "name" : "Recommendation Annotation PA166301422", + "alternateDrugAvailable" : false, + "dosingInformation" : false, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Poor Metabolizer"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA449969", + "name" : "imipramine", + "version" : 46 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104999", + "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", + "version" : 136 + }, + "text" : { + "id" : 1452095761, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166301423", + "name" : "Recommendation Annotation PA166301423", + "alternateDrugAvailable" : false, + "dosingInformation" : false, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Ultrarapid Metabolizer"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA449969", + "name" : "imipramine", + "version" : 46 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104999", + "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", + "version" : 136 + }, + "text" : { + "id" : 1452095762, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166301424", + "name" : "Recommendation Annotation PA166301424", + "alternateDrugAvailable" : false, + "dosingInformation" : false, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Rapid Metabolizer"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA449969", + "name" : "imipramine", + "version" : 46 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104999", + "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", + "version" : 136 + }, + "text" : { + "id" : 1452095763, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166297989", + "name" : "Recommendation PA166297989", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -67049,10 +67065,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -67060,26 +67076,26 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060692, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452060591, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298156", - "name" : "Recommendation PA166298156", + "id" : "PA166298088", + "name" : "Recommendation PA166298088", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -67092,10 +67108,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -67103,21 +67119,21 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104999", "name" : "Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6", - "version" : 48 + "version" : 136 }, "text" : { - "id" : 1452060758, - "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452060690, + "html" : "

Avoid imipramine use; If imipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166104999" @@ -67240,7 +67256,7 @@ "date" : "2016-05-10T14:57:16.865-07:00", "description" : "Guideline on PharmGKB updated due to changes to the FDA-approved label for ivacaftor", "type" : "Update", - "version" : 0 + "version" : 1 }, { "id" : 1448624943, @@ -67254,7 +67270,7 @@ "date" : "2018-06-14T00:00:00-07:00", "description" : "Added guideline video.", "type" : "Update", - "version" : 0 + "version" : 1 }, { "id" : 1449717117, @@ -67304,7 +67320,7 @@ "id" : "PA166164959", "symbol" : "rs11971167", "name" : "rs11971167", - "version" : 6 + "version" : 8 }, { "objCls" : "Variant", @@ -67325,21 +67341,21 @@ "id" : "PA166157529", "symbol" : "rs121908755", "name" : "rs121908755", - "version" : 5 + "version" : 8 }, { "objCls" : "Variant", "id" : "PA166157530", "symbol" : "rs121908757", "name" : "rs121908757", - "version" : 5 + "version" : 6 }, { "objCls" : "Variant", "id" : "PA166157532", "symbol" : "rs121909013", "name" : "rs121909013", - "version" : 5 + "version" : 6 }, { "objCls" : "Variant", @@ -67353,7 +67369,7 @@ "id" : "PA166157533", "symbol" : "rs121909041", "name" : "rs121909041", - "version" : 5 + "version" : 6 }, { "objCls" : "Variant", @@ -67381,7 +67397,7 @@ "id" : "PA166157534", "symbol" : "rs193922525", "name" : "rs193922525", - "version" : 5 + "version" : 6 }, { "objCls" : "Variant", @@ -67395,7 +67411,7 @@ "id" : "PA166157537", "symbol" : "rs267606723", "name" : "rs267606723", - "version" : 6 + "version" : 7 }, { "objCls" : "Variant", @@ -67451,21 +67467,21 @@ "id" : "PA166157511", "symbol" : "rs74503330", "name" : "rs74503330", - "version" : 5 + "version" : 6 }, { "objCls" : "Variant", "id" : "PA166162705", "symbol" : "rs74551128", "name" : "rs74551128", - "version" : 5 + "version" : 6 }, { "objCls" : "Variant", "id" : "PA166157516", "symbol" : "rs75527207", "name" : "rs75527207", - "version" : 5 + "version" : 6 }, { "objCls" : "Variant", @@ -67507,7 +67523,7 @@ "id" : "PA166157521", "symbol" : "rs80282562", "name" : "rs80282562", - "version" : 5 + "version" : 6 } ], "relatedChemicals" : [ @@ -67515,7 +67531,7 @@ "objCls" : "Chemical", "id" : "PA165950341", "name" : "ivacaftor", - "version" : 6 + "version" : 16 } ], "relatedGenes" : [ @@ -67524,14 +67540,14 @@ "id" : "PA109", "symbol" : "CFTR", "name" : "cystic fibrosis transmembrane conductance regulator", - "version" : 18 + "version" : 5399 } ], "source" : "CPIC", "summaryMarkdown" : { "id" : 1447981606, "html" : "

Ivacaftor treatment is recommended only in cystic fibrosis (CF) patients that are either homozygous or heterozygous for certain CFTR variants. See full guideline for disclaimers, further details and supporting evidence.

\n", - "version" : 0 + "version" : 1 }, "terms" : [], "textMarkdown" : { @@ -67540,7 +67556,7 @@ "version" : 0 }, "userId" : "rachel", - "version" : 62 + "version" : 285 }, "recommendations" : [ { @@ -67569,21 +67585,21 @@ "objCls" : "Chemical", "id" : "PA165950341", "name" : "ivacaftor", - "version" : 6 + "version" : 16 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166114461", "name" : "Annotation of CPIC Guideline for ivacaftor and CFTR", - "version" : 62 + "version" : 285 }, "text" : { "id" : 1452060790, "html" : "

Use ivacaftor according to the product label

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -67611,14 +67627,14 @@ "objCls" : "Chemical", "id" : "PA165950341", "name" : "ivacaftor", - "version" : 6 + "version" : 16 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166114461", "name" : "Annotation of CPIC Guideline for ivacaftor and CFTR", - "version" : 62 + "version" : 285 }, "text" : { "id" : 1452060789, @@ -67770,19 +67786,19 @@ "objCls" : "Chemical", "id" : "PA450180", "name" : "lansoprazole", - "version" : 16 + "version" : 40 }, { "objCls" : "Chemical", "id" : "PA450704", "name" : "omeprazole", - "version" : 21 + "version" : 52 }, { "objCls" : "Chemical", "id" : "PA450774", "name" : "pantoprazole", - "version" : 15 + "version" : 37 } ], "relatedGenes" : [ @@ -67791,14 +67807,14 @@ "id" : "PA124", "symbol" : "CYP2C19", "name" : "cytochrome P450 family 2 subfamily C member 19", - "version" : 7210 + "version" : 7266 } ], "source" : "CPIC", "summaryMarkdown" : { "id" : 1451226172, "html" : "

The CPIC Dosing Guideline for omeprazole, lansoprazole, pantoprazole recommends to increase the starting daily dose and to monitor efficacy in CYP2C19 ultrarapid metabolizer. For CYP2C19 rapid and normal metabolizers in the treatment of H. pylori infection and erosive esophagitis increasing the dose might be considered after initiation with the standard starting daily dose. The recommendations for intermediate and poor metabolizer for chronic therapy (>12 weeks) and efficacy achieved is to consider 50% reduction in daily dose. See full guideline for further details and supporting evidence.

\n", - "version" : 0 + "version" : 1 }, "terms" : [], "textMarkdown" : { @@ -67807,55 +67823,55 @@ "version" : 2 }, "userId" : "katrin", - "version" : 8 + "version" : 41 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166298272", - "name" : "Recommendation PA166298272", + "id" : "PA166298284", + "name" : "Recommendation PA166298284", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Normal PPI metabolism; may be at increased risk of therapeutic failure compared to CYP2C19 IMs and PMs" + "CYP2C19: n/a" ], - "lookupKey" : {"CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA450704", - "name" : "omeprazole", - "version" : 21 + "id" : "PA450180", + "name" : "lansoprazole", + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166219103", "name" : "Annotation of CPIC Guideline for lansoprazole, omeprazole, pantoprazole and CYP2C19", - "version" : 8 + "version" : 41 }, "text" : { - "id" : 1452060874, - "html" : "

Initiate standard starting daily dose. Consider increasing dose by 50-100% for the treatment of H. pylori infection and erosive esophagitis. Daily dose may be given in divided doses.\nMonitor for efficacy.

\n", + "id" : 1452060886, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298285", - "name" : "Recommendation PA166298285", + "id" : "PA166297992", + "name" : "Recommendation PA166297992", "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, @@ -67868,9 +67884,9 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Decreased plasma concentrations of PPIs compared to CYP2C19 NMs; increased risk of therapeutic failure" + "CYP2C19: Increased plasma concentration of PPI compared to CYP2C19 NMs; increased chance of efficacy and potentially toxicity" ], - "lookupKey" : {"CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -67878,68 +67894,68 @@ "objCls" : "Chemical", "id" : "PA450774", "name" : "pantoprazole", - "version" : 15 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166219103", "name" : "Annotation of CPIC Guideline for lansoprazole, omeprazole, pantoprazole and CYP2C19", - "version" : 8 + "version" : 41 }, "text" : { - "id" : 1452060887, - "html" : "

Increase starting daily dose by 100%. Daily dose may be given in divided doses. Monitor for efficacy.

\n", + "id" : 1452060594, + "html" : "

Initiate standard starting daily dose. For chronic therapy (>12 weeks) and efficacy achieved, consider 50% reduction in daily dose and monitor for continued efficacy.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298290", - "name" : "Recommendation PA166298290", + "id" : "PA166298263", + "name" : "Recommendation PA166298263", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased plasma concentration of PPI compared to CYP2C19 NMs; increased chance of efficacy and potentially toxicity" + "CYP2C19: Likely increased plasma concentration of PPI compared to CYP2C19 NMs; likely increased chance of efficacy and potentially toxicity" ], - "lookupKey" : {"CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA450774", - "name" : "pantoprazole", - "version" : 15 + "id" : "PA450704", + "name" : "omeprazole", + "version" : 52 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166219103", "name" : "Annotation of CPIC Guideline for lansoprazole, omeprazole, pantoprazole and CYP2C19", - "version" : 8 + "version" : 41 }, "text" : { - "id" : 1452060892, - "html" : "

Initiate standard starting daily dose. For chronic therapy (>12 weeks) and efficacy achieved, consider 50% reduction in daily dose and monitor for continued efficacy.

\n", + "id" : 1452060865, + "html" : "

Initiate standard starting daily dose. For chronic therapy (>12 weeks) and efficacy achieved, consider 50% reduction in daily dose and monitor for continued efficacy.

\n

Other Considerations

\n

The strength of recommendation for "likely" phenotypes are the same as their respective confirmed phenotypes. "Likely" indicates the uncertainty in the phenotype assignment, but it is reasonable to apply the recommendation for the confirmed phenotype to the corresponding "likely" phenotype.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298281", - "name" : "Recommendation PA166298281", + "id" : "PA166298270", + "name" : "Recommendation PA166298270", "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, @@ -67952,51 +67968,51 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased plasma concentration of PPI compared to CYP2C19 NMs; increased chance of efficacy and potentially toxicity" + "CYP2C19: Decreased plasma concentrations of PPIs compared to CYP2C19 NMs; increased risk of therapeutic failure" ], - "lookupKey" : {"CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA450180", - "name" : "lansoprazole", - "version" : 16 + "id" : "PA450704", + "name" : "omeprazole", + "version" : 52 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166219103", "name" : "Annotation of CPIC Guideline for lansoprazole, omeprazole, pantoprazole and CYP2C19", - "version" : 8 + "version" : 41 }, "text" : { - "id" : 1452060883, - "html" : "

Initiate standard starting daily dose. For chronic therapy (>12 weeks) and efficacy achieved, consider 50% reduction in daily dose and monitor for continued efficacy.

\n", + "id" : 1452060872, + "html" : "

Increase starting daily dose by 100%. Daily dose may be given in divided doses. Monitor for efficacy.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298263", - "name" : "Recommendation PA166298263", + "id" : "PA166298271", + "name" : "Recommendation PA166298271", "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Likely increased plasma concentration of PPI compared to CYP2C19 NMs; likely increased chance of efficacy and potentially toxicity" + "CYP2C19: Decreased plasma concentrations of PPIs compared to CYP2C19 NMs; increased risk of therapeutic failure" ], - "lookupKey" : {"CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -68004,41 +68020,41 @@ "objCls" : "Chemical", "id" : "PA450704", "name" : "omeprazole", - "version" : 21 + "version" : 52 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166219103", "name" : "Annotation of CPIC Guideline for lansoprazole, omeprazole, pantoprazole and CYP2C19", - "version" : 8 + "version" : 41 }, "text" : { - "id" : 1452060865, - "html" : "

Initiate standard starting daily dose. For chronic therapy (>12 weeks) and efficacy achieved, consider 50% reduction in daily dose and monitor for continued efficacy.

\n

Other Considerations

\n

The strength of recommendation for "likely" phenotypes are the same as their respective confirmed phenotypes. "Likely" indicates the uncertainty in the phenotype assignment, but it is reasonable to apply the recommendation for the confirmed phenotype to the corresponding "likely" phenotype.

\n", + "id" : 1452060873, + "html" : "

Initiate standard starting daily dose. Consider increasing dose by 50-100% for the treatment of H. pylori infection and erosive esophagitis. Daily dose may be given in divided doses.\nMonitor for efficacy.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298276", - "name" : "Recommendation PA166298276", + "id" : "PA166298272", + "name" : "Recommendation PA166298272", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a" + "CYP2C19: Normal PPI metabolism; may be at increased risk of therapeutic failure compared to CYP2C19 IMs and PMs" ], - "lookupKey" : {"CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -68046,68 +68062,68 @@ "objCls" : "Chemical", "id" : "PA450704", "name" : "omeprazole", - "version" : 21 + "version" : 52 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166219103", "name" : "Annotation of CPIC Guideline for lansoprazole, omeprazole, pantoprazole and CYP2C19", - "version" : 8 + "version" : 41 }, "text" : { - "id" : 1452060878, - "html" : "

No recommendation

\n", + "id" : 1452060874, + "html" : "

Initiate standard starting daily dose. Consider increasing dose by 50-100% for the treatment of H. pylori infection and erosive esophagitis. Daily dose may be given in divided doses.\nMonitor for efficacy.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298289", - "name" : "Recommendation PA166298289", + "id" : "PA166298273", + "name" : "Recommendation PA166298273", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Likely increased plasma concentration of PPI compared to CYP2C19 NMs; likely increased chance of efficacy and potentially toxicity" + "CYP2C19: Increased plasma concentration of PPI compared to CYP2C19 NMs; increased chance of efficacy and potentially toxicity" ], - "lookupKey" : {"CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA450774", - "name" : "pantoprazole", - "version" : 15 + "id" : "PA450704", + "name" : "omeprazole", + "version" : 52 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166219103", "name" : "Annotation of CPIC Guideline for lansoprazole, omeprazole, pantoprazole and CYP2C19", - "version" : 8 + "version" : 41 }, "text" : { - "id" : 1452060891, - "html" : "

Initiate standard starting daily dose. For chronic therapy (>12 weeks) and efficacy achieved, consider 50% reduction in daily dose and monitor for continued efficacy.

\n

Other Considerations

\n

The strength of recommendation for "likely" phenotypes are the same as their respective confirmed phenotypes. "Likely" indicates the uncertainty in the phenotype assignment, but it is reasonable to apply the recommendation for the confirmed phenotype to the corresponding "likely" phenotype.

\n", + "id" : 1452060875, + "html" : "

Initiate standard starting daily dose. For chronic therapy (>12 weeks) and efficacy achieved, consider 50% reduction in daily dose and monitor for continued efficacy.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298282", - "name" : "Recommendation PA166298282", + "id" : "PA166298274", + "name" : "Recommendation PA166298274", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -68128,19 +68144,19 @@ "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA450180", - "name" : "lansoprazole", - "version" : 16 + "id" : "PA450704", + "name" : "omeprazole", + "version" : 52 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166219103", "name" : "Annotation of CPIC Guideline for lansoprazole, omeprazole, pantoprazole and CYP2C19", - "version" : 8 + "version" : 41 }, "text" : { - "id" : 1452060884, + "id" : 1452060876, "html" : "

Initiate standard starting daily dose. For chronic therapy (>12 weeks) and efficacy achieved, consider 50% reduction in daily dose and monitor for continued efficacy.

\n

Other Considerations

\n

The strength of recommendation for "likely" phenotypes are the same as their respective confirmed phenotypes. "Likely" indicates the uncertainty in the phenotype assignment, but it is reasonable to apply the recommendation for the confirmed phenotype to the corresponding "likely" phenotype.

\n", "version" : 0 }, @@ -68148,15 +68164,15 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298273", - "name" : "Recommendation PA166298273", + "id" : "PA166298275", + "name" : "Recommendation PA166298275", "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, @@ -68164,7 +68180,7 @@ "implications" : [ "CYP2C19: Increased plasma concentration of PPI compared to CYP2C19 NMs; increased chance of efficacy and potentially toxicity" ], - "lookupKey" : {"CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -68172,17 +68188,17 @@ "objCls" : "Chemical", "id" : "PA450704", "name" : "omeprazole", - "version" : 21 + "version" : 52 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166219103", "name" : "Annotation of CPIC Guideline for lansoprazole, omeprazole, pantoprazole and CYP2C19", - "version" : 8 + "version" : 41 }, "text" : { - "id" : 1452060875, + "id" : 1452060877, "html" : "

Initiate standard starting daily dose. For chronic therapy (>12 weeks) and efficacy achieved, consider 50% reduction in daily dose and monitor for continued efficacy.

\n", "version" : 0 }, @@ -68190,50 +68206,50 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298291", - "name" : "Recommendation PA166298291", + "id" : "PA166298277", + "name" : "Recommendation PA166298277", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a" + "CYP2C19: Decreased plasma concentrations of PPIs compared to CYP2C19 NMs; increased risk of therapeutic failure" ], - "lookupKey" : {"CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA450774", - "name" : "pantoprazole", - "version" : 15 + "id" : "PA450180", + "name" : "lansoprazole", + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166219103", "name" : "Annotation of CPIC Guideline for lansoprazole, omeprazole, pantoprazole and CYP2C19", - "version" : 8 + "version" : 41 }, "text" : { - "id" : 1452060893, - "html" : "

No recommendation

\n", + "id" : 1452060879, + "html" : "

Increase starting daily dose by 100%. Daily dose may be given in divided doses. Monitor for efficacy.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298286", - "name" : "Recommendation PA166298286", + "id" : "PA166298278", + "name" : "Recommendation PA166298278", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -68254,19 +68270,19 @@ "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA450774", - "name" : "pantoprazole", - "version" : 15 + "id" : "PA450180", + "name" : "lansoprazole", + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166219103", "name" : "Annotation of CPIC Guideline for lansoprazole, omeprazole, pantoprazole and CYP2C19", - "version" : 8 + "version" : 41 }, "text" : { - "id" : 1452060888, + "id" : 1452060880, "html" : "

Initiate standard starting daily dose. Consider increasing dose by 50-100% for the treatment of H. pylori infection and erosive esophagitis. Daily dose may be given in divided doses.\nMonitor for efficacy.

\n", "version" : 0 }, @@ -68274,23 +68290,23 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298277", - "name" : "Recommendation PA166298277", + "id" : "PA166298279", + "name" : "Recommendation PA166298279", "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Decreased plasma concentrations of PPIs compared to CYP2C19 NMs; increased risk of therapeutic failure" + "CYP2C19: Normal PPI metabolism; may be at increased risk of therapeutic failure compared to CYP2C19 IMs and PMs" ], - "lookupKey" : {"CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -68298,26 +68314,26 @@ "objCls" : "Chemical", "id" : "PA450180", "name" : "lansoprazole", - "version" : 16 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166219103", "name" : "Annotation of CPIC Guideline for lansoprazole, omeprazole, pantoprazole and CYP2C19", - "version" : 8 + "version" : 41 }, "text" : { - "id" : 1452060879, - "html" : "

Increase starting daily dose by 100%. Daily dose may be given in divided doses. Monitor for efficacy.

\n", + "id" : 1452060881, + "html" : "

Initiate standard starting daily dose. Consider increasing dose by 50-100% for the treatment of H. pylori infection and erosive esophagitis. Daily dose may be given in divided doses.\nMonitor for efficacy.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298270", - "name" : "Recommendation PA166298270", + "id" : "PA166298280", + "name" : "Recommendation PA166298280", "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, @@ -68330,43 +68346,43 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Decreased plasma concentrations of PPIs compared to CYP2C19 NMs; increased risk of therapeutic failure" + "CYP2C19: Likely increased plasma concentration of PPI compared to CYP2C19 NMs; likely increased chance of efficacy and potentially toxicity" ], - "lookupKey" : {"CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA450704", - "name" : "omeprazole", - "version" : 21 + "id" : "PA450180", + "name" : "lansoprazole", + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166219103", "name" : "Annotation of CPIC Guideline for lansoprazole, omeprazole, pantoprazole and CYP2C19", - "version" : 8 + "version" : 41 }, "text" : { - "id" : 1452060872, - "html" : "

Increase starting daily dose by 100%. Daily dose may be given in divided doses. Monitor for efficacy.

\n", + "id" : 1452060882, + "html" : "

Initiate standard starting daily dose. For chronic therapy (>12 weeks) and efficacy achieved, consider 50% reduction in daily dose and monitor for continued efficacy.

\n

Other Considerations

\n

The strength of recommendation for "likely" phenotypes are the same as their respective confirmed phenotypes. "Likely" indicates the uncertainty in the phenotype assignment, but it is reasonable to apply the recommendation for the confirmed phenotype to the corresponding "likely" phenotype.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298283", - "name" : "Recommendation PA166298283", + "id" : "PA166298281", + "name" : "Recommendation PA166298281", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, @@ -68374,7 +68390,7 @@ "implications" : [ "CYP2C19: Increased plasma concentration of PPI compared to CYP2C19 NMs; increased chance of efficacy and potentially toxicity" ], - "lookupKey" : {"CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -68382,17 +68398,17 @@ "objCls" : "Chemical", "id" : "PA450180", "name" : "lansoprazole", - "version" : 16 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166219103", "name" : "Annotation of CPIC Guideline for lansoprazole, omeprazole, pantoprazole and CYP2C19", - "version" : 8 + "version" : 41 }, "text" : { - "id" : 1452060885, + "id" : 1452060883, "html" : "

Initiate standard starting daily dose. For chronic therapy (>12 weeks) and efficacy achieved, consider 50% reduction in daily dose and monitor for continued efficacy.

\n", "version" : 0 }, @@ -68400,8 +68416,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298278", - "name" : "Recommendation PA166298278", + "id" : "PA166298282", + "name" : "Recommendation PA166298282", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -68414,9 +68430,9 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Decreased plasma concentrations of PPIs compared to CYP2C19 NMs; increased risk of therapeutic failure" + "CYP2C19: Likely increased plasma concentration of PPI compared to CYP2C19 NMs; likely increased chance of efficacy and potentially toxicity" ], - "lookupKey" : {"CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -68424,26 +68440,26 @@ "objCls" : "Chemical", "id" : "PA450180", "name" : "lansoprazole", - "version" : 16 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166219103", "name" : "Annotation of CPIC Guideline for lansoprazole, omeprazole, pantoprazole and CYP2C19", - "version" : 8 + "version" : 41 }, "text" : { - "id" : 1452060880, - "html" : "

Initiate standard starting daily dose. Consider increasing dose by 50-100% for the treatment of H. pylori infection and erosive esophagitis. Daily dose may be given in divided doses.\nMonitor for efficacy.

\n", + "id" : 1452060884, + "html" : "

Initiate standard starting daily dose. For chronic therapy (>12 weeks) and efficacy achieved, consider 50% reduction in daily dose and monitor for continued efficacy.

\n

Other Considerations

\n

The strength of recommendation for "likely" phenotypes are the same as their respective confirmed phenotypes. "Likely" indicates the uncertainty in the phenotype assignment, but it is reasonable to apply the recommendation for the confirmed phenotype to the corresponding "likely" phenotype.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298274", - "name" : "Recommendation PA166298274", + "id" : "PA166298283", + "name" : "Recommendation PA166298283", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -68456,51 +68472,51 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Likely increased plasma concentration of PPI compared to CYP2C19 NMs; likely increased chance of efficacy and potentially toxicity" + "CYP2C19: Increased plasma concentration of PPI compared to CYP2C19 NMs; increased chance of efficacy and potentially toxicity" ], - "lookupKey" : {"CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA450704", - "name" : "omeprazole", - "version" : 21 + "id" : "PA450180", + "name" : "lansoprazole", + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166219103", "name" : "Annotation of CPIC Guideline for lansoprazole, omeprazole, pantoprazole and CYP2C19", - "version" : 8 + "version" : 41 }, "text" : { - "id" : 1452060876, - "html" : "

Initiate standard starting daily dose. For chronic therapy (>12 weeks) and efficacy achieved, consider 50% reduction in daily dose and monitor for continued efficacy.

\n

Other Considerations

\n

The strength of recommendation for "likely" phenotypes are the same as their respective confirmed phenotypes. "Likely" indicates the uncertainty in the phenotype assignment, but it is reasonable to apply the recommendation for the confirmed phenotype to the corresponding "likely" phenotype.

\n", + "id" : 1452060885, + "html" : "

Initiate standard starting daily dose. For chronic therapy (>12 weeks) and efficacy achieved, consider 50% reduction in daily dose and monitor for continued efficacy.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298287", - "name" : "Recommendation PA166298287", + "id" : "PA166298285", + "name" : "Recommendation PA166298285", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal PPI metabolism; may be at increased risk of therapeutic failure compared to CYP2C19 IMs and PMs" + "CYP2C19: Decreased plasma concentrations of PPIs compared to CYP2C19 NMs; increased risk of therapeutic failure" ], - "lookupKey" : {"CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -68508,26 +68524,26 @@ "objCls" : "Chemical", "id" : "PA450774", "name" : "pantoprazole", - "version" : 15 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166219103", "name" : "Annotation of CPIC Guideline for lansoprazole, omeprazole, pantoprazole and CYP2C19", - "version" : 8 + "version" : 41 }, "text" : { - "id" : 1452060889, - "html" : "

Initiate standard starting daily dose. Consider increasing dose by 50-100% for the treatment of H. pylori infection and erosive esophagitis. Daily dose may be given in divided doses.\nMonitor for efficacy.

\n", + "id" : 1452060887, + "html" : "

Increase starting daily dose by 100%. Daily dose may be given in divided doses. Monitor for efficacy.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298271", - "name" : "Recommendation PA166298271", + "id" : "PA166298286", + "name" : "Recommendation PA166298286", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -68548,19 +68564,19 @@ "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA450704", - "name" : "omeprazole", - "version" : 21 + "id" : "PA450774", + "name" : "pantoprazole", + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166219103", "name" : "Annotation of CPIC Guideline for lansoprazole, omeprazole, pantoprazole and CYP2C19", - "version" : 8 + "version" : 41 }, "text" : { - "id" : 1452060873, + "id" : 1452060888, "html" : "

Initiate standard starting daily dose. Consider increasing dose by 50-100% for the treatment of H. pylori infection and erosive esophagitis. Daily dose may be given in divided doses.\nMonitor for efficacy.

\n", "version" : 0 }, @@ -68568,23 +68584,23 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297992", - "name" : "Recommendation PA166297992", + "id" : "PA166298287", + "name" : "Recommendation PA166298287", "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased plasma concentration of PPI compared to CYP2C19 NMs; increased chance of efficacy and potentially toxicity" + "CYP2C19: Normal PPI metabolism; may be at increased risk of therapeutic failure compared to CYP2C19 IMs and PMs" ], - "lookupKey" : {"CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -68592,75 +68608,75 @@ "objCls" : "Chemical", "id" : "PA450774", "name" : "pantoprazole", - "version" : 15 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166219103", "name" : "Annotation of CPIC Guideline for lansoprazole, omeprazole, pantoprazole and CYP2C19", - "version" : 8 + "version" : 41 }, "text" : { - "id" : 1452060594, - "html" : "

Initiate standard starting daily dose. For chronic therapy (>12 weeks) and efficacy achieved, consider 50% reduction in daily dose and monitor for continued efficacy.

\n", + "id" : 1452060889, + "html" : "

Initiate standard starting daily dose. Consider increasing dose by 50-100% for the treatment of H. pylori infection and erosive esophagitis. Daily dose may be given in divided doses.\nMonitor for efficacy.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298284", - "name" : "Recommendation PA166298284", + "id" : "PA166298288", + "name" : "Recommendation PA166298288", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a" + "CYP2C19: Likely increased plasma concentration of PPI compared to CYP2C19 NMs; likely increased chance of efficacy and potentially toxicity" ], - "lookupKey" : {"CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA450180", - "name" : "lansoprazole", - "version" : 16 + "id" : "PA450774", + "name" : "pantoprazole", + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166219103", "name" : "Annotation of CPIC Guideline for lansoprazole, omeprazole, pantoprazole and CYP2C19", - "version" : 8 + "version" : 41 }, "text" : { - "id" : 1452060886, - "html" : "

No recommendation

\n", + "id" : 1452060890, + "html" : "

Initiate standard starting daily dose. For chronic therapy (>12 weeks) and efficacy achieved, consider 50% reduction in daily dose and monitor for continued efficacy.

\n

Other Considerations

\n

The strength of recommendation for "likely" phenotypes are the same as their respective confirmed phenotypes. "Likely" indicates the uncertainty in the phenotype assignment, but it is reasonable to apply the recommendation for the confirmed phenotype to the corresponding "likely" phenotype.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298280", - "name" : "Recommendation PA166298280", + "id" : "PA166298289", + "name" : "Recommendation PA166298289", "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, @@ -68668,25 +68684,25 @@ "implications" : [ "CYP2C19: Likely increased plasma concentration of PPI compared to CYP2C19 NMs; likely increased chance of efficacy and potentially toxicity" ], - "lookupKey" : {"CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA450180", - "name" : "lansoprazole", - "version" : 16 + "id" : "PA450774", + "name" : "pantoprazole", + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166219103", "name" : "Annotation of CPIC Guideline for lansoprazole, omeprazole, pantoprazole and CYP2C19", - "version" : 8 + "version" : 41 }, "text" : { - "id" : 1452060882, + "id" : 1452060891, "html" : "

Initiate standard starting daily dose. For chronic therapy (>12 weeks) and efficacy achieved, consider 50% reduction in daily dose and monitor for continued efficacy.

\n

Other Considerations

\n

The strength of recommendation for "likely" phenotypes are the same as their respective confirmed phenotypes. "Likely" indicates the uncertainty in the phenotype assignment, but it is reasonable to apply the recommendation for the confirmed phenotype to the corresponding "likely" phenotype.

\n", "version" : 0 }, @@ -68694,8 +68710,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298279", - "name" : "Recommendation PA166298279", + "id" : "PA166298290", + "name" : "Recommendation PA166298290", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -68708,51 +68724,51 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal PPI metabolism; may be at increased risk of therapeutic failure compared to CYP2C19 IMs and PMs" + "CYP2C19: Increased plasma concentration of PPI compared to CYP2C19 NMs; increased chance of efficacy and potentially toxicity" ], - "lookupKey" : {"CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA450180", - "name" : "lansoprazole", - "version" : 16 + "id" : "PA450774", + "name" : "pantoprazole", + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166219103", "name" : "Annotation of CPIC Guideline for lansoprazole, omeprazole, pantoprazole and CYP2C19", - "version" : 8 + "version" : 41 }, "text" : { - "id" : 1452060881, - "html" : "

Initiate standard starting daily dose. Consider increasing dose by 50-100% for the treatment of H. pylori infection and erosive esophagitis. Daily dose may be given in divided doses.\nMonitor for efficacy.

\n", + "id" : 1452060892, + "html" : "

Initiate standard starting daily dose. For chronic therapy (>12 weeks) and efficacy achieved, consider 50% reduction in daily dose and monitor for continued efficacy.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298275", - "name" : "Recommendation PA166298275", + "id" : "PA166298276", + "name" : "Recommendation PA166298276", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Increased plasma concentration of PPI compared to CYP2C19 NMs; increased chance of efficacy and potentially toxicity" + "CYP2C19: n/a" ], - "lookupKey" : {"CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -68760,41 +68776,41 @@ "objCls" : "Chemical", "id" : "PA450704", "name" : "omeprazole", - "version" : 21 + "version" : 52 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166219103", "name" : "Annotation of CPIC Guideline for lansoprazole, omeprazole, pantoprazole and CYP2C19", - "version" : 8 + "version" : 41 }, "text" : { - "id" : 1452060877, - "html" : "

Initiate standard starting daily dose. For chronic therapy (>12 weeks) and efficacy achieved, consider 50% reduction in daily dose and monitor for continued efficacy.

\n", + "id" : 1452060878, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298288", - "name" : "Recommendation PA166298288", + "id" : "PA166298291", + "name" : "Recommendation PA166298291", "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Likely increased plasma concentration of PPI compared to CYP2C19 NMs; likely increased chance of efficacy and potentially toxicity" + "CYP2C19: n/a" ], - "lookupKey" : {"CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -68802,21 +68818,21 @@ "objCls" : "Chemical", "id" : "PA450774", "name" : "pantoprazole", - "version" : 15 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166219103", "name" : "Annotation of CPIC Guideline for lansoprazole, omeprazole, pantoprazole and CYP2C19", - "version" : 8 + "version" : 41 }, "text" : { - "id" : 1452060890, - "html" : "

Initiate standard starting daily dose. For chronic therapy (>12 weeks) and efficacy achieved, consider 50% reduction in daily dose and monitor for continued efficacy.

\n

Other Considerations

\n

The strength of recommendation for "likely" phenotypes are the same as their respective confirmed phenotypes. "Likely" indicates the uncertainty in the phenotype assignment, but it is reasonable to apply the recommendation for the confirmed phenotype to the corresponding "likely" phenotype.

\n", + "id" : 1452060893, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166219103" @@ -68978,14 +68994,14 @@ "id" : "PA165819265", "symbol" : "SLCO1B1*15", "name" : "*15", - "version" : 23 + "version" : 39 }, { "objCls" : "Haplotype", "id" : "PA165819255", "symbol" : "SLCO1B1*5", "name" : "*5", - "version" : 23 + "version" : 39 } ], "relatedChemicals" : [ @@ -68993,7 +69009,7 @@ "objCls" : "Chemical", "id" : "PA450272", "name" : "lovastatin", - "version" : 21 + "version" : 46 } ], "relatedGenes" : [ @@ -69002,7 +69018,7 @@ "id" : "PA134865839", "symbol" : "SLCO1B1", "name" : "solute carrier organic anion transporter family member 1B1", - "version" : 49 + "version" : 109 } ], "source" : "CPIC", @@ -69015,31 +69031,31 @@ "textMarkdown" : { "id" : 1451668781, "html" : "

This annotation is based on the CPIC® guideline for SLCO1B1, ABCG2, and CYP2C9 and statin-associated musculoskeletal symptoms.

\n

February 2022

\n\n\n

Adapted from Table 1 and 2 of the 2022 guideline update manuscript.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
PhenotypeGenotypeExamples of diplotypes aImplications for lovastatinDosing recommendations for lovastatin b,cClassification of recommendations d
Normal functionAn individual carrying two normal function alleles or one normal plus one increased function allele*1/*1, *1/*14Typical myopathy risk and statin exposurePrescribe desired starting dose and adjust doses based on disease-specific guidelines.Strong
Increased functionAn individual carrying two increased function alleles*14/*14Typical myopathy risk and statin exposurePrescribe desired starting dose and adjust doses based on disease-specific guidelines.Strong
Decreased functionAn individual carrying one normal or increased function allele plus one no function allele*1/*5, *1/*15Increased lovastatin acid exposure as compared to normal function which may translate to increased myopathy riskPrescribe an alternative statin depending on the desired potency (see Figure 1 for recommendations for alternative statins). If lovastatin therapy is warranted, limit dose to ≤20mg/day.Moderate
Possible decreased functionAn individual carrying one no function allele plus one uncertain/unknown function allele*5/*6, *15/*10, *5/*43Increased lovastatin acid exposure as compared to normal function which may translate to increased myopathy riskPrescribe an alternative statin depending on the desired potency (see Figure 1 for recommendations for alternative statins). If lovastatin therapy is warranted, limit dose to ≤20mg/day.Moderate
Poor functionAn individual carrying two no function alleles*5/*5, *5/*15, *15/*15Increased lovastatin acid exposure as compared to normal and decreased function which may translate to increased myopathy riskPrescribe an alternative statin depending on the desired potency (see Figure 1 for recommendations for alternative statins).Moderate
IndeterminateAn individual carrying one normal function allele plus one uncertain or unknown function allele OR allele combinations with uncertain and/or unknown function alleles*1/*7, *1/*10, *7/*10n/aNo recommendation.No recommendation.
\n

Figure 1 : SLCO1B1 recommendations with intensity and statin dose stratified by SLCO1B1 phenotype; all doses assume adult dosing.

\n

Adapted from Figure 1 of the 2022 guideline manuscript

\n

\"Fig1\"

\n\n", - "version" : 3 + "version" : 9 }, "userId" : "lgong", - "version" : 5 + "version" : 21 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166298192", - "name" : "Recommendation PA166298192", + "id" : "PA166297982", + "name" : "Recommendation PA166297982", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "SLCO1B1: n/a" + "SLCO1B1: Typical myopathy risk and statin exposure" ], - "lookupKey" : {"SLCO1B1": "Indeterminate"}, + "lookupKey" : {"SLCO1B1": "Normal Function"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -69047,21 +69063,21 @@ "objCls" : "Chemical", "id" : "PA450272", "name" : "lovastatin", - "version" : 21 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262241", "name" : "Annotation of CPIC Guideline for lovastatin and SLCO1B1", - "version" : 5 + "version" : 21 }, "text" : { - "id" : 1452060794, - "html" : "

No recommendation

\n", + "id" : 1452060584, + "html" : "

Prescribe desired starting dose and adjust doses based on disease-specific guidelines.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and ancestry should be evaluated prior to initiating a statin.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -69089,26 +69105,26 @@ "objCls" : "Chemical", "id" : "PA450272", "name" : "lovastatin", - "version" : 21 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262241", "name" : "Annotation of CPIC Guideline for lovastatin and SLCO1B1", - "version" : 5 + "version" : 21 }, "text" : { "id" : 1452060750, "html" : "

Prescribe desired starting dose and adjust doses based on disease-specific guidelines.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and ancestry should be evaluated prior to initiating a statin.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298189", - "name" : "Recommendation PA166298189", + "id" : "PA166298190", + "name" : "Recommendation PA166298190", "alternateDrugAvailable" : true, "classification" : { "id" : 981501931, @@ -69123,7 +69139,7 @@ "implications" : [ "SLCO1B1: Increased lovastatin acid exposure as compared to normal function which may translate to increased myopathy risk" ], - "lookupKey" : {"SLCO1B1": "Possible Decreased Function"}, + "lookupKey" : {"SLCO1B1": "Decreased Function"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -69131,41 +69147,41 @@ "objCls" : "Chemical", "id" : "PA450272", "name" : "lovastatin", - "version" : 21 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262241", "name" : "Annotation of CPIC Guideline for lovastatin and SLCO1B1", - "version" : 5 + "version" : 21 }, "text" : { - "id" : 1452060791, + "id" : 1452060792, "html" : "

Prescribe an alternative statin depending on the desired potency (see Figure 1 of PMID: 35152405 for recommendations for alternative statins). If lovastatin therapy is warranted, limit dose to ≤20mg/day.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297982", - "name" : "Recommendation PA166297982", + "id" : "PA166298192", + "name" : "Recommendation PA166298192", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "SLCO1B1: Typical myopathy risk and statin exposure" + "SLCO1B1: n/a" ], - "lookupKey" : {"SLCO1B1": "Normal Function"}, + "lookupKey" : {"SLCO1B1": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -69173,26 +69189,26 @@ "objCls" : "Chemical", "id" : "PA450272", "name" : "lovastatin", - "version" : 21 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262241", "name" : "Annotation of CPIC Guideline for lovastatin and SLCO1B1", - "version" : 5 + "version" : 21 }, "text" : { - "id" : 1452060584, - "html" : "

Prescribe desired starting dose and adjust doses based on disease-specific guidelines.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and ancestry should be evaluated prior to initiating a statin.

\n", + "id" : 1452060794, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298190", - "name" : "Recommendation PA166298190", + "id" : "PA166298191", + "name" : "Recommendation PA166298191", "alternateDrugAvailable" : true, "classification" : { "id" : 981501931, @@ -69203,11 +69219,11 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "SLCO1B1: Increased lovastatin acid exposure as compared to normal function which may translate to increased myopathy risk" + "SLCO1B1: Increased lovastatin acid exposure as compared to normal and decreased function which may translate to increased myopathy risk" ], - "lookupKey" : {"SLCO1B1": "Decreased Function"}, + "lookupKey" : {"SLCO1B1": "Poor Function"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -69215,26 +69231,26 @@ "objCls" : "Chemical", "id" : "PA450272", "name" : "lovastatin", - "version" : 21 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262241", "name" : "Annotation of CPIC Guideline for lovastatin and SLCO1B1", - "version" : 5 + "version" : 21 }, "text" : { - "id" : 1452060792, - "html" : "

Prescribe an alternative statin depending on the desired potency (see Figure 1 of PMID: 35152405 for recommendations for alternative statins). If lovastatin therapy is warranted, limit dose to ≤20mg/day.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452060793, + "html" : "

Prescribe an alternative statin depending on the desired potency (see Figure 1 of PMID: 35152405 for recommendations for alternative statins).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298191", - "name" : "Recommendation PA166298191", + "id" : "PA166298189", + "name" : "Recommendation PA166298189", "alternateDrugAvailable" : true, "classification" : { "id" : 981501931, @@ -69245,11 +69261,11 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "SLCO1B1: Increased lovastatin acid exposure as compared to normal and decreased function which may translate to increased myopathy risk" + "SLCO1B1: Increased lovastatin acid exposure as compared to normal function which may translate to increased myopathy risk" ], - "lookupKey" : {"SLCO1B1": "Poor Function"}, + "lookupKey" : {"SLCO1B1": "Possible Decreased Function"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -69257,21 +69273,21 @@ "objCls" : "Chemical", "id" : "PA450272", "name" : "lovastatin", - "version" : 21 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262241", "name" : "Annotation of CPIC Guideline for lovastatin and SLCO1B1", - "version" : 5 + "version" : 21 }, "text" : { - "id" : 1452060793, - "html" : "

Prescribe an alternative statin depending on the desired potency (see Figure 1 of PMID: 35152405 for recommendations for alternative statins).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452060791, + "html" : "

Prescribe an alternative statin depending on the desired potency (see Figure 1 of PMID: 35152405 for recommendations for alternative statins). If lovastatin therapy is warranted, limit dose to ≤20mg/day.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166262241" @@ -69617,7 +69633,7 @@ "objCls" : "Chemical", "id" : "PA450353", "name" : "meloxicam", - "version" : 14 + "version" : 32 } ], "relatedGenes" : [ @@ -69626,7 +69642,7 @@ "id" : "PA126", "symbol" : "CYP2C9", "name" : "cytochrome P450 family 2 subfamily C member 9", - "version" : 7877 + "version" : 7952 } ], "source" : "CPIC", @@ -69639,16 +69655,16 @@ "textMarkdown" : { "id" : 1451433675, "html" : "

This annotation is based on the CPIC® guideline for Nonsteroidal Anti-inflammatory Drugs and CYP2C9.

\n

March 2020

\n

Advance online publication March 2020.

\n\n\n

Adapted from Tables 1 and 3 of the 2020 guideline.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
PhenotypeaActivity ScoreGenotypeExamples of genotypesbImplicationsTherapeutic recommendationscClassification of recommendationsdOther considerations
CYP2C9 Normal metabolizer2cAn individual carrying two normal function alleles*1/*1Normal metabolismInitiate therapy with recommended starting dose. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals.Strong
CYP2C9 Intermediate metabolizerf1.5cAn individual carrying one normal function and one decreased function allele.*1/*2Mildly reduced metabolismInitiate therapy with recommended starting dose. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals.ModerateIMs might have a higher than normal risk of adverse events especially in individuals with other factors affecting clearance of these drugs such as hepatic impairment or advanced age.
CYP2C9 Intermediate metabolizerf1cAn individual carrying one normal function allele plus one no function allele OR two decreased function alleles.*1/*3, *2/*2Moderately reduced metabolism; higher plasma concentrations may increase probability of toxicitiesInitiate therapy with 50% of the lowest recommended starting dose. Titrate dose upward to clinical effect or 50% of the maximum recommended dose with caution. In accordance with the meloxicam prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals. Upward dose titration should not occur until after steady state is reached (at least 7 days). Carefully monitor adverse events such as blood pressure and kidney function during course of therapy. Alternatively, consider alternative therapy. Choose an alternative therapy not metabolized by CYP2C9 or not significantly impacted by CYP2C9 genetic variants in vivo or choose an NSAID metabolized by CYP2C9 but with a shorter half-life (Table 2).ModerateIMs might have a higher than normal risk of adverse events especially in individuals with other factors affecting clearance of these drugs such as hepatic impairment or advanced age. Alternative therapies not primarily metabolized by CYP2C9 include aspirin, ketorolac, naproxen and sulindac. Selection of therapy will depend on individual patient treatment goals and risks for toxicity.
CYP2C9 Poor metabolizer0 or 0.5cAn individual carrying one no function allele plus one decreased function allele; OR two no function alleles*2/*3, *3/*3Significantly reduced metabolism and prolonged half life; higher plasma concentrations may increase probability and/or severity of toxicitiesChoose an alternative therapy not metabolized by CYP2C9 or not significantly impacted by CYP2C9 genetic variants in vivo or choose an NSAID metabolized by CYP2C9 but with a shorter half-life (Table 2).Moderate
Indeterminaten/acAn individual carrying allele combinations with uncertain and/or unknown function alleles*1/*7, *1/*10, *7/*10, *1/*57n/aNo recommendation.n/a
\n

a See the CYP2C9 frequency table for race-specific allele and phenotype frequencies.
\nb For a complete list of CYP2C9 diplotypes and resulting phenotypes, see the CYP2C9 genotype to phenotype table.

\n

c CPIC assigned each allele functional status an activity value ranging from 0 to 1 (e.g., 0 for no function, 0.5 for decreased, and 1.0 for normal function), which are summed to calculate the activity score (AS) for each diplotype. The CYP2C9 AS has been translated into the phenotype classification system as follows: individuals with an AS of 0 or 0.5 are poor\nmetabolizers (PMs), those with a score of 1 or 1.5 are intermediate metabolizers (IMs), and those with a score of 2 are normal metabolizers (NMs).
\nd Rating scheme described in Supplement.

\n", - "version" : 1 + "version" : 2 }, "userId" : "lgong", - "version" : 9 + "version" : 95 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166298197", - "name" : "Recommendation PA166298197", + "id" : "PA166298195", + "name" : "Recommendation PA166298195", "alternateDrugAvailable" : true, "classification" : { "id" : 981501931, @@ -69659,11 +69675,11 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C9: Significantly reduced metabolism and prolonged half-life; higher plasma concentrations may increase probability and/or severity of toxicities" + "CYP2C9: Moderately reduced metabolism; higher plasma concentrations may increase probability of toxicities" ], - "lookupKey" : {"CYP2C9": "0.0"}, + "lookupKey" : {"CYP2C9": "1.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -69671,18 +69687,18 @@ "objCls" : "Chemical", "id" : "PA450353", "name" : "meloxicam", - "version" : 14 + "version" : 32 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166192301", "name" : "Annotation of CPIC Guideline for meloxicam and CYP2C9", - "version" : 9 + "version" : 95 }, "text" : { - "id" : 1452060799, - "html" : "

Choose an alternative therapy not metabolized by CYP2C9 or not significantly impacted by CYP2C9 genetic variants in vivo or choose an NSAID metabolized by CYP2C9 but with a shorter half-life (see CPIC THERAPEUTIC RECOMMENDATIONS FOR CELECOXIB, FLURBIPROFEN, LORNOXICAM, AND IBUPROFEN BASED ON CYP2C9 PHENOTYPE).

\n", + "id" : 1452060797, + "html" : "

Initiate therapy with 50% of the lowest recommended starting dose. Titrate dose upward to clinical effect or 50% of the maximum recommended dose with caution. In accordance with the meloxicam prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals. Upward dose titration should not occur until after steady state is reached (at least 7 days). Carefully monitor adverse events such as blood pressure and kidney function during course of therapy. Alternatively, consider alternative therapy. Choose an alternative therapy not metabolized by CYP2C9 or not significantly impacted by CYP2C9 genetic variants in vivo or choose an NSAID metabolized by CYP2C9 but with a shorter half-life (see CPIC THERAPEUTIC RECOMMENDATIONS FOR CELECOXIB, FLURBIPROFEN, LORNOXICAM, AND IBUPROFEN BASED ON CYP2C9 PHENOTYPE).

\n

Other Considerations

\n

IMs might have a higher than normal risk of adverse events especially in individuals with other factors affecting clearance of these drugs such as hepatic impairment or advanced age. Alternative therapies not primarily metabolized by CYP2C9 include aspirin, ketorolac, naproxen and sulindac. Selection of therapy will depend on individual patient treatment goals and risks for toxicity.

\n", "version" : 0 }, "version" : 0 @@ -69713,41 +69729,41 @@ "objCls" : "Chemical", "id" : "PA450353", "name" : "meloxicam", - "version" : 14 + "version" : 32 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166192301", "name" : "Annotation of CPIC Guideline for meloxicam and CYP2C9", - "version" : 9 + "version" : 95 }, "text" : { "id" : 1452060795, "html" : "

Initiate therapy with recommended starting dose. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298198", - "name" : "Recommendation PA166298198", + "id" : "PA166298194", + "name" : "Recommendation PA166298194", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2C9: n/a" + "CYP2C9: Mildly reduced metabolism" ], - "lookupKey" : {"CYP2C9": "n/a"}, + "lookupKey" : {"CYP2C9": "1.5"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -69755,27 +69771,27 @@ "objCls" : "Chemical", "id" : "PA450353", "name" : "meloxicam", - "version" : 14 + "version" : 32 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166192301", "name" : "Annotation of CPIC Guideline for meloxicam and CYP2C9", - "version" : 9 + "version" : 95 }, "text" : { - "id" : 1452060800, - "html" : "

No recommendation

\n", + "id" : 1452060796, + "html" : "

Initiate therapy with recommended starting dose. In accordance with the meloxicam prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals.

\n

Other Considerations

\n

IMs might have a higher than normal risk of adverse events especially in individuals with other factors affecting clearance of these drugs such as hepatic impairment or advanced age.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298194", - "name" : "Recommendation PA166298194", - "alternateDrugAvailable" : false, + "id" : "PA166298196", + "name" : "Recommendation PA166298196", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501931, "parents" : [], @@ -69787,9 +69803,9 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2C9: Mildly reduced metabolism" + "CYP2C9: Significantly reduced metabolism and prolonged half-life; higher plasma concentrations may increase probability and/or severity of toxicities" ], - "lookupKey" : {"CYP2C9": "1.5"}, + "lookupKey" : {"CYP2C9": "0.5"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -69797,26 +69813,26 @@ "objCls" : "Chemical", "id" : "PA450353", "name" : "meloxicam", - "version" : 14 + "version" : 32 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166192301", "name" : "Annotation of CPIC Guideline for meloxicam and CYP2C9", - "version" : 9 + "version" : 95 }, "text" : { - "id" : 1452060796, - "html" : "

Initiate therapy with recommended starting dose. In accordance with the meloxicam prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals.

\n

Other Considerations

\n

IMs might have a higher than normal risk of adverse events especially in individuals with other factors affecting clearance of these drugs such as hepatic impairment or advanced age.

\n", + "id" : 1452060798, + "html" : "

Choose an alternative therapy not metabolized by CYP2C9 or not significantly impacted by CYP2C9 genetic variants in vivo or choose an NSAID metabolized by CYP2C9 but with a shorter half-life (see CPIC THERAPEUTIC RECOMMENDATIONS FOR CELECOXIB, FLURBIPROFEN, LORNOXICAM, AND IBUPROFEN BASED ON CYP2C9 PHENOTYPE).

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298195", - "name" : "Recommendation PA166298195", + "id" : "PA166298197", + "name" : "Recommendation PA166298197", "alternateDrugAvailable" : true, "classification" : { "id" : 981501931, @@ -69827,11 +69843,11 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C9: Moderately reduced metabolism; higher plasma concentrations may increase probability of toxicities" + "CYP2C9: Significantly reduced metabolism and prolonged half-life; higher plasma concentrations may increase probability and/or severity of toxicities" ], - "lookupKey" : {"CYP2C9": "1.0"}, + "lookupKey" : {"CYP2C9": "0.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -69839,41 +69855,41 @@ "objCls" : "Chemical", "id" : "PA450353", "name" : "meloxicam", - "version" : 14 + "version" : 32 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166192301", "name" : "Annotation of CPIC Guideline for meloxicam and CYP2C9", - "version" : 9 + "version" : 95 }, "text" : { - "id" : 1452060797, - "html" : "

Initiate therapy with 50% of the lowest recommended starting dose. Titrate dose upward to clinical effect or 50% of the maximum recommended dose with caution. In accordance with the meloxicam prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals. Upward dose titration should not occur until after steady state is reached (at least 7 days). Carefully monitor adverse events such as blood pressure and kidney function during course of therapy. Alternatively, consider alternative therapy. Choose an alternative therapy not metabolized by CYP2C9 or not significantly impacted by CYP2C9 genetic variants in vivo or choose an NSAID metabolized by CYP2C9 but with a shorter half-life (see CPIC THERAPEUTIC RECOMMENDATIONS FOR CELECOXIB, FLURBIPROFEN, LORNOXICAM, AND IBUPROFEN BASED ON CYP2C9 PHENOTYPE).

\n

Other Considerations

\n

IMs might have a higher than normal risk of adverse events especially in individuals with other factors affecting clearance of these drugs such as hepatic impairment or advanced age. Alternative therapies not primarily metabolized by CYP2C9 include aspirin, ketorolac, naproxen and sulindac. Selection of therapy will depend on individual patient treatment goals and risks for toxicity.

\n", + "id" : 1452060799, + "html" : "

Choose an alternative therapy not metabolized by CYP2C9 or not significantly impacted by CYP2C9 genetic variants in vivo or choose an NSAID metabolized by CYP2C9 but with a shorter half-life (see CPIC THERAPEUTIC RECOMMENDATIONS FOR CELECOXIB, FLURBIPROFEN, LORNOXICAM, AND IBUPROFEN BASED ON CYP2C9 PHENOTYPE).

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298196", - "name" : "Recommendation PA166298196", - "alternateDrugAvailable" : true, + "id" : "PA166298198", + "name" : "Recommendation PA166298198", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2C9: Significantly reduced metabolism and prolonged half-life; higher plasma concentrations may increase probability and/or severity of toxicities" + "CYP2C9: n/a" ], - "lookupKey" : {"CYP2C9": "0.5"}, + "lookupKey" : {"CYP2C9": "n/a"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -69881,21 +69897,21 @@ "objCls" : "Chemical", "id" : "PA450353", "name" : "meloxicam", - "version" : 14 + "version" : 32 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166192301", "name" : "Annotation of CPIC Guideline for meloxicam and CYP2C9", - "version" : 9 + "version" : 95 }, "text" : { - "id" : 1452060798, - "html" : "

Choose an alternative therapy not metabolized by CYP2C9 or not significantly impacted by CYP2C9 genetic variants in vivo or choose an NSAID metabolized by CYP2C9 but with a shorter half-life (see CPIC THERAPEUTIC RECOMMENDATIONS FOR CELECOXIB, FLURBIPROFEN, LORNOXICAM, AND IBUPROFEN BASED ON CYP2C9 PHENOTYPE).

\n", + "id" : 1452060800, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166192301" @@ -70196,7 +70212,7 @@ "objCls" : "Chemical", "id" : "PA450379", "name" : "mercaptopurine", - "version" : 31 + "version" : 73 } ], "relatedGenes" : [ @@ -70205,14 +70221,14 @@ "id" : "PA134963132", "symbol" : "NUDT15", "name" : "nudix hydrolase 15", - "version" : 11 + "version" : 39 }, { "objCls" : "Gene", "id" : "PA356", "symbol" : "TPMT", "name" : "thiopurine S-methyltransferase", - "version" : 7545 + "version" : 7628 } ], "source" : "CPIC", @@ -70228,9 +70244,396 @@ "version" : 3 }, "userId" : "rachel", - "version" : 47 + "version" : 243 }, "recommendations" : [ + { + "objCls" : "Recommendation Annotation", + "id" : "PA166298201", + "name" : "Recommendation PA166298201", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501930, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "NUDT15: n/a", + "TPMT: Moderate to high concentrations of TGN metabolites; low concentrations of MeTIMP. Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." + ], + "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Indeterminate"}, + "otherPrescribingGuidance" : false, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA450379", + "name" : "mercaptopurine", + "version" : 73 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104945", + "name" : "Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT", + "version" : 243 + }, + "text" : { + "id" : 1452060803, + "html" : "

Based on TPMT status, start with reduced starting doses (30%-80% of normal dose) if normal starting dose is ≥ 75 mg/m2/day or ≥ 1.5 mg/kg/day (e.g., start at 22.5-60 mg/m2/day or 0.45-1.2 mg/kg/day) and adjust doses of mercaptopurine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing mercaptopurine over other agents (PMID 20354201,18685564, 8857546, 18987654, 20010622, 16401827, 11302950, 16530532, 9634537). If normal starting dose is already < 75 mg/m2/day or < 1.5 mg/kg/day, dose reduction may not be recommended. NUDT15 phenotype could not be assigned based on genotyping. If thiopurines are required and either TPMT or NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "version" : 0 + }, + "version" : 1 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166298217", + "name" : "Recommendation PA166298217", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981501930, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "TPMT: Extremely high concentrations of TGN metabolites; fatal toxicity possible without dose decrease; no MeTIMP metabolites. Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." + ], + "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Intermediate Metabolizer"}, + "otherPrescribingGuidance" : false, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA450379", + "name" : "mercaptopurine", + "version" : 73 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104945", + "name" : "Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT", + "version" : 243 + }, + "text" : { + "id" : 1452060819, + "html" : "

For malignancy, start with drastically reduced doses (reduce daily dose by 10-fold and reduce frequency to thrice weekly instead of daily, e.g., 10 mg/m2/day given just 3 days/week) and adjust doses of mercaptopurine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing mercaptopurine over other agents. For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy (PMID 20354201, 1960624, 11302950, 16530532).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166298223", + "name" : "Recommendation PA166298223", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981501930, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "NUDT15: Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "TPMT: Extremely high concentrations of TGN metabolites; fatal toxicity possible without dose decrease; no MeTIMP metabolites. Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." + ], + "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Normal Metabolizer"}, + "otherPrescribingGuidance" : false, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA450379", + "name" : "mercaptopurine", + "version" : 73 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104945", + "name" : "Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT", + "version" : 243 + }, + "text" : { + "id" : 1452060825, + "html" : "

For malignancy, start with drastically reduced doses (reduce daily dose by 10-fold and reduce frequency to thrice weekly instead of daily, e.g., 10 mg/m2/day given just 3 days/week) and adjust doses of mercaptopurine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing mercaptopurine over other agents. For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy (PMID 20354201, 1960624, 11302950, 16530532).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166298225", + "name" : "Recommendation PA166298225", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981501930, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "NUDT15: Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "TPMT: n/a" + ], + "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "Poor Metabolizer"}, + "otherPrescribingGuidance" : false, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA450379", + "name" : "mercaptopurine", + "version" : 73 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104945", + "name" : "Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT", + "version" : 243 + }, + "text" : { + "id" : 1452060827, + "html" : "

Based on NUDT15 status, for malignancy, initiate dose at 10 mg/m2/day and adjust dose based on myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing mercaptopurine over other agents. For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy (PMID 20354201, 1960624, 11302950, 16530532). TPMT phenotype could not be assigned based on genotyping performed. Consider evaluating TPMT erythrocyte activity to assess TPMT phenotype. If thiopurines are required and TPMT status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers. Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166298226", + "name" : "Recommendation PA166298226", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981501930, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "NUDT15: Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "TPMT: Moderate to high concentrations of TGN metabolites; low concentrations of MeTIMP. Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." + ], + "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Poor Metabolizer"}, + "otherPrescribingGuidance" : false, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA450379", + "name" : "mercaptopurine", + "version" : 73 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104945", + "name" : "Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT", + "version" : 243 + }, + "text" : { + "id" : 1452060828, + "html" : "

For malignancy, initiate dose at 10 mg/m2/day and adjust dose based on myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing mercaptopurine over other agents. For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy (PMID 20354201, 1960624, 11302950, 16530532).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166298227", + "name" : "Recommendation PA166298227", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981501930, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "NUDT15: Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "TPMT: Moderate to high concentrations of TGN metabolites; low concentrations of MeTIMP. Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." + ], + "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Poor Metabolizer"}, + "otherPrescribingGuidance" : false, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA450379", + "name" : "mercaptopurine", + "version" : 73 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104945", + "name" : "Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT", + "version" : 243 + }, + "text" : { + "id" : 1452060829, + "html" : "

For malignancy, initiate dose at 10 mg/m2/day and adjust dose based on myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing mercaptopurine over other agents. For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy (PMID 20354201, 1960624, 11302950, 16530532).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166298228", + "name" : "Recommendation PA166298228", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981501930, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "NUDT15: Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "TPMT: Lower concentrations of TGN metabolites, higher MeTIMP, this is the ‘normal’ pattern. Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression." + ], + "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "Poor Metabolizer"}, + "otherPrescribingGuidance" : false, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA450379", + "name" : "mercaptopurine", + "version" : 73 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104945", + "name" : "Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT", + "version" : 243 + }, + "text" : { + "id" : 1452060830, + "html" : "

For malignancy, initiate dose at 10 mg/m2/day and adjust dose based on myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing mercaptopurine over other agents. For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy (PMID 20354201, 1960624, 11302950, 16530532).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166298229", + "name" : "Recommendation PA166298229", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981501930, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "NUDT15: Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "TPMT: Extremely high concentrations of TGN metabolites; fatal toxicity possible without dose decrease; no MeTIMP metabolites. Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." + ], + "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Poor Metabolizer"}, + "otherPrescribingGuidance" : false, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA450379", + "name" : "mercaptopurine", + "version" : 73 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104945", + "name" : "Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT", + "version" : 243 + }, + "text" : { + "id" : 1452060831, + "html" : "

For malignancy, start with drastically reduced doses (reduce daily dose by 10-fold and reduce frequency to thrice weekly instead of daily, e.g., 10 mg/m2/day given just 3 days/week) and adjust doses of mercaptopurine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing mercaptopurine over other agents. For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy (PMID 20354201, 1960624, 11302950, 16530532).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166298199", + "name" : "Recommendation PA166298199", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501930, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : false, + "implications" : [ + "NUDT15: n/a", + "TPMT: n/a" + ], + "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "Indeterminate"}, + "otherPrescribingGuidance" : true, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA450379", + "name" : "mercaptopurine", + "version" : 73 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104945", + "name" : "Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT", + "version" : 243 + }, + "text" : { + "id" : 1452060801, + "html" : "

Neither TPMT or NUDT15 phenotype could be assigned based on genotyping performed. Consider evaluating TPMT erythrocyte activity to assess TPMT phenotype. If thiopurines are required and either TPMT or NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", + "version" : 0 + }, + "version" : 1 + }, { "objCls" : "Recommendation Annotation", "id" : "PA166298202", @@ -70250,7 +70653,437 @@ "NUDT15: n/a", "TPMT: Moderate to high concentrations of TGN metabolites; low concentrations of MeTIMP. Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." ], - "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Indeterminate"}, + "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Indeterminate"}, + "otherPrescribingGuidance" : false, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA450379", + "name" : "mercaptopurine", + "version" : 73 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104945", + "name" : "Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT", + "version" : 243 + }, + "text" : { + "id" : 1452060804, + "html" : "

Based on TPMT status, start with reduced starting doses (30%-80% of normal dose) if normal starting dose is ≥ 75 mg/m2/day or ≥ 1.5 mg/kg/day (e.g., start at 22.5-60 mg/m2/day or 0.45-1.2 mg/kg/day) and adjust doses of mercaptopurine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing mercaptopurine over other agents (PMID 20354201,18685564, 8857546, 18987654, 20010622, 16401827, 11302950, 16530532, 9634537). If normal starting dose is already < 75 mg/m2/day or < 1.5 mg/kg/day, dose reduction may not be recommended. NUDT15 phenotype could not be assigned based on genotyping. If thiopurines are required and either TPMT or NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "version" : 0 + }, + "version" : 1 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166298224", + "name" : "Recommendation PA166298224", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501930, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : false, + "implications" : [ + "NUDT15: Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "TPMT: n/a" + ], + "lookupKey" : {"TPMT": "No Result", "NUDT15": "Normal Metabolizer"}, + "otherPrescribingGuidance" : false, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA450379", + "name" : "mercaptopurine", + "version" : 73 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104945", + "name" : "Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT", + "version" : 243 + }, + "text" : { + "id" : 1452060826, + "html" : "

Based on NUDT15 status, start with normal starting dose (e.g., 75 mg/m2/day or 1.5 mg/kg/day) and adjust doses of mercaptopurine (and of any other myelosuppressive therapy) without any special emphasis on mercaptopurine compared to other agents. Allow at least 2 weeks to reach steady-state after each dose adjustment (PMID 20354201, 16401827, 11302950). TPMT genotype result is not available. Consider evaluating TPMT erythrocyte activity to assess TPMT phenotype. If thiopurines are required and TPMT status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers. Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", + "version" : 0 + }, + "version" : 2 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166298211", + "name" : "Recommendation PA166298211", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981501930, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "NUDT15: n/a", + "TPMT: Extremely high concentrations of TGN metabolites; fatal toxicity possible without dose decrease; no MeTIMP metabolites. Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." + ], + "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "No Result"}, + "otherPrescribingGuidance" : false, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA450379", + "name" : "mercaptopurine", + "version" : 73 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104945", + "name" : "Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT", + "version" : 243 + }, + "text" : { + "id" : 1452060813, + "html" : "

Based on TPMT status, for malignancy, start with drastically reduced doses (reduce daily dose by 10-fold and reduce frequency to thrice weekly instead of daily, e.g., 10 mg/m2/day given just 3 days/week) and adjust doses of mercaptopurine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing mercaptopurine over other agents. For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy (PMID 20354201, 1960624, 11302950, 16530532). NUDT15 genotype result is not available. If thiopurines are required and either TPMT or NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "version" : 0 + }, + "version" : 2 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166298210", + "name" : "Recommendation PA166298210", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501930, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : false, + "implications" : [ + "NUDT15: n/a", + "TPMT: Lower concentrations of TGN metabolites, higher MeTIMP, this is the ‘normal’ pattern. Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression." + ], + "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "No Result"}, + "otherPrescribingGuidance" : false, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA450379", + "name" : "mercaptopurine", + "version" : 73 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104945", + "name" : "Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT", + "version" : 243 + }, + "text" : { + "id" : 1452060812, + "html" : "

Based on TPMT status, start with normal starting dose (e.g., 75 mg/m2/day or 1.5 mg/kg/day) and adjust doses of mercaptopurine (and of any other myelosuppressive therapy) without any special emphasis on mercaptopurine compared to other agents. Allow at least 2 weeks to reach steady-state after each dose adjustment (PMID 20354201, 16401827, 11302950). NUDT15 genotype result is not available. If thiopurines are required and either TPMT or NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "version" : 0 + }, + "version" : 2 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166298206", + "name" : "Recommendation PA166298206", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501930, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : false, + "implications" : [ + "NUDT15: n/a", + "TPMT: n/a" + ], + "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "No Result"}, + "otherPrescribingGuidance" : true, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA450379", + "name" : "mercaptopurine", + "version" : 73 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104945", + "name" : "Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT", + "version" : 243 + }, + "text" : { + "id" : 1452060808, + "html" : "

TPMT phenotype could not be assigned based on genotyping performed and there is no NUDT15 genotype result available. Consider evaluating TPMT erythrocyte activity to assess TPMT phenotype. If thiopurines are required and either TPMT or NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", + "version" : 0 + }, + "version" : 1 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166298208", + "name" : "Recommendation PA166298208", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501930, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "NUDT15: n/a", + "TPMT: Moderate to high concentrations of TGN metabolites; low concentrations of MeTIMP. Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." + ], + "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "No Result"}, + "otherPrescribingGuidance" : false, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA450379", + "name" : "mercaptopurine", + "version" : 73 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104945", + "name" : "Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT", + "version" : 243 + }, + "text" : { + "id" : 1452060810, + "html" : "

Based on TPMT status, start with reduced starting doses (30%-80% of normal dose) if normal starting dose is ≥ 75 mg/m2/day or ≥ 1.5 mg/kg/day (e.g., start at 22.5-60 mg/m2/day or 0.45-1.2 mg/kg/day) and adjust doses of mercaptopurine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing mercaptopurine over other agents (PMID 20354201,18685564, 8857546, 18987654, 20010622, 16401827, 11302950, 16530532, 9634537). If normal starting dose is already < 75 mg/m2/day or < 1.5 mg/kg/day, dose reduction may not be recommended. NUDT15 genotype result is not available. If thiopurines are required and either TPMT or NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "version" : 0 + }, + "version" : 1 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166298209", + "name" : "Recommendation PA166298209", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501930, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "NUDT15: n/a", + "TPMT: Moderate to high concentrations of TGN metabolites; low concentrations of MeTIMP. Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." + ], + "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "No Result"}, + "otherPrescribingGuidance" : false, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA450379", + "name" : "mercaptopurine", + "version" : 73 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104945", + "name" : "Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT", + "version" : 243 + }, + "text" : { + "id" : 1452060811, + "html" : "

Based on TPMT status, start with reduced starting doses (30%-80% of normal dose) if normal starting dose is ≥ 75 mg/m2/day or ≥ 1.5 mg/kg/day (e.g., start at 22.5-60 mg/m2/day or 0.45-1.2 mg/kg/day) and adjust doses of mercaptopurine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing mercaptopurine over other agents (PMID 20354201,18685564, 8857546, 18987654, 20010622, 16401827, 11302950, 16530532, 9634537). If normal starting dose is already < 75 mg/m2/day or < 1.5 mg/kg/day, dose reduction may not be recommended. NUDT15 genotype result is not available. If thiopurines are required and either TPMT or NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "version" : 0 + }, + "version" : 1 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166298203", + "name" : "Recommendation PA166298203", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501930, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : false, + "implications" : [ + "NUDT15: n/a", + "TPMT: Lower concentrations of TGN metabolites, higher MeTIMP, this is the ‘normal’ pattern. Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression." + ], + "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "Indeterminate"}, + "otherPrescribingGuidance" : false, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA450379", + "name" : "mercaptopurine", + "version" : 73 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104945", + "name" : "Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT", + "version" : 243 + }, + "text" : { + "id" : 1452060805, + "html" : "

Based on TPMT status, start with normal starting dose (e.g., 75 mg/m2/day or 1.5 mg/kg/day) and adjust doses of mercaptopurine (and of any other myelosuppressive therapy) without any special emphasis on mercaptopurine compared to other agents. Allow at least 2 weeks to reach steady-state after each dose adjustment (PMID 20354201, 16401827, 11302950). NUDT15 phenotype could not be assigned based on genotyping. If thiopurines are required and either TPMT or NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "version" : 0 + }, + "version" : 2 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166298212", + "name" : "Recommendation PA166298212", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501930, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "TPMT: n/a" + ], + "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "Intermediate Metabolizer"}, + "otherPrescribingGuidance" : false, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA450379", + "name" : "mercaptopurine", + "version" : 73 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104945", + "name" : "Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT", + "version" : 243 + }, + "text" : { + "id" : 1452060814, + "html" : "

Based NUDT15 status, start with reduced starting doses (30%-80% of normal dose) if normal starting dose is ≥75 mg/m2/day or ≥ 1.5 mg/kg/day (e.g., start at 22.5-60 mg/m2/day or 0.45-1.2 mg/kg/day) and adjust doses of mercaptopurine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing mercaptopurine over other agents (PMID 20354201, 18685564, 8857546, 18987654, 20010622, 16401827, 11302950, 16530532, 9634537). If normal starting dose is already < 75 mg/m2/day or < 1.5 mg/kg/day, dose reduction may not be recommended. TPMT phenotype could not be assigned based on genotyping. Consider evaluating TPMT erythrocyte activity to assess TPMT phenotype. If thiopurines are required and either TPMT or NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers. Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", + "version" : 0 + }, + "version" : 1 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166298216", + "name" : "Recommendation PA166298216", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501930, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "TPMT: Lower concentrations of TGN metabolites, higher MeTIMP, this is the ‘normal’ pattern. Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression." + ], + "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "Intermediate Metabolizer"}, + "otherPrescribingGuidance" : false, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA450379", + "name" : "mercaptopurine", + "version" : 73 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104945", + "name" : "Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT", + "version" : 243 + }, + "text" : { + "id" : 1452060818, + "html" : "

Start with reduced starting doses (30%-80% of normal dose) if normal starting dose is ≥75 mg/m2/day or ≥ 1.5 mg/kg/day (e.g., start at 22.5-60 mg/m2/day or 0.45-1.2 mg/kg/day) and adjust doses of mercaptopurine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing mercaptopurine over other agents (PMID 20354201, 18685564, 8857546, 18987654, 20010622, 16401827, 11302950, 16530532, 9634537). If normal starting dose is already < 75 mg/m2/day or < 1.5 mg/kg/day, dose reduction may not be recommended.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "version" : 0 + }, + "version" : 1 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166298218", + "name" : "Recommendation PA166298218", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501930, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "TPMT: n/a" + ], + "lookupKey" : {"TPMT": "No Result", "NUDT15": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -70258,27 +71091,27 @@ "objCls" : "Chemical", "id" : "PA450379", "name" : "mercaptopurine", - "version" : 31 + "version" : 73 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104945", "name" : "Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT", - "version" : 47 + "version" : 243 }, "text" : { - "id" : 1452060804, - "html" : "

Based on TPMT status, start with reduced starting doses (30%-80% of normal dose) if normal starting dose is ≥ 75 mg/m2/day or ≥ 1.5 mg/kg/day (e.g., start at 22.5-60 mg/m2/day or 0.45-1.2 mg/kg/day) and adjust doses of mercaptopurine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing mercaptopurine over other agents (PMID 20354201,18685564, 8857546, 18987654, 20010622, 16401827, 11302950, 16530532, 9634537). If normal starting dose is already < 75 mg/m2/day or < 1.5 mg/kg/day, dose reduction may not be recommended. NUDT15 phenotype could not be assigned based on genotyping. If thiopurines are required and either TPMT or NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "id" : 1452060820, + "html" : "

Based NUDT15 status, start with reduced starting doses (30%-80% of normal dose) if normal starting dose is ≥75 mg/m2/day or ≥ 1.5 mg/kg/day (e.g., start at 22.5-60 mg/m2/day or 0.45-1.2 mg/kg/day) and adjust doses of mercaptopurine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing mercaptopurine over other agents (PMID 20354201, 18685564, 8857546, 18987654, 20010622, 16401827, 11302950, 16530532, 9634537). If normal starting dose is already < 75 mg/m2/day or < 1.5 mg/kg/day, dose reduction may not be recommended. TPMT genotype result is not available. Consider evaluating TPMT erythrocyte activity to assess TPMT phenotype. If thiopurines are required and either TPMT or NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers. Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298228", - "name" : "Recommendation PA166298228", - "alternateDrugAvailable" : true, + "id" : "PA166298220", + "name" : "Recommendation PA166298220", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, "parents" : [], @@ -70290,10 +71123,10 @@ }, "dosingInformation" : true, "implications" : [ - "NUDT15: Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", - "TPMT: Lower concentrations of TGN metabolites, higher MeTIMP, this is the ‘normal’ pattern. Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression." + "NUDT15: Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "TPMT: Moderate to high concentrations of TGN metabolites; low concentrations of MeTIMP. Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." ], - "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "Poor Metabolizer"}, + "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -70301,26 +71134,26 @@ "objCls" : "Chemical", "id" : "PA450379", "name" : "mercaptopurine", - "version" : 31 + "version" : 73 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104945", "name" : "Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT", - "version" : 47 + "version" : 243 }, "text" : { - "id" : 1452060830, - "html" : "

For malignancy, initiate dose at 10 mg/m2/day and adjust dose based on myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing mercaptopurine over other agents. For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy (PMID 20354201, 1960624, 11302950, 16530532).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "id" : 1452060822, + "html" : "

Start with reduced starting doses (30%-80% of normal dose) if normal starting dose is ≥ 75 mg/m2/day or ≥ 1.5 mg/kg/day (e.g. start at 22.5-60 mg/m2/day or 0.45-1.2 mg/kg/day) and adjust doses of mercaptopurine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing mercaptopurine over other agents (PMID 20354201,18685564, 8857546, 18987654, 20010622, 16401827, 11302950, 16530532, 9634537). If normal starting dose is already < 75 mg/m2/day or < 1.5 mg/kg/day, dose reduction may not be recommended.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298215", - "name" : "Recommendation PA166298215", + "id" : "PA166298221", + "name" : "Recommendation PA166298221", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -70333,10 +71166,10 @@ }, "dosingInformation" : true, "implications" : [ - "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "NUDT15: Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression", "TPMT: Moderate to high concentrations of TGN metabolites; low concentrations of MeTIMP. Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." ], - "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -70344,26 +71177,26 @@ "objCls" : "Chemical", "id" : "PA450379", "name" : "mercaptopurine", - "version" : 31 + "version" : 73 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104945", "name" : "Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT", - "version" : 47 + "version" : 243 }, "text" : { - "id" : 1452060817, - "html" : "

Start with reduced starting doses (20%-50% of normal dose) if normal starting dose is ≥ 75 mg/m2/day or ≥ 1.5 mg/kg/day (e.g., start at 15-37.5 mg/m2/day or 0.3-0.75 mg/kg/day) and adjust doses of mercaptopurine based on degree of myelosuppression and disease-specific guidelines. At least 2-4 weeks will be required to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing mercaptopurine over other agents (PMID 20354201,18685564, 8857546, 18987654, 20010622, 16401827, 11302950, 16530532, 9634537, 38230823). If normal starting dose is already < 37.5 mg/m2/day or < 0.75 mg/kg/day, dose reduction may not be recommended.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", - "version" : 1 + "id" : 1452060823, + "html" : "

Start with reduced starting doses (30%-80% of normal dose) if normal starting dose is ≥ 75 mg/m2/day or ≥ 1.5 mg/kg/day (e.g. start at 22.5-60 mg/m2/day or 0.45-1.2 mg/kg/day) and adjust doses of mercaptopurine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing mercaptopurine over other agents (PMID 20354201,18685564, 8857546, 18987654, 20010622, 16401827, 11302950, 16530532, 9634537). If normal starting dose is already < 75 mg/m2/day or < 1.5 mg/kg/day, dose reduction may not be recommended.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "version" : 0 }, "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298206", - "name" : "Recommendation PA166298206", + "id" : "PA166298222", + "name" : "Recommendation PA166298222", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -70376,38 +71209,38 @@ }, "dosingInformation" : false, "implications" : [ - "NUDT15: n/a", - "TPMT: n/a" + "NUDT15: Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "TPMT: Lower concentrations of TGN metabolites, higher MeTIMP, this is the ‘normal’ pattern. Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression." ], - "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "No Result"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "Normal Metabolizer"}, + "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450379", "name" : "mercaptopurine", - "version" : 31 + "version" : 73 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104945", "name" : "Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT", - "version" : 47 + "version" : 243 }, "text" : { - "id" : 1452060808, - "html" : "

TPMT phenotype could not be assigned based on genotyping performed and there is no NUDT15 genotype result available. Consider evaluating TPMT erythrocyte activity to assess TPMT phenotype. If thiopurines are required and either TPMT or NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", + "id" : 1452060824, + "html" : "

Start with normal starting dose (e.g., 75 mg/m2/day or 1.5 mg/kg/day) and adjust doses of mercaptopurine (and of any other myelosuppressive therapy) without any special emphasis on mercaptopurine compared to other agents. Allow at least 2 weeks to reach steady-state after each dose adjustment (PMID 20354201, 16401827, 11302950).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298211", - "name" : "Recommendation PA166298211", - "alternateDrugAvailable" : true, + "id" : "PA166298219", + "name" : "Recommendation PA166298219", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, "parents" : [], @@ -70417,40 +71250,40 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "NUDT15: n/a", - "TPMT: Extremely high concentrations of TGN metabolites; fatal toxicity possible without dose decrease; no MeTIMP metabolites. Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." + "NUDT15: Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "TPMT: n/a" ], - "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "No Result"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "Normal Metabolizer"}, + "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450379", "name" : "mercaptopurine", - "version" : 31 + "version" : 73 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104945", "name" : "Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT", - "version" : 47 + "version" : 243 }, "text" : { - "id" : 1452060813, - "html" : "

Based on TPMT status, for malignancy, start with drastically reduced doses (reduce daily dose by 10-fold and reduce frequency to thrice weekly instead of daily, e.g., 10 mg/m2/day given just 3 days/week) and adjust doses of mercaptopurine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing mercaptopurine over other agents. For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy (PMID 20354201, 1960624, 11302950, 16530532). NUDT15 genotype result is not available. If thiopurines are required and either TPMT or NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "id" : 1452060821, + "html" : "

Based on NUDT15 status, start with normal starting dose (e.g., 75 mg/m2/day or 1.5 mg/kg/day) and adjust doses of mercaptopurine (and of any other myelosuppressive therapy) without any special emphasis on mercaptopurine compared to other agents. Allow at least 2 weeks to reach steady-state after each dose adjustment (PMID 20354201, 16401827, 11302950). TPMT phenotype could not be assigned based on genotyping performed. Consider evaluating TPMT erythrocyte activity to assess TPMT phenotype. If thiopurines are required and TPMT status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers. Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298224", - "name" : "Recommendation PA166298224", - "alternateDrugAvailable" : false, + "id" : "PA166298204", + "name" : "Recommendation PA166298204", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, "parents" : [], @@ -70460,12 +71293,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "NUDT15: Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression", - "TPMT: n/a" + "NUDT15: n/a", + "TPMT: Extremely high concentrations of TGN metabolites; fatal toxicity possible without dose decrease; no MeTIMP metabolites. Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." ], - "lookupKey" : {"TPMT": "No Result", "NUDT15": "Normal Metabolizer"}, + "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -70473,26 +71306,26 @@ "objCls" : "Chemical", "id" : "PA450379", "name" : "mercaptopurine", - "version" : 31 + "version" : 73 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104945", "name" : "Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT", - "version" : 47 + "version" : 243 }, "text" : { - "id" : 1452060826, - "html" : "

Based on NUDT15 status, start with normal starting dose (e.g., 75 mg/m2/day or 1.5 mg/kg/day) and adjust doses of mercaptopurine (and of any other myelosuppressive therapy) without any special emphasis on mercaptopurine compared to other agents. Allow at least 2 weeks to reach steady-state after each dose adjustment (PMID 20354201, 16401827, 11302950). TPMT genotype result is not available. Consider evaluating TPMT erythrocyte activity to assess TPMT phenotype. If thiopurines are required and TPMT status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers. Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", + "id" : 1452060806, + "html" : "

Based on TPMT status, for malignancy, start with drastically reduced doses (reduce daily dose by 10-fold and reduce frequency to thrice weekly instead of daily, e.g., 10 mg/m2/day given just 3 days/week) and adjust doses of mercaptopurine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing mercaptopurine over other agents. For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy (PMID 20354201, 1960624, 11302950, 16530532). NUDT15 phenotype could not be assigned based on genotyping. If thiopurines are required and either TPMT or NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298232", - "name" : "Recommendation PA166298232", + "id" : "PA166298215", + "name" : "Recommendation PA166298215", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -70506,9 +71339,9 @@ "dosingInformation" : true, "implications" : [ "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", - "TPMT: n/a" + "TPMT: Moderate to high concentrations of TGN metabolites; low concentrations of MeTIMP. Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." ], - "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "Possible Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -70516,26 +71349,26 @@ "objCls" : "Chemical", "id" : "PA450379", "name" : "mercaptopurine", - "version" : 31 + "version" : 73 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104945", "name" : "Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT", - "version" : 47 + "version" : 243 }, "text" : { - "id" : 1452060834, - "html" : "

Based on NUDT15 status, start with reduced starting doses (30%-80% of normal dose) if normal starting dose is ≥75 mg/m2/day or ≥ 1.5 mg/kg/day (e.g., start at 22.5-60 mg/m2/day or 0.45-1.2 mg/kg/day) and adjust doses of mercaptopurine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing mercaptopurine over other agents (PMID 20354201, 18685564, 8857546, 18987654, 20010622, 16401827, 11302950, 16530532, 9634537). If normal starting dose is already < 75 mg/m2/day or < 1.5 mg/kg/day, dose reduction may not be recommended. TPMT phenotype could not be assigned based on genotyping performed. Consider evaluating TPMT erythrocyte activity to assess TPMT phenotype. If thiopurines are required and TPMT status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers. Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", - "version" : 0 + "id" : 1452060817, + "html" : "

Start with reduced starting doses (20%-50% of normal dose) if normal starting dose is ≥ 75 mg/m2/day or ≥ 1.5 mg/kg/day (e.g., start at 15-37.5 mg/m2/day or 0.3-0.75 mg/kg/day) and adjust doses of mercaptopurine based on degree of myelosuppression and disease-specific guidelines. At least 2-4 weeks will be required to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing mercaptopurine over other agents (PMID 20354201,18685564, 8857546, 18987654, 20010622, 16401827, 11302950, 16530532, 9634537, 38230823). If normal starting dose is already < 37.5 mg/m2/day or < 0.75 mg/kg/day, dose reduction may not be recommended.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298219", - "name" : "Recommendation PA166298219", + "id" : "PA166298205", + "name" : "Recommendation PA166298205", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -70548,10 +71381,10 @@ }, "dosingInformation" : false, "implications" : [ - "NUDT15: Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "NUDT15: n/a", "TPMT: n/a" ], - "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "Normal Metabolizer"}, + "lookupKey" : {"TPMT": "No Result", "NUDT15": "Indeterminate"}, "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ @@ -70559,27 +71392,27 @@ "objCls" : "Chemical", "id" : "PA450379", "name" : "mercaptopurine", - "version" : 31 + "version" : 73 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104945", "name" : "Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT", - "version" : 47 + "version" : 243 }, "text" : { - "id" : 1452060821, - "html" : "

Based on NUDT15 status, start with normal starting dose (e.g., 75 mg/m2/day or 1.5 mg/kg/day) and adjust doses of mercaptopurine (and of any other myelosuppressive therapy) without any special emphasis on mercaptopurine compared to other agents. Allow at least 2 weeks to reach steady-state after each dose adjustment (PMID 20354201, 16401827, 11302950). TPMT phenotype could not be assigned based on genotyping performed. Consider evaluating TPMT erythrocyte activity to assess TPMT phenotype. If thiopurines are required and TPMT status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers. Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", - "version" : 0 + "id" : 1452060807, + "html" : "

NUDT15 phenotype could not be assigned based on genotyping performed and there is no TPMT genotype result. Consider evaluating TPMT erythrocyte activity to assess TPMT phenotype. If thiopurines are required and either TPMT or NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298238", - "name" : "Recommendation PA166298238", - "alternateDrugAvailable" : false, + "id" : "PA166298230", + "name" : "Recommendation PA166298230", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, "parents" : [], @@ -70591,10 +71424,10 @@ }, "dosingInformation" : true, "implications" : [ - "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "NUDT15: Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", "TPMT: n/a" ], - "lookupKey" : {"TPMT": "No Result", "NUDT15": "Possible Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "No Result", "NUDT15": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -70602,26 +71435,26 @@ "objCls" : "Chemical", "id" : "PA450379", "name" : "mercaptopurine", - "version" : 31 + "version" : 73 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104945", "name" : "Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT", - "version" : 47 + "version" : 243 }, "text" : { - "id" : 1452060840, - "html" : "

Based on NUDT15 status, start with reduced starting doses (30%-80% of normal dose) if normal starting dose is ≥75 mg/m2/day or ≥ 1.5 mg/kg/day (e.g., start at 22.5-60 mg/m2/day or 0.45-1.2 mg/kg/day) and adjust doses of mercaptopurine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing mercaptopurine over other agents (PMID 20354201, 18685564, 8857546, 18987654, 20010622, 16401827, 11302950, 16530532, 9634537). If normal starting dose is already < 75 mg/m2/day or < 1.5 mg/kg/day, dose reduction may not be recommended. TPMT genotype result is not available. Consider evaluating TPMT erythrocyte activity to assess TPMT phenotype. If thiopurines are required and TPMT status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers. Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", + "id" : 1452060832, + "html" : "

Based on NUDT15 status, for malignancy, initiate dose at 10 mg/m2/day and adjust dose based on myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing mercaptopurine over other agents. For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy (PMID 20354201, 1960624, 11302950, 16530532). TPMT genotype result is not available. Consider evaluating TPMT erythrocyte activity to assess TPMT phenotype. If thiopurines are required and TPMT status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers. Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298229", - "name" : "Recommendation PA166298229", + "id" : "PA166298236", + "name" : "Recommendation PA166298236", "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, @@ -70634,10 +71467,10 @@ }, "dosingInformation" : true, "implications" : [ - "NUDT15: Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", "TPMT: Extremely high concentrations of TGN metabolites; fatal toxicity possible without dose decrease; no MeTIMP metabolites. Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." ], - "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Poor Metabolizer"}, + "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Possible Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -70645,17 +71478,17 @@ "objCls" : "Chemical", "id" : "PA450379", "name" : "mercaptopurine", - "version" : 31 + "version" : 73 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104945", "name" : "Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT", - "version" : 47 + "version" : 243 }, "text" : { - "id" : 1452060831, + "id" : 1452060838, "html" : "

For malignancy, start with drastically reduced doses (reduce daily dose by 10-fold and reduce frequency to thrice weekly instead of daily, e.g., 10 mg/m2/day given just 3 days/week) and adjust doses of mercaptopurine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing mercaptopurine over other agents. For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy (PMID 20354201, 1960624, 11302950, 16530532).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", "version" : 0 }, @@ -70663,8 +71496,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298216", - "name" : "Recommendation PA166298216", + "id" : "PA166298232", + "name" : "Recommendation PA166298232", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -70678,9 +71511,9 @@ "dosingInformation" : true, "implications" : [ "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", - "TPMT: Lower concentrations of TGN metabolites, higher MeTIMP, this is the ‘normal’ pattern. Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression." + "TPMT: n/a" ], - "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "Possible Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -70688,26 +71521,26 @@ "objCls" : "Chemical", "id" : "PA450379", "name" : "mercaptopurine", - "version" : 31 + "version" : 73 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104945", "name" : "Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT", - "version" : 47 + "version" : 243 }, "text" : { - "id" : 1452060818, - "html" : "

Start with reduced starting doses (30%-80% of normal dose) if normal starting dose is ≥75 mg/m2/day or ≥ 1.5 mg/kg/day (e.g., start at 22.5-60 mg/m2/day or 0.45-1.2 mg/kg/day) and adjust doses of mercaptopurine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing mercaptopurine over other agents (PMID 20354201, 18685564, 8857546, 18987654, 20010622, 16401827, 11302950, 16530532, 9634537). If normal starting dose is already < 75 mg/m2/day or < 1.5 mg/kg/day, dose reduction may not be recommended.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "id" : 1452060834, + "html" : "

Based on NUDT15 status, start with reduced starting doses (30%-80% of normal dose) if normal starting dose is ≥75 mg/m2/day or ≥ 1.5 mg/kg/day (e.g., start at 22.5-60 mg/m2/day or 0.45-1.2 mg/kg/day) and adjust doses of mercaptopurine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing mercaptopurine over other agents (PMID 20354201, 18685564, 8857546, 18987654, 20010622, 16401827, 11302950, 16530532, 9634537). If normal starting dose is already < 75 mg/m2/day or < 1.5 mg/kg/day, dose reduction may not be recommended. TPMT phenotype could not be assigned based on genotyping performed. Consider evaluating TPMT erythrocyte activity to assess TPMT phenotype. If thiopurines are required and TPMT status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers. Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298234", - "name" : "Recommendation PA166298234", + "id" : "PA166298235", + "name" : "Recommendation PA166298235", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -70721,9 +71554,9 @@ "dosingInformation" : true, "implications" : [ "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", - "TPMT: Moderate to high concentrations of TGN metabolites; low concentrations of MeTIMP. Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." + "TPMT: Lower concentrations of TGN metabolites, higher MeTIMP, this is the ‘normal’ pattern. Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression." ], - "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Possible Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "Possible Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -70731,26 +71564,26 @@ "objCls" : "Chemical", "id" : "PA450379", "name" : "mercaptopurine", - "version" : 31 + "version" : 73 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104945", "name" : "Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT", - "version" : 47 + "version" : 243 }, "text" : { - "id" : 1452060836, - "html" : "

Start with reduced starting doses (20%-50% of normal dose) if normal starting dose is ≥ 75 mg/m2/day or ≥ 1.5 mg/kg/day (e.g., start at 15-37.5 mg/m2/day or 0.3-0.75 mg/kg/day) and adjust doses of mercaptopurine based on degree of myelosuppression and disease-specific guidelines. At least 2-4 weeks will be required to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing mercaptopurine over other agents (PMID 20354201,18685564, 8857546, 18987654, 20010622, 16401827, 11302950, 16530532, 9634537, 38230823). If normal starting dose is already < 37.5 mg/m2/day or < 0.75 mg/kg/day, dose reduction may not be recommended.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", - "version" : 1 + "id" : 1452060837, + "html" : "

Start with reduced starting doses (30%-80% of normal dose) if normal starting dose is ≥75 mg/m2/day or ≥ 1.5 mg/kg/day (e.g., start at 22.5-60 mg/m2/day or 0.45-1.2 mg/kg/day) and adjust doses of mercaptopurine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing mercaptopurine over other agents (PMID 20354201, 18685564, 8857546, 18987654, 20010622, 16401827, 11302950, 16530532, 9634537). If normal starting dose is already < 75 mg/m2/day or < 1.5 mg/kg/day, dose reduction may not be recommended.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "version" : 0 }, "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298212", - "name" : "Recommendation PA166298212", + "id" : "PA166298238", + "name" : "Recommendation PA166298238", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -70766,7 +71599,7 @@ "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", "TPMT: n/a" ], - "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "No Result", "NUDT15": "Possible Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -70774,27 +71607,27 @@ "objCls" : "Chemical", "id" : "PA450379", "name" : "mercaptopurine", - "version" : 31 + "version" : 73 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104945", "name" : "Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT", - "version" : 47 + "version" : 243 }, "text" : { - "id" : 1452060814, - "html" : "

Based NUDT15 status, start with reduced starting doses (30%-80% of normal dose) if normal starting dose is ≥75 mg/m2/day or ≥ 1.5 mg/kg/day (e.g., start at 22.5-60 mg/m2/day or 0.45-1.2 mg/kg/day) and adjust doses of mercaptopurine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing mercaptopurine over other agents (PMID 20354201, 18685564, 8857546, 18987654, 20010622, 16401827, 11302950, 16530532, 9634537). If normal starting dose is already < 75 mg/m2/day or < 1.5 mg/kg/day, dose reduction may not be recommended. TPMT phenotype could not be assigned based on genotyping. Consider evaluating TPMT erythrocyte activity to assess TPMT phenotype. If thiopurines are required and either TPMT or NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers. Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", + "id" : 1452060840, + "html" : "

Based on NUDT15 status, start with reduced starting doses (30%-80% of normal dose) if normal starting dose is ≥75 mg/m2/day or ≥ 1.5 mg/kg/day (e.g., start at 22.5-60 mg/m2/day or 0.45-1.2 mg/kg/day) and adjust doses of mercaptopurine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing mercaptopurine over other agents (PMID 20354201, 18685564, 8857546, 18987654, 20010622, 16401827, 11302950, 16530532, 9634537). If normal starting dose is already < 75 mg/m2/day or < 1.5 mg/kg/day, dose reduction may not be recommended. TPMT genotype result is not available. Consider evaluating TPMT erythrocyte activity to assess TPMT phenotype. If thiopurines are required and TPMT status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers. Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298225", - "name" : "Recommendation PA166298225", - "alternateDrugAvailable" : true, + "id" : "PA166298234", + "name" : "Recommendation PA166298234", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, "parents" : [], @@ -70806,10 +71639,10 @@ }, "dosingInformation" : true, "implications" : [ - "NUDT15: Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", - "TPMT: n/a" + "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "TPMT: Moderate to high concentrations of TGN metabolites; low concentrations of MeTIMP. Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." ], - "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "Poor Metabolizer"}, + "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Possible Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -70817,26 +71650,26 @@ "objCls" : "Chemical", "id" : "PA450379", "name" : "mercaptopurine", - "version" : 31 + "version" : 73 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104945", "name" : "Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT", - "version" : 47 + "version" : 243 }, "text" : { - "id" : 1452060827, - "html" : "

Based on NUDT15 status, for malignancy, initiate dose at 10 mg/m2/day and adjust dose based on myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing mercaptopurine over other agents. For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy (PMID 20354201, 1960624, 11302950, 16530532). TPMT phenotype could not be assigned based on genotyping performed. Consider evaluating TPMT erythrocyte activity to assess TPMT phenotype. If thiopurines are required and TPMT status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers. Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", - "version" : 0 + "id" : 1452060836, + "html" : "

Start with reduced starting doses (20%-50% of normal dose) if normal starting dose is ≥ 75 mg/m2/day or ≥ 1.5 mg/kg/day (e.g., start at 15-37.5 mg/m2/day or 0.3-0.75 mg/kg/day) and adjust doses of mercaptopurine based on degree of myelosuppression and disease-specific guidelines. At least 2-4 weeks will be required to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing mercaptopurine over other agents (PMID 20354201,18685564, 8857546, 18987654, 20010622, 16401827, 11302950, 16530532, 9634537, 38230823). If normal starting dose is already < 37.5 mg/m2/day or < 0.75 mg/kg/day, dose reduction may not be recommended.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298220", - "name" : "Recommendation PA166298220", + "id" : "PA166298214", + "name" : "Recommendation PA166298214", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -70849,10 +71682,10 @@ }, "dosingInformation" : true, "implications" : [ - "NUDT15: Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", "TPMT: Moderate to high concentrations of TGN metabolites; low concentrations of MeTIMP. Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." ], - "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Normal Metabolizer"}, + "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -70860,21 +71693,21 @@ "objCls" : "Chemical", "id" : "PA450379", "name" : "mercaptopurine", - "version" : 31 + "version" : 73 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104945", "name" : "Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT", - "version" : 47 + "version" : 243 }, "text" : { - "id" : 1452060822, - "html" : "

Start with reduced starting doses (30%-80% of normal dose) if normal starting dose is ≥ 75 mg/m2/day or ≥ 1.5 mg/kg/day (e.g. start at 22.5-60 mg/m2/day or 0.45-1.2 mg/kg/day) and adjust doses of mercaptopurine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing mercaptopurine over other agents (PMID 20354201,18685564, 8857546, 18987654, 20010622, 16401827, 11302950, 16530532, 9634537). If normal starting dose is already < 75 mg/m2/day or < 1.5 mg/kg/day, dose reduction may not be recommended.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", - "version" : 0 + "id" : 1452060816, + "html" : "

Start with reduced starting doses (20%-50% of normal dose) if normal starting dose is ≥ 75 mg/m2/day or ≥ 1.5 mg/kg/day (e.g., start at 15-37.5 mg/m2/day or 0.3-0.75 mg/kg/day) and adjust doses of mercaptopurine based on degree of myelosuppression and disease-specific guidelines. At least 2-4 weeks will be required to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing mercaptopurine over other agents (PMID 20354201,18685564, 8857546, 18987654, 20010622, 16401827, 11302950, 16530532, 9634537, 38230823). If normal starting dose is already < 37.5 mg/m2/day or < 0.75 mg/kg/day, dose reduction may not be recommended.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", @@ -70903,70 +71736,208 @@ "objCls" : "Chemical", "id" : "PA450379", "name" : "mercaptopurine", - "version" : 31 + "version" : 73 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104945", "name" : "Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT", - "version" : 47 + "version" : 243 }, "text" : { "id" : 1452060835, "html" : "

Start with reduced starting doses (20%-50% of normal dose) if normal starting dose is ≥ 75 mg/m2/day or ≥ 1.5 mg/kg/day (e.g., start at 15-37.5 mg/m2/day or 0.3-0.75 mg/kg/day) and adjust doses of mercaptopurine based on degree of myelosuppression and disease-specific guidelines. At least 2-4 weeks will be required to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing mercaptopurine over other agents (PMID 20354201,18685564, 8857546, 18987654, 20010622, 16401827, 11302950, 16530532, 9634537, 38230823). If normal starting dose is already < 37.5 mg/m2/day or < 0.75 mg/kg/day, dose reduction may not be recommended.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", "version" : 1 }, - "version" : 1 + "version" : 2 + } + ], + "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166104945" + }, + { + "citations" : [], + "guideline" : { + "objCls" : "Guideline Annotation", + "id" : "PA166341321", + "name" : "Annotation of CPIC Guideline for metoprolol and CYP2D6", + "alternateDrugAvailable" : true, + "cancerGenome" : false, + "crossReferences" : [], + "dosingInformation" : false, + "hasTestingInfo" : false, + "history" : [], + "literature" : [], + "otherPrescribingGuidance" : true, + "pediatric" : true, + "pediatricMarkdown" : { + "id" : 1452498460, + "html" : "

Excerpt from the guideline:

\n
\n

Pediatrics. Beta-blockers are used to treat a variety of indications in children, such as heart failure, hemangiomas, migraine, aggression, and anxiety. However, only two pediatric pharmacogenetic studies of beta-blockers were identified. Therefore, more evidence is needed before clinical recommendations can be specifically made for pediatric patients. It may be appropriate, with caution, to extrapolate the recommendations for CYP2D6 and metoprolol to most children because CYP2D6 genotype appears to correlate with CYP2D6 activity as early as two weeks of age.

\n
\n", + "version" : 0 + }, + "recommendation" : true, + "relatedAlleles" : [], + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA450480", + "name" : "metoprolol", + "version" : 37 + } + ], + "relatedGenes" : [ + { + "objCls" : "Gene", + "id" : "PA128", + "symbol" : "CYP2D6", + "name" : "cytochrome P450 family 2 subfamily D member 6", + "version" : 8001 + } + ], + "source" : "CPIC", + "summaryMarkdown" : { + "id" : 1452497740, + "html" : "

Patients who are CYP2D6 poor metabolizers should initiate metoprolol therapy at the lowest recommended starting dose and carefully titrate upwards to clinical effect or guideline-recommended dose. Alternatively, a different beta-blocker may be selected. There is no recommendation for CYP2D6 ultrarapid metabolizers.

\n", + "version" : 0 + }, + "terms" : [], + "textMarkdown" : { + "id" : 1452497741, + "html" : "

Month Year (add ‘Update’ if applicable)

\n

The authors of the [CPIC® guideline for beta-blocker therapy and CYP2D6, ADRB1, ADRB2, ADRA2C, GRK4 and GRK5] (insert URL to guideline page on CPIC website) evaluated the available evidence for the use of metoprolol in patients carrying CYP2D6 variants.

\n

These guidelines are applicable to:

\n\n

Excerpts from the guideline:

\n
\n

The evidence supporting the association of CYP2D6 genotype with metoprolol exposure and response included participants with a variety of health statuses (e.g., healthy, hypertension, heart failure, etc.). Therefore, it may be reasonable to assume that the pharmacokinetic effects of CYP2D6 variation would affect clinical metoprolol response similarly across a variety of indications, and the dosing recommendations provided could be utilized for most cardiovascular indications.

\n
\n
\n

Recommendations primarily focus on minimizing the risk of adverse effects in CYP2D6 poor metabolizers related to the greater observed reductions in heart rate and blood pressure stemming from increased metoprolol systemic exposure. In addition, the maximally tolerated metoprolol dose may be lower in poor metabolizers compared to normal metabolizers due to these pharmacokinetic differences.

\n
\n
\n

While the evidence suggests metoprolol plasma concentrations are also increased in CYP2D6 intermediate metabolizers compared with normal metabolizers, these effects appear smaller in magnitude than those observed with poor metabolizers, and there was insufficient evidence to clarify whether these smaller pharmacokinetic differences significantly affect clinical response.

\n
\n
\n

There was insufficient evidence to determine whether CYP2D6 ultrarapid metabolizers experience clinically significant differences in metoprolol exposure or response.

\n
\n
\n

Importantly, none of the recommendations provided in this guideline should be interpreted in a way that would prevent or impede the up-titration of beta-blocker doses to maximally tolerated or guideline-recommended levels, such as in heart failure with reduced ejection fraction and in the post-myocardial infarction setting.

\n
\n

Download and read:

\n\n\n

Adapted from Tables 1 and 2 of the guideline

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
PhenotypeaActivity score rangeActivity scorebExamples of CYP2D6 diplotypescImplicationsdRecommendationsClassification of recommendationse
Ultrarapid metabolizer>2.25>2.25*1/*1xN, *1/*2xN, *2/*2xNIncreased metabolism of metoprolol leading to decreased drug concentrations; however, it is unclear whether this results in clinically significant changes in heart rate, blood pressure, or clinical outcomes.No recommendation for metoprolol therapy due to insufficient evidence regarding diminished metoprolol effectiveness clinicallyNo recommendation
Normal metabolizer1.25 ≤ x ≤ 2.252.25
2
1.75
1.5
1.25		*2x2*10
*1/*1, *1/*2
*1/*10x3
*1/*17, *2/*29
*1/*10, *1/*41, *1/*9		Normal metabolism of metoprololInitiate standard dosingStrong
Intermediate metabolizer0 < x < 1.251
0.75
0.5
0.25		*1/*5
*10/*17, *29/*41
*10/*10, *41/*41, *10/*41
*4/*10, *4/*41		Decreased metabolism of metoprolol leading to increased drug concentrations; however, this does not appear to translate into clinically significant changes in heart rate, blood pressure, or clinical outcomesInitiate standard dosingModerate
Poor metabolizer00*3/*4, *4/*4, *5/*5, *5/*6Decreased metabolism of metoprolol leading to markedly increased drug concentrations; this leads to greater heart rate and blood pressure reductions, but the effect on clinical outcomes is unclearInitiate therapy with lowest recommended starting dose. Carefully titrate dose upward to clinical effect or guideline-recommended dose; monitor more closely for bradycardia. Alternatively, consider selecting another beta-blocker.Moderate
Indeterminaten/aAn individual carrying one or two uncertain function alleles*1/*22, *1/*25, *22/*25n/aNo recommendationNo recommendation
\n

a See the CYP2D6 Allele Frequency Table on the CYP2D6 Gene-Specific Information Tables page for ancestry-specific allele and phenotype frequencies.
\nb Assignment of allele function and allele activity values, including citations for allele function, can be found in the CYP2D6 Allele Definition Table and the CYP2D6 Allele Functionality Table on the CYP2D6 Gene-Specific Information Tables page. For a complete list of CYP2D6 diplotypes and predicted phenotypes, see the CYP2D6 Diplotype to Phenotype Table on the CYP2D6 Gene-Specific Information Tables page.
\nc Where xN represents the number of CYP2D6 gene copies.
\nd Metoprolol has no known active metabolites via CYP2D6.
\ne Rating scheme described in the Strength of Recommendations section in the [guideline supplement](add link to guideline supplement PDF and remove '' from 'guideline supplement').

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Initiate therapy with lowest recommended starting dose. Carefully titrate dose upward to clinical effect or guideline-recommended dose; monitor more closely for bradycardia. Alternatively, consider selecting another beta-blocker.

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For malignancy, initiate dose at 10 mg/m2/day and adjust dose based on myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing mercaptopurine over other agents. For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy (PMID 20354201, 1960624, 11302950, 16530532).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "id" : 1452497910, + "html" : "

Initiate standard dosing

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Initiate standard dosing

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For malignancy, start with drastically reduced doses (reduce daily dose by 10-fold and reduce frequency to thrice weekly instead of daily, e.g., 10 mg/m2/day given just 3 days/week) and adjust doses of mercaptopurine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing mercaptopurine over other agents. For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy (PMID 20354201, 1960624, 11302950, 16530532).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "id" : 1452497947, + "html" : "

Initiate standard dosing

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298204", - "name" : "Recommendation PA166298204", - "alternateDrugAvailable" : true, + "id" : "PA166341351", + "name" : "Recommendation Annotation PA166341351", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, "parents" : [], @@ -71019,39 +71988,37 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "NUDT15: n/a", - "TPMT: Extremely high concentrations of TGN metabolites; fatal toxicity possible without dose decrease; no MeTIMP metabolites. Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." + "Normal metabolism of metoprolol" ], - "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "1.5"}, "otherPrescribingGuidance" : false, - "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA450379", - "name" : "mercaptopurine", - "version" : 31 + "id" : "PA450480", + "name" : "metoprolol", + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", - "id" : "PA166104945", - "name" : "Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT", - "version" : 47 + "id" : "PA166341321", + "name" : "Annotation of CPIC Guideline for metoprolol and CYP2D6", + "version" : 4 }, "text" : { - "id" : 1452060806, - "html" : "

Based on TPMT status, for malignancy, start with drastically reduced doses (reduce daily dose by 10-fold and reduce frequency to thrice weekly instead of daily, e.g., 10 mg/m2/day given just 3 days/week) and adjust doses of mercaptopurine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing mercaptopurine over other agents. For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy (PMID 20354201, 1960624, 11302950, 16530532). NUDT15 phenotype could not be assigned based on genotyping. If thiopurines are required and either TPMT or NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "id" : 1452497948, + "html" : "

Initiate standard dosing

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298199", - "name" : "Recommendation PA166298199", + "id" : "PA166341352", + "name" : "Recommendation Annotation PA166341352", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -71064,468 +72031,446 @@ }, "dosingInformation" : false, "implications" : [ - "NUDT15: n/a", - "TPMT: n/a" + "Normal metabolism of metoprolol" ], - "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "Indeterminate"}, - "otherPrescribingGuidance" : true, - "population" : "general", + "lookupKey" : {"CYP2D6": "1.75"}, + "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA450379", - "name" : "mercaptopurine", - "version" : 31 + "id" : "PA450480", + "name" : "metoprolol", + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", - "id" : "PA166104945", - "name" : "Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT", - "version" : 47 + "id" : "PA166341321", + "name" : "Annotation of CPIC Guideline for metoprolol and CYP2D6", + "version" : 4 }, "text" : { - "id" : 1452060801, - "html" : "

Neither TPMT or NUDT15 phenotype could be assigned based on genotyping performed. Consider evaluating TPMT erythrocyte activity to assess TPMT phenotype. If thiopurines are required and either TPMT or NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", + "id" : 1452497949, + "html" : "

Initiate standard dosing

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298222", - "name" : "Recommendation PA166298222", + "id" : "PA166341353", + "name" : "Recommendation Annotation PA166341353", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "NUDT15: Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression", - "TPMT: Lower concentrations of TGN metabolites, higher MeTIMP, this is the ‘normal’ pattern. Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression." + "n/a" ], - "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "n/a"}, "otherPrescribingGuidance" : false, - "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA450379", - "name" : "mercaptopurine", - "version" : 31 + "id" : "PA450480", + "name" : "metoprolol", + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", - "id" : "PA166104945", - "name" : "Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT", - "version" : 47 + "id" : "PA166341321", + "name" : "Annotation of CPIC Guideline for metoprolol and CYP2D6", + "version" : 4 }, "text" : { - "id" : 1452060824, - "html" : "

Start with normal starting dose (e.g., 75 mg/m2/day or 1.5 mg/kg/day) and adjust doses of mercaptopurine (and of any other myelosuppressive therapy) without any special emphasis on mercaptopurine compared to other agents. Allow at least 2 weeks to reach steady-state after each dose adjustment (PMID 20354201, 16401827, 11302950).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "id" : 1452497950, + "html" : "

No recommendation

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298235", - "name" : "Recommendation PA166298235", + "id" : "PA166341354", + "name" : "Recommendation Annotation PA166341354", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", - "TPMT: Lower concentrations of TGN metabolites, higher MeTIMP, this is the ‘normal’ pattern. Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression." + "Increased metabolism of metoprolol leading to decreased drug concentrations; however, it is unclear whether this results in clinically significant changes in heart rate, blood pressure, or clinical outcomes" ], - "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "Possible Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "3.0"}, "otherPrescribingGuidance" : false, - "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA450379", - "name" : "mercaptopurine", - "version" : 31 + "id" : "PA450480", + "name" : "metoprolol", + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", - "id" : "PA166104945", - "name" : "Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT", - "version" : 47 + "id" : "PA166341321", + "name" : "Annotation of CPIC Guideline for metoprolol and CYP2D6", + "version" : 4 }, "text" : { - "id" : 1452060837, - "html" : "

Start with reduced starting doses (30%-80% of normal dose) if normal starting dose is ≥75 mg/m2/day or ≥ 1.5 mg/kg/day (e.g., start at 22.5-60 mg/m2/day or 0.45-1.2 mg/kg/day) and adjust doses of mercaptopurine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing mercaptopurine over other agents (PMID 20354201, 18685564, 8857546, 18987654, 20010622, 16401827, 11302950, 16530532, 9634537). If normal starting dose is already < 75 mg/m2/day or < 1.5 mg/kg/day, dose reduction may not be recommended.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "id" : 1452497951, + "html" : "

No recommendation for metoprolol therapy due to insufficient evidence regarding diminished metoprolol effectiveness clinically

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298230", - "name" : "Recommendation PA166298230", - "alternateDrugAvailable" : true, + "id" : "PA166341355", + "name" : "Recommendation Annotation PA166341355", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "NUDT15: Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", - "TPMT: n/a" + "Increased metabolism of metoprolol leading to decreased drug concentrations; however, it is unclear whether this results in clinically significant changes in heart rate, blood pressure, or clinical outcomes" ], - "lookupKey" : {"TPMT": "No Result", "NUDT15": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "4.0"}, "otherPrescribingGuidance" : false, - "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA450379", - "name" : "mercaptopurine", - "version" : 31 + "id" : "PA450480", + "name" : "metoprolol", + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", - "id" : "PA166104945", - "name" : "Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT", - "version" : 47 + "id" : "PA166341321", + "name" : "Annotation of CPIC Guideline for metoprolol and CYP2D6", + "version" : 4 }, "text" : { - "id" : 1452060832, - "html" : "

Based on NUDT15 status, for malignancy, initiate dose at 10 mg/m2/day and adjust dose based on myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing mercaptopurine over other agents. For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy (PMID 20354201, 1960624, 11302950, 16530532). TPMT genotype result is not available. Consider evaluating TPMT erythrocyte activity to assess TPMT phenotype. If thiopurines are required and TPMT status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers. Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", + "id" : 1452497952, + "html" : "

No recommendation for metoprolol therapy due to insufficient evidence regarding diminished metoprolol effectiveness clinically

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298221", - "name" : "Recommendation PA166298221", + "id" : "PA166341356", + "name" : "Recommendation Annotation PA166341356", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "NUDT15: Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression", - "TPMT: Moderate to high concentrations of TGN metabolites; low concentrations of MeTIMP. Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." + "Increased metabolism of metoprolol leading to decreased drug concentrations; however, it is unclear whether this results in clinically significant changes in heart rate, blood pressure, or clinical outcomes" ], - "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.0"}, "otherPrescribingGuidance" : false, - "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA450379", - "name" : "mercaptopurine", - "version" : 31 + "id" : "PA450480", + "name" : "metoprolol", + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", - "id" : "PA166104945", - "name" : "Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT", - "version" : 47 + "id" : "PA166341321", + "name" : "Annotation of CPIC Guideline for metoprolol and CYP2D6", + "version" : 4 }, "text" : { - "id" : 1452060823, - "html" : "

Start with reduced starting doses (30%-80% of normal dose) if normal starting dose is ≥ 75 mg/m2/day or ≥ 1.5 mg/kg/day (e.g. start at 22.5-60 mg/m2/day or 0.45-1.2 mg/kg/day) and adjust doses of mercaptopurine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing mercaptopurine over other agents (PMID 20354201,18685564, 8857546, 18987654, 20010622, 16401827, 11302950, 16530532, 9634537). If normal starting dose is already < 75 mg/m2/day or < 1.5 mg/kg/day, dose reduction may not be recommended.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "id" : 1452497953, + "html" : "

No recommendation for metoprolol therapy due to insufficient evidence regarding diminished metoprolol effectiveness clinically

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298208", - "name" : "Recommendation PA166298208", + "id" : "PA166341357", + "name" : "Recommendation Annotation PA166341357", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "NUDT15: n/a", - "TPMT: Moderate to high concentrations of TGN metabolites; low concentrations of MeTIMP. Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." + "Increased metabolism of metoprolol leading to decreased drug concentrations; however, it is unclear whether this results in clinically significant changes in heart rate, blood pressure, or clinical outcomes" ], - "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "No Result"}, + "lookupKey" : {"CYP2D6": "≥3.25"}, "otherPrescribingGuidance" : false, - "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA450379", - "name" : "mercaptopurine", - "version" : 31 + "id" : "PA450480", + "name" : "metoprolol", + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", - "id" : "PA166104945", - "name" : "Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT", - "version" : 47 + "id" : "PA166341321", + "name" : "Annotation of CPIC Guideline for metoprolol and CYP2D6", + "version" : 4 }, "text" : { - "id" : 1452060810, - "html" : "

Based on TPMT status, start with reduced starting doses (30%-80% of normal dose) if normal starting dose is ≥ 75 mg/m2/day or ≥ 1.5 mg/kg/day (e.g., start at 22.5-60 mg/m2/day or 0.45-1.2 mg/kg/day) and adjust doses of mercaptopurine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing mercaptopurine over other agents (PMID 20354201,18685564, 8857546, 18987654, 20010622, 16401827, 11302950, 16530532, 9634537). If normal starting dose is already < 75 mg/m2/day or < 1.5 mg/kg/day, dose reduction may not be recommended. NUDT15 genotype result is not available. If thiopurines are required and either TPMT or NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "id" : 1452497954, + "html" : "

No recommendation for metoprolol therapy due to insufficient evidence regarding diminished metoprolol effectiveness clinically

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298214", - "name" : "Recommendation PA166298214", + "id" : "PA166341358", + "name" : "Recommendation Annotation PA166341358", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", - "TPMT: Moderate to high concentrations of TGN metabolites; low concentrations of MeTIMP. Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." + "Increased metabolism of metoprolol leading to decreased drug concentrations; however, it is unclear whether this results in clinically significant changes in heart rate, blood pressure, or clinical outcomes" ], - "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.5"}, "otherPrescribingGuidance" : false, - "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA450379", - "name" : "mercaptopurine", - "version" : 31 + "id" : "PA450480", + "name" : "metoprolol", + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", - "id" : "PA166104945", - "name" : "Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT", - "version" : 47 + "id" : "PA166341321", + "name" : "Annotation of CPIC Guideline for metoprolol and CYP2D6", + "version" : 4 }, "text" : { - "id" : 1452060816, - "html" : "

Start with reduced starting doses (20%-50% of normal dose) if normal starting dose is ≥ 75 mg/m2/day or ≥ 1.5 mg/kg/day (e.g., start at 15-37.5 mg/m2/day or 0.3-0.75 mg/kg/day) and adjust doses of mercaptopurine based on degree of myelosuppression and disease-specific guidelines. At least 2-4 weeks will be required to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing mercaptopurine over other agents (PMID 20354201,18685564, 8857546, 18987654, 20010622, 16401827, 11302950, 16530532, 9634537, 38230823). If normal starting dose is already < 37.5 mg/m2/day or < 0.75 mg/kg/day, dose reduction may not be recommended.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", - "version" : 1 + "id" : 1452497955, + "html" : "

No recommendation for metoprolol therapy due to insufficient evidence regarding diminished metoprolol effectiveness clinically

\n", + "version" : 0 }, - "version" : 1 + "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298227", - "name" : "Recommendation PA166298227", - "alternateDrugAvailable" : true, + "id" : "PA166341359", + "name" : "Recommendation Annotation PA166341359", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "NUDT15: Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", - "TPMT: Moderate to high concentrations of TGN metabolites; low concentrations of MeTIMP. Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." + "Increased metabolism of metoprolol leading to decreased drug concentrations; however, it is unclear whether this results in clinically significant changes in heart rate, blood pressure, or clinical outcomes" ], - "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥4.0"}, "otherPrescribingGuidance" : false, - "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA450379", - "name" : "mercaptopurine", - "version" : 31 + "id" : "PA450480", + "name" : "metoprolol", + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", - "id" : "PA166104945", - "name" : "Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT", - "version" : 47 + "id" : "PA166341321", + "name" : "Annotation of CPIC Guideline for metoprolol and CYP2D6", + "version" : 4 }, "text" : { - "id" : 1452060829, - "html" : "

For malignancy, initiate dose at 10 mg/m2/day and adjust dose based on myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing mercaptopurine over other agents. For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy (PMID 20354201, 1960624, 11302950, 16530532).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "id" : 1452497956, + "html" : "

No recommendation for metoprolol therapy due to insufficient evidence regarding diminished metoprolol effectiveness clinically

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298218", - "name" : "Recommendation PA166298218", + "id" : "PA166341360", + "name" : "Recommendation Annotation PA166341360", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", - "TPMT: n/a" + "Increased metabolism of metoprolol leading to decreased drug concentrations; however, it is unclear whether this results in clinically significant changes in heart rate, blood pressure, or clinical outcomes" ], - "lookupKey" : {"TPMT": "No Result", "NUDT15": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥5.0"}, "otherPrescribingGuidance" : false, - "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA450379", - "name" : "mercaptopurine", - "version" : 31 + "id" : "PA450480", + "name" : "metoprolol", + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", - "id" : "PA166104945", - "name" : "Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT", - "version" : 47 + "id" : "PA166341321", + "name" : "Annotation of CPIC Guideline for metoprolol and CYP2D6", + "version" : 4 }, "text" : { - "id" : 1452060820, - "html" : "

Based NUDT15 status, start with reduced starting doses (30%-80% of normal dose) if normal starting dose is ≥75 mg/m2/day or ≥ 1.5 mg/kg/day (e.g., start at 22.5-60 mg/m2/day or 0.45-1.2 mg/kg/day) and adjust doses of mercaptopurine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing mercaptopurine over other agents (PMID 20354201, 18685564, 8857546, 18987654, 20010622, 16401827, 11302950, 16530532, 9634537). If normal starting dose is already < 75 mg/m2/day or < 1.5 mg/kg/day, dose reduction may not be recommended. TPMT genotype result is not available. Consider evaluating TPMT erythrocyte activity to assess TPMT phenotype. If thiopurines are required and either TPMT or NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers. Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", + "id" : 1452497957, + "html" : "

No recommendation for metoprolol therapy due to insufficient evidence regarding diminished metoprolol effectiveness clinically

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298205", - "name" : "Recommendation PA166298205", + "id" : "PA166341361", + "name" : "Recommendation Annotation PA166341361", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "NUDT15: n/a", - "TPMT: n/a" + "Decreased metabolism of metoprolol leading to increased drug concentrations; however, this does not appear to translate into clinically significant changes in heart rate, blood pressure, or clinical outcomes" ], - "lookupKey" : {"TPMT": "No Result", "NUDT15": "Indeterminate"}, - "otherPrescribingGuidance" : true, - "population" : "general", + "lookupKey" : {"CYP2D6": "0.5"}, + "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA450379", - "name" : "mercaptopurine", - "version" : 31 + "id" : "PA450480", + "name" : "metoprolol", + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", - "id" : "PA166104945", - "name" : "Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT", - "version" : 47 + "id" : "PA166341321", + "name" : "Annotation of CPIC Guideline for metoprolol and CYP2D6", + "version" : 4 }, "text" : { - "id" : 1452060807, - "html" : "

NUDT15 phenotype could not be assigned based on genotyping performed and there is no TPMT genotype result. Consider evaluating TPMT erythrocyte activity to assess TPMT phenotype. If thiopurines are required and either TPMT or NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", + "id" : 1452497960, + "html" : "

Initiate standard dosing

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298210", - "name" : "Recommendation PA166298210", + "id" : "PA166341362", + "name" : "Recommendation Annotation PA166341362", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "NUDT15: n/a", - "TPMT: Lower concentrations of TGN metabolites, higher MeTIMP, this is the ‘normal’ pattern. Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression." + "Decreased metabolism of metoprolol leading to increased drug concentrations; however, this does not appear to translate into clinically significant changes in heart rate, blood pressure, or clinical outcomes" ], - "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "No Result"}, + "lookupKey" : {"CYP2D6": "1.0"}, "otherPrescribingGuidance" : false, - "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA450379", - "name" : "mercaptopurine", - "version" : 31 + "id" : "PA450480", + "name" : "metoprolol", + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", - "id" : "PA166104945", - "name" : "Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT", - "version" : 47 + "id" : "PA166341321", + "name" : "Annotation of CPIC Guideline for metoprolol and CYP2D6", + "version" : 4 }, "text" : { - "id" : 1452060812, - "html" : "

Based on TPMT status, start with normal starting dose (e.g., 75 mg/m2/day or 1.5 mg/kg/day) and adjust doses of mercaptopurine (and of any other myelosuppressive therapy) without any special emphasis on mercaptopurine compared to other agents. Allow at least 2 weeks to reach steady-state after each dose adjustment (PMID 20354201, 16401827, 11302950). NUDT15 genotype result is not available. If thiopurines are required and either TPMT or NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "id" : 1452497961, + "html" : "

Initiate standard dosing

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298223", - "name" : "Recommendation PA166298223", - "alternateDrugAvailable" : true, + "id" : "PA166341363", + "name" : "Recommendation Annotation PA166341363", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, "parents" : [], @@ -71535,40 +72480,38 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "NUDT15: Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression", - "TPMT: Extremely high concentrations of TGN metabolites; fatal toxicity possible without dose decrease; no MeTIMP metabolites. Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." + "Normal metabolism of metoprolol" ], - "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.0"}, "otherPrescribingGuidance" : false, - "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA450379", - "name" : "mercaptopurine", - "version" : 31 + "id" : "PA450480", + "name" : "metoprolol", + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", - "id" : "PA166104945", - "name" : "Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT", - "version" : 47 + "id" : "PA166341321", + "name" : "Annotation of CPIC Guideline for metoprolol and CYP2D6", + "version" : 4 }, "text" : { - "id" : 1452060825, - "html" : "

For malignancy, start with drastically reduced doses (reduce daily dose by 10-fold and reduce frequency to thrice weekly instead of daily, e.g., 10 mg/m2/day given just 3 days/week) and adjust doses of mercaptopurine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing mercaptopurine over other agents. For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy (PMID 20354201, 1960624, 11302950, 16530532).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "id" : 1452497962, + "html" : "

Initiate standard dosing

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298236", - "name" : "Recommendation PA166298236", - "alternateDrugAvailable" : true, + "id" : "PA166341364", + "name" : "Recommendation Annotation PA166341364", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, "parents" : [], @@ -71578,166 +72521,199 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", - "TPMT: Extremely high concentrations of TGN metabolites; fatal toxicity possible without dose decrease; no MeTIMP metabolites. Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." + "Normal metabolism of metoprolol" ], - "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Possible Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.25"}, "otherPrescribingGuidance" : false, - "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA450379", - "name" : "mercaptopurine", - "version" : 31 + "id" : "PA450480", + "name" : "metoprolol", + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", - "id" : "PA166104945", - "name" : "Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT", - "version" : 47 + "id" : "PA166341321", + "name" : "Annotation of CPIC Guideline for metoprolol and CYP2D6", + "version" : 4 }, "text" : { - "id" : 1452060838, - "html" : "

For malignancy, start with drastically reduced doses (reduce daily dose by 10-fold and reduce frequency to thrice weekly instead of daily, e.g., 10 mg/m2/day given just 3 days/week) and adjust doses of mercaptopurine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing mercaptopurine over other agents. For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy (PMID 20354201, 1960624, 11302950, 16530532).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "id" : 1452497963, + "html" : "

Initiate standard dosing

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298201", - "name" : "Recommendation PA166298201", + "id" : "PA166341365", + "name" : "Recommendation Annotation PA166341365", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "NUDT15: n/a", - "TPMT: Moderate to high concentrations of TGN metabolites; low concentrations of MeTIMP. Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." + "Increased metabolism of metoprolol leading to decreased drug concentrations; however, it is unclear whether this results in clinically significant changes in heart rate, blood pressure, or clinical outcomes" ], - "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "2.5"}, "otherPrescribingGuidance" : false, - "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA450379", - "name" : "mercaptopurine", - "version" : 31 + "id" : "PA450480", + "name" : "metoprolol", + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", - "id" : "PA166104945", - "name" : "Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT", - "version" : 47 + "id" : "PA166341321", + "name" : "Annotation of CPIC Guideline for metoprolol and CYP2D6", + "version" : 4 }, "text" : { - "id" : 1452060803, - "html" : "

Based on TPMT status, start with reduced starting doses (30%-80% of normal dose) if normal starting dose is ≥ 75 mg/m2/day or ≥ 1.5 mg/kg/day (e.g., start at 22.5-60 mg/m2/day or 0.45-1.2 mg/kg/day) and adjust doses of mercaptopurine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing mercaptopurine over other agents (PMID 20354201,18685564, 8857546, 18987654, 20010622, 16401827, 11302950, 16530532, 9634537). If normal starting dose is already < 75 mg/m2/day or < 1.5 mg/kg/day, dose reduction may not be recommended. NUDT15 phenotype could not be assigned based on genotyping. If thiopurines are required and either TPMT or NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "id" : 1452497964, + "html" : "

No recommendation for metoprolol therapy due to insufficient evidence regarding diminished metoprolol effectiveness clinically

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298209", - "name" : "Recommendation PA166298209", + "id" : "PA166341366", + "name" : "Recommendation Annotation PA166341366", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "NUDT15: n/a", - "TPMT: Moderate to high concentrations of TGN metabolites; low concentrations of MeTIMP. Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." + "Increased metabolism of metoprolol leading to decreased drug concentrations; however, it is unclear whether this results in clinically significant changes in heart rate, blood pressure, or clinical outcomes" ], - "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "No Result"}, + "lookupKey" : {"CYP2D6": "2.75"}, "otherPrescribingGuidance" : false, - "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA450379", - "name" : "mercaptopurine", - "version" : 31 + "id" : "PA450480", + "name" : "metoprolol", + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", - "id" : "PA166104945", - "name" : "Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT", - "version" : 47 + "id" : "PA166341321", + "name" : "Annotation of CPIC Guideline for metoprolol and CYP2D6", + "version" : 4 }, "text" : { - "id" : 1452060811, - "html" : "

Based on TPMT status, start with reduced starting doses (30%-80% of normal dose) if normal starting dose is ≥ 75 mg/m2/day or ≥ 1.5 mg/kg/day (e.g., start at 22.5-60 mg/m2/day or 0.45-1.2 mg/kg/day) and adjust doses of mercaptopurine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing mercaptopurine over other agents (PMID 20354201,18685564, 8857546, 18987654, 20010622, 16401827, 11302950, 16530532, 9634537). If normal starting dose is already < 75 mg/m2/day or < 1.5 mg/kg/day, dose reduction may not be recommended. NUDT15 genotype result is not available. If thiopurines are required and either TPMT or NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "id" : 1452497965, + "html" : "

No recommendation for metoprolol therapy due to insufficient evidence regarding diminished metoprolol effectiveness clinically

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298203", - "name" : "Recommendation PA166298203", + "id" : "PA166341367", + "name" : "Recommendation Annotation PA166341367", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "NUDT15: n/a", - "TPMT: Lower concentrations of TGN metabolites, higher MeTIMP, this is the ‘normal’ pattern. Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression." + "Increased metabolism of metoprolol leading to decreased drug concentrations; however, it is unclear whether this results in clinically significant changes in heart rate, blood pressure, or clinical outcomes" ], - "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "≥3.75"}, "otherPrescribingGuidance" : false, - "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", - "id" : "PA450379", - "name" : "mercaptopurine", - "version" : 31 + "id" : "PA450480", + "name" : "metoprolol", + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", - "id" : "PA166104945", - "name" : "Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT", - "version" : 47 + "id" : "PA166341321", + "name" : "Annotation of CPIC Guideline for metoprolol and CYP2D6", + "version" : 4 }, "text" : { - "id" : 1452060805, - "html" : "

Based on TPMT status, start with normal starting dose (e.g., 75 mg/m2/day or 1.5 mg/kg/day) and adjust doses of mercaptopurine (and of any other myelosuppressive therapy) without any special emphasis on mercaptopurine compared to other agents. Allow at least 2 weeks to reach steady-state after each dose adjustment (PMID 20354201, 16401827, 11302950). NUDT15 phenotype could not be assigned based on genotyping. If thiopurines are required and either TPMT or NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "id" : 1452497966, + "html" : "

No recommendation for metoprolol therapy due to insufficient evidence regarding diminished metoprolol effectiveness clinically

\n", "version" : 0 }, - "version" : 1 + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166341368", + "name" : "Recommendation Annotation PA166341368", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 1448526251, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : false, + "implications" : [ + "Increased metabolism of metoprolol leading to decreased drug concentrations; however, it is unclear whether this results in clinically significant changes in heart rate, blood pressure, or clinical outcomes" + ], + "lookupKey" : {"CYP2D6": "≥6.0"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA450480", + "name" : "metoprolol", + "version" : 37 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166341321", + "name" : "Annotation of CPIC Guideline for metoprolol and CYP2D6", + "version" : 4 + }, + "text" : { + "id" : 1452497967, + "html" : "

No recommendation for metoprolol therapy due to insufficient evidence regarding diminished metoprolol effectiveness clinically

\n", + "version" : 0 + }, + "version" : 0 } ], - "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166104945" + "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166341321" }, { "citations" : [], @@ -71790,7 +72766,7 @@ "objCls" : "Chemical", "id" : "PA450640", "name" : "nitrofurantoin", - "version" : 6 + "version" : 20 } ], "relatedGenes" : [ @@ -71799,30 +72775,30 @@ "id" : "PA28469", "symbol" : "G6PD", "name" : "glucose-6-phosphate dehydrogenase", - "version" : 135 + "version" : 1326 } ], "source" : "CPIC", "summaryMarkdown" : { "id" : 1451901160, "html" : "

Nitrofurantoin should be use with caution in G6PD deficient patients without chronic non-spherocytic hemolytic anemia (CNSHA) and completely avoided by G6PD deficient patients with CNSHA. In patients with a G6PD variable or indeterminate phenotype an enzyme activity test should be carried out before initiating drug therapy.

\n

The G6PD gene is located on the X chromosome. Therefore, some patients will only have one copy, whereas others will have two copies. See full guideline for disclaimers, further details and supporting evidence.

\n", - "version" : 0 + "version" : 1 }, "terms" : [], "textMarkdown" : { "id" : 1451901161, "html" : "

This annotation is based on the Expanded CPIC® Guideline for Medication Use in the Context of G6PD Genotype. The CPIC authors evaluated the available evidence for the use of various drugs in patients carrying G6PD variants.

\n

September 2022

\n\n\n

Adapted from Tables 1, 2 and 5 of the guideline

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Predicted PhenotypeGenotypeaExample genotypesbImplicationsTherapeutic RecommendationsClassification of recommendationscConsiderations
NormalA person with one X chromosome carrying a non-deficient (class IV) allele
OR
A person carrying two non-deficient (class IV) alleles		B, Sao Boria, IV
 
B/B, B/Sao Boria, B/A, IV/IV		Low risk of acute hemolytic anemiaNo reason to avoid medium risk drugs based on G6PD statusStrong
DeficientA person with one X chromosome carrying a deficient (class II-III) allele
OR
A person carrying two deficient (class II-III) alleles OR one class I allele and one class II or III allele		A-, Orissa, Kalyan-Kerala, Mediterranean, Canton, Chatham, II, III
 
A-/A-, A-/Orissa, Orissa/ Kalyan-Kerala, Mediterranean/ Mediterranean, Chatham /Mediterranean, Canton/ Viangchan, II/II, II/III, III/III, I/II, I/III		Medium risk of acute hemolytic anemiaUse medium risk drugs at standard doses with caution and with close monitoring for anemiaOptionalClose monitoring may be more important at higher or more chronic dosage schedules, and in the setting of infection or other oxidative stress, including concomitant use of multiple medium and low-to-no risk drugs.
Deficient with CNSHAA person with one X chromosome carrying a deficient (class I) allele
OR
A person carrying two deficient (class I) allelesd		Bangkok, Villeurbanne, I
 
Bangkok/Bangkok, Bangkok/Villeurbanne, I/I		High risk of acute exacerbation of chronic hemolysisAvoid medium risk drugsModerateThere are insufficient data in patients with the G6PD Deficient with CNSHA phenotype to rate as “strong,” but all medium risk drugs should be avoided in these rare patients due to the underlying pathophysiology that confers high risk for acute exacerbation of chronic hemolysis.
VariableeA person carrying one non-deficient (class IV) allele and one deficient (class I-III) alleleB /Bangkok, B/Mediterranean, B/A-, IV/I, IV/II, IV/IIIVariable risk of acute hemolytic anemiaIf deemed necessary to ascertain G6PD status, enzyme activity must be measured. Drug use should be guided per the recommendations based on the activity-based phenotype.ModerateDue to X-linked mosaicism, individuals with more than one X chromosome (e.g., females, individuals with Klinefelter syndrome) and heterozygous for one non-deficient (class IV) and one deficient (class I–III) allele may display a normal or a deficient phenotype; an enzyme activity test is needed to assign G6PD phenotype in such cases.
IndeterminateA person carrying at least one allele with uncertain functionDagua
 
B/Dagua		Unknown risk of acute hemolytic anemiaTo ascertain G6PD status, enzyme activity must be measured. Drug use should be guided per the recommendations based on the activity-based phenotype.Moderate
\n

CNSHA: chronic non-spherocytic hemolytic anemia
\na WHO classifications from [Article:22293322], other details from [Article:4963040]. Class I alleles are extremely rare; the distinction between Class II and III alleles is not clear. Almost all patients will carry class II, III, or IV alleles.
\nb Due to the large number of G6PD alleles, other genotypes may be possible besides those given as examples here; see the G6PD Allele Definition Table for a more comprehensive list of alleles and G6PD Allele Functionality Table for their assigned function (WHO class). Note that some labs use the designation “B allele” to indicate an allele carrying no known class I-III variants. The G6PD Frequency Table can be referenced for the frequency of G6PD alleles across major biogeographical groups.
\nc Rating scheme described in the Strength of Recommendations section in the guideline supplement.
\nd Such genotypes have never been seen and are presumably exceedingly rare.
\ne Due to X-linked mosaicism, persons heterozygous (generally females) for one non-deficient (class IV) and one deficient (class I-III alleles) allele may display a normal or a deficient phenotype. It is therefore difficult to predict the phenotype of these individuals (see Supplement, G6PD Heterozygotes).

\n", - "version" : 1 + "version" : 8 }, "userId" : "rachel", - "version" : 3 + "version" : 16 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166298246", - "name" : "Recommendation PA166298246", - "alternateDrugAvailable" : true, + "id" : "PA166298247", + "name" : "Recommendation PA166298247", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, "parents" : [], @@ -71834,135 +72810,135 @@ }, "dosingInformation" : false, "implications" : [ - "G6PD: High risk of acute of acute exacerbation of chronic hemolysis" + "G6PD: Variable risk of acute hemolytic anemia" ], - "lookupKey" : {"G6PD": "Deficient with CNSHA"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"G6PD": "Variable"}, + "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450640", "name" : "nitrofurantoin", - "version" : 6 + "version" : 20 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166279721", "name" : "Annotation of CPIC Guideline for nitrofurantoin and G6PD", - "version" : 3 + "version" : 16 }, "text" : { - "id" : 1452060848, - "html" : "

Avoid

\n

Other Considerations

\n

There are insufficient data in patients with the G6PD Deficient with CNSHA phenotype to rate as "strong," but all medium risk drugs should be avoided in these rare patients due to the underlying pathophysiology that confers high risk for acute exacerbation of chronic hemolysis.

\n", + "id" : 1452060849, + "html" : "

If deemed necessary to ascertain G6PD status, enzyme activity must be measured. Drug use should be guided per the recommendations based on the activity-based phenotype.

\n

Other Considerations

\n

Due to X-linked mosaicism, individuals with more than one X chromosome (e.g., females, individuals with Klinefelter syndrome) and heterozygous for one non-deficient (class IV) and one deficient (class I–III) allele may display a normal or a deficient phenotype; an enzyme activity test is needed to assign G6PD phenotype in such cases.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298245", - "name" : "Recommendation PA166298245", - "alternateDrugAvailable" : false, + "id" : "PA166298246", + "name" : "Recommendation PA166298246", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981565059, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "G6PD: Medium risk of acute hemolytic anemia" + "G6PD: High risk of acute of acute exacerbation of chronic hemolysis" ], - "lookupKey" : {"G6PD": "Deficient"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"G6PD": "Deficient with CNSHA"}, + "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450640", "name" : "nitrofurantoin", - "version" : 6 + "version" : 20 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166279721", "name" : "Annotation of CPIC Guideline for nitrofurantoin and G6PD", - "version" : 3 + "version" : 16 }, "text" : { - "id" : 1452060847, - "html" : "

Use at standard doses with caution and with close monitoring for anemia

\n

Other Considerations

\n

Close monitoring may be more important at higher or more chronic dosage schedules, and in the setting of infection or other oxidative stress including concomitant use of multiple medium and low-to-no risk drugs.

\n", + "id" : 1452060848, + "html" : "

Avoid

\n

Other Considerations

\n

There are insufficient data in patients with the G6PD Deficient with CNSHA phenotype to rate as "strong," but all medium risk drugs should be avoided in these rare patients due to the underlying pathophysiology that confers high risk for acute exacerbation of chronic hemolysis.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298247", - "name" : "Recommendation PA166298247", + "id" : "PA166298244", + "name" : "Recommendation PA166298244", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "G6PD: Variable risk of acute hemolytic anemia" + "G6PD: Low risk of acute hemolytic anemia" ], - "lookupKey" : {"G6PD": "Variable"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"G6PD": "Normal"}, + "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450640", "name" : "nitrofurantoin", - "version" : 6 + "version" : 20 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166279721", "name" : "Annotation of CPIC Guideline for nitrofurantoin and G6PD", - "version" : 3 + "version" : 16 }, "text" : { - "id" : 1452060849, - "html" : "

If deemed necessary to ascertain G6PD status, enzyme activity must be measured. Drug use should be guided per the recommendations based on the activity-based phenotype.

\n

Other Considerations

\n

Due to X-linked mosaicism, individuals with more than one X chromosome (e.g., females, individuals with Klinefelter syndrome) and heterozygous for one non-deficient (class IV) and one deficient (class I–III) allele may display a normal or a deficient phenotype; an enzyme activity test is needed to assign G6PD phenotype in such cases.

\n", + "id" : 1452060846, + "html" : "

No reason to avoid based on G6PD status

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298248", - "name" : "Recommendation PA166298248", + "id" : "PA166298245", + "name" : "Recommendation PA166298245", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "G6PD: Unknown risk of acute hemolytic anemia" + "G6PD: Medium risk of acute hemolytic anemia" ], - "lookupKey" : {"G6PD": "Indeterminate"}, + "lookupKey" : {"G6PD": "Deficient"}, "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ @@ -71970,63 +72946,63 @@ "objCls" : "Chemical", "id" : "PA450640", "name" : "nitrofurantoin", - "version" : 6 + "version" : 20 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166279721", "name" : "Annotation of CPIC Guideline for nitrofurantoin and G6PD", - "version" : 3 + "version" : 16 }, "text" : { - "id" : 1452060850, - "html" : "

To ascertain G6PD status, enzyme activity must be measured. Drug use should be guided per the recommendations based on the activity-based phenotype.

\n", + "id" : 1452060847, + "html" : "

Use at standard doses with caution and with close monitoring for anemia

\n

Other Considerations

\n

Close monitoring may be more important at higher or more chronic dosage schedules, and in the setting of infection or other oxidative stress including concomitant use of multiple medium and low-to-no risk drugs.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298244", - "name" : "Recommendation PA166298244", + "id" : "PA166298248", + "name" : "Recommendation PA166298248", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "G6PD: Low risk of acute hemolytic anemia" + "G6PD: Unknown risk of acute hemolytic anemia" ], - "lookupKey" : {"G6PD": "Normal"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"G6PD": "Indeterminate"}, + "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450640", "name" : "nitrofurantoin", - "version" : 6 + "version" : 20 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166279721", "name" : "Annotation of CPIC Guideline for nitrofurantoin and G6PD", - "version" : 3 + "version" : 16 }, "text" : { - "id" : 1452060846, - "html" : "

No reason to avoid based on G6PD status

\n", + "id" : 1452060850, + "html" : "

To ascertain G6PD status, enzyme activity must be measured. Drug use should be guided per the recommendations based on the activity-based phenotype.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166279721" @@ -72267,7 +73243,7 @@ "pediatricMarkdown" : { "id" : 1451266640, "html" : "

Guideline excerpt: "There are scarce studies focusing solely on CYP2D6 or CYP2C19 genotype and association with pharmacokinetic parameters or treatment outcomes of TCAs in pediatric patients. Although further genomic ontogeny studies are needed, there is a lack of evidence suggesting that this guideline cannot be extrapolated to pediatric patients."

\n", - "version" : 0 + "version" : 1 }, "recommendation" : true, "relatedAlleles" : [], @@ -72276,7 +73252,7 @@ "objCls" : "Chemical", "id" : "PA450657", "name" : "nortriptyline", - "version" : 7 + "version" : 36 } ], "relatedGenes" : [ @@ -72285,14 +73261,14 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "CPIC", "summaryMarkdown" : { "id" : 1447982024, "html" : "

The CPIC Dosing Guideline update for nortriptyline recommends a 25% dose reduction for CYP2D6 intermediate metabolizers. For CYP2D6 ultrarapid or poor metabolizers, an alternative drug should be considered. If nortriptyline is warranted, consider a 50% dose reduction in CYP2D6 poor metabolizers.

\n", - "version" : 1 + "version" : 2 }, "terms" : [], "textMarkdown" : { @@ -72301,9 +73277,51 @@ "version" : 0 }, "userId" : "whaleyr", - "version" : 54 + "version" : 135 }, "recommendations" : [ + { + "objCls" : "Recommendation Annotation", + "id" : "PA166298258", + "name" : "Recommendation PA166298258", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501930, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : false, + "implications" : [ + "CYP2D6: Normal metabolism of tricyclic antidepressants" + ], + "lookupKey" : {"CYP2D6": "2.25"}, + "otherPrescribingGuidance" : false, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA450657", + "name" : "nortriptyline", + "version" : 36 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104998", + "name" : "Annotation of CPIC Guideline for nortriptyline and CYP2D6", + "version" : 135 + }, + "text" : { + "id" : 1452060860, + "html" : "

Initiate therapy with recommended starting dose

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "version" : 0 + }, + "version" : 1 + }, { "objCls" : "Recommendation Annotation", "id" : "PA166301325", @@ -72318,14 +73336,14 @@ "objCls" : "Chemical", "id" : "PA450657", "name" : "nortriptyline", - "version" : 7 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104998", "name" : "Annotation of CPIC Guideline for nortriptyline and CYP2D6", - "version" : 54 + "version" : 135 }, "text" : { "id" : 1452095644, @@ -72336,9 +73354,9 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298259", - "name" : "Recommendation PA166298259", - "alternateDrugAvailable" : false, + "id" : "PA166298207", + "name" : "Recommendation PA166298207", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, "parents" : [], @@ -72348,11 +73366,11 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2D6: Normal metabolism of tricyclic antidepressants" + "CYP2D6: Increased metabolism of tricyclic antidepressants to less active compounds compared to normal metabolizers. Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure." ], - "lookupKey" : {"CYP2D6": "2.0"}, + "lookupKey" : {"CYP2D6": "≥4.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -72360,26 +73378,26 @@ "objCls" : "Chemical", "id" : "PA450657", "name" : "nortriptyline", - "version" : 7 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104998", "name" : "Annotation of CPIC Guideline for nortriptyline and CYP2D6", - "version" : 54 + "version" : 135 }, "text" : { - "id" : 1452060861, - "html" : "

Initiate therapy with recommended starting dose

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060809, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a tricyclic antidepressant is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Utilize therapeutic drug monitoring to guide dose adjustments.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298254", - "name" : "Recommendation PA166298254", + "id" : "PA166298213", + "name" : "Recommendation PA166298213", "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, @@ -72394,7 +73412,7 @@ "implications" : [ "CYP2D6: Increased metabolism of tricyclic antidepressants to less active compounds compared to normal metabolizers. Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure." ], - "lookupKey" : {"CYP2D6": "4.0"}, + "lookupKey" : {"CYP2D6": "≥3.5"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -72402,17 +73420,17 @@ "objCls" : "Chemical", "id" : "PA450657", "name" : "nortriptyline", - "version" : 7 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104998", "name" : "Annotation of CPIC Guideline for nortriptyline and CYP2D6", - "version" : 54 + "version" : 135 }, "text" : { - "id" : 1452060856, + "id" : 1452060815, "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a tricyclic antidepressant is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Utilize therapeutic drug monitoring to guide dose adjustments.

\n", "version" : 0 }, @@ -72420,23 +73438,23 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298267", - "name" : "Recommendation PA166298267", - "alternateDrugAvailable" : false, + "id" : "PA166298200", + "name" : "Recommendation PA166298200", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501931, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2D6: Reduced metabolism of tricyclic antidepressants to less active compounds compared to normal metabolizers. Higher plasma concentrations of active drug will increase the probability of side effects." + "CYP2D6: Increased metabolism of tricyclic antidepressants to less active compounds compared to normal metabolizers. Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure." ], - "lookupKey" : {"CYP2D6": "0.25"}, + "lookupKey" : {"CYP2D6": "≥3.75"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -72444,26 +73462,26 @@ "objCls" : "Chemical", "id" : "PA450657", "name" : "nortriptyline", - "version" : 7 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104998", "name" : "Annotation of CPIC Guideline for nortriptyline and CYP2D6", - "version" : 54 + "version" : 135 }, "text" : { - "id" : 1452060869, - "html" : "

Consider a 25% reduction of recommended starting dose. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of tricyclic antidepressants for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452060802, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a tricyclic antidepressant is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Utilize therapeutic drug monitoring to guide dose adjustments.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298250", - "name" : "Recommendation PA166298250", + "id" : "PA166298249", + "name" : "Recommendation PA166298249", "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, @@ -72478,7 +73496,7 @@ "implications" : [ "CYP2D6: Increased metabolism of tricyclic antidepressants to less active compounds compared to normal metabolizers. Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure." ], - "lookupKey" : {"CYP2D6": "≥5.0"}, + "lookupKey" : {"CYP2D6": "≥6.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -72486,17 +73504,17 @@ "objCls" : "Chemical", "id" : "PA450657", "name" : "nortriptyline", - "version" : 7 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104998", "name" : "Annotation of CPIC Guideline for nortriptyline and CYP2D6", - "version" : 54 + "version" : 135 }, "text" : { - "id" : 1452060852, + "id" : 1452060851, "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a tricyclic antidepressant is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Utilize therapeutic drug monitoring to guide dose adjustments.

\n", "version" : 0 }, @@ -72504,9 +73522,9 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298260", - "name" : "Recommendation PA166298260", - "alternateDrugAvailable" : false, + "id" : "PA166298250", + "name" : "Recommendation PA166298250", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, "parents" : [], @@ -72516,11 +73534,11 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2D6: Normal metabolism of tricyclic antidepressants" + "CYP2D6: Increased metabolism of tricyclic antidepressants to less active compounds compared to normal metabolizers. Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure." ], - "lookupKey" : {"CYP2D6": "1.75"}, + "lookupKey" : {"CYP2D6": "≥5.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -72528,26 +73546,26 @@ "objCls" : "Chemical", "id" : "PA450657", "name" : "nortriptyline", - "version" : 7 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104998", "name" : "Annotation of CPIC Guideline for nortriptyline and CYP2D6", - "version" : 54 + "version" : 135 }, "text" : { - "id" : 1452060862, - "html" : "

Initiate therapy with recommended starting dose

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060852, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a tricyclic antidepressant is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Utilize therapeutic drug monitoring to guide dose adjustments.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298255", - "name" : "Recommendation PA166298255", + "id" : "PA166298252", + "name" : "Recommendation PA166298252", "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, @@ -72562,7 +73580,7 @@ "implications" : [ "CYP2D6: Increased metabolism of tricyclic antidepressants to less active compounds compared to normal metabolizers. Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure." ], - "lookupKey" : {"CYP2D6": "2.75"}, + "lookupKey" : {"CYP2D6": "≥3.25"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -72570,17 +73588,17 @@ "objCls" : "Chemical", "id" : "PA450657", "name" : "nortriptyline", - "version" : 7 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104998", "name" : "Annotation of CPIC Guideline for nortriptyline and CYP2D6", - "version" : 54 + "version" : 135 }, "text" : { - "id" : 1452060857, + "id" : 1452060854, "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a tricyclic antidepressant is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Utilize therapeutic drug monitoring to guide dose adjustments.

\n", "version" : 0 }, @@ -72588,8 +73606,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298268", - "name" : "Recommendation PA166298268", + "id" : "PA166298253", + "name" : "Recommendation PA166298253", "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, @@ -72602,9 +73620,9 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2D6: Greatly reduced metabolism of tricyclic antidepressants to less active compounds compared to normal metabolizers. Higher plasma concentrations of active drug will increase the probability of side effects." + "CYP2D6: Increased metabolism of tricyclic antidepressants to less active compounds compared to normal metabolizers. Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure." ], - "lookupKey" : {"CYP2D6": "0.0"}, + "lookupKey" : {"CYP2D6": "≥3.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -72612,26 +73630,26 @@ "objCls" : "Chemical", "id" : "PA450657", "name" : "nortriptyline", - "version" : 7 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104998", "name" : "Annotation of CPIC Guideline for nortriptyline and CYP2D6", - "version" : 54 + "version" : 135 }, "text" : { - "id" : 1452060870, - "html" : "

Avoid tricyclic use due to potential for side effects. Consider alternative drug not metabolized by CYP2D6. If a tricyclic antidepressant is warranted, consider a 50% reduction of recommended starting dose. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of tricyclic antidepressants for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452060855, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a tricyclic antidepressant is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Utilize therapeutic drug monitoring to guide dose adjustments.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298207", - "name" : "Recommendation PA166298207", + "id" : "PA166298254", + "name" : "Recommendation PA166298254", "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, @@ -72646,7 +73664,7 @@ "implications" : [ "CYP2D6: Increased metabolism of tricyclic antidepressants to less active compounds compared to normal metabolizers. Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure." ], - "lookupKey" : {"CYP2D6": "≥4.0"}, + "lookupKey" : {"CYP2D6": "4.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -72654,17 +73672,17 @@ "objCls" : "Chemical", "id" : "PA450657", "name" : "nortriptyline", - "version" : 7 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104998", "name" : "Annotation of CPIC Guideline for nortriptyline and CYP2D6", - "version" : 54 + "version" : 135 }, "text" : { - "id" : 1452060809, + "id" : 1452060856, "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a tricyclic antidepressant is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Utilize therapeutic drug monitoring to guide dose adjustments.

\n", "version" : 0 }, @@ -72672,23 +73690,23 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298264", - "name" : "Recommendation PA166298264", - "alternateDrugAvailable" : false, + "id" : "PA166298256", + "name" : "Recommendation PA166298256", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2D6: Reduced metabolism of tricyclic antidepressants to less active compounds compared to normal metabolizers. Higher plasma concentrations of active drug will increase the probability of side effects." + "CYP2D6: Increased metabolism of tricyclic antidepressants to less active compounds compared to normal metabolizers. Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure." ], - "lookupKey" : {"CYP2D6": "1.0"}, + "lookupKey" : {"CYP2D6": "3.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -72696,27 +73714,27 @@ "objCls" : "Chemical", "id" : "PA450657", "name" : "nortriptyline", - "version" : 7 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104998", "name" : "Annotation of CPIC Guideline for nortriptyline and CYP2D6", - "version" : 54 + "version" : 135 }, "text" : { - "id" : 1452060866, - "html" : "

Consider a 25% reduction of recommended starting dose. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of tricyclic antidepressants for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452060858, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a tricyclic antidepressant is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Utilize therapeutic drug monitoring to guide dose adjustments.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298261", - "name" : "Recommendation PA166298261", - "alternateDrugAvailable" : false, + "id" : "PA166298257", + "name" : "Recommendation PA166298257", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, "parents" : [], @@ -72726,11 +73744,11 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2D6: Normal metabolism of tricyclic antidepressants" + "CYP2D6: Increased metabolism of tricyclic antidepressants to less active compounds compared to normal metabolizers. Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure." ], - "lookupKey" : {"CYP2D6": "1.5"}, + "lookupKey" : {"CYP2D6": "2.5"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -72738,26 +73756,26 @@ "objCls" : "Chemical", "id" : "PA450657", "name" : "nortriptyline", - "version" : 7 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104998", "name" : "Annotation of CPIC Guideline for nortriptyline and CYP2D6", - "version" : 54 + "version" : 135 }, "text" : { - "id" : 1452060863, - "html" : "

Initiate therapy with recommended starting dose

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060859, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a tricyclic antidepressant is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Utilize therapeutic drug monitoring to guide dose adjustments.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298200", - "name" : "Recommendation PA166298200", + "id" : "PA166298268", + "name" : "Recommendation PA166298268", "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, @@ -72770,9 +73788,9 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2D6: Increased metabolism of tricyclic antidepressants to less active compounds compared to normal metabolizers. Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure." + "CYP2D6: Greatly reduced metabolism of tricyclic antidepressants to less active compounds compared to normal metabolizers. Higher plasma concentrations of active drug will increase the probability of side effects." ], - "lookupKey" : {"CYP2D6": "≥3.75"}, + "lookupKey" : {"CYP2D6": "0.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -72780,27 +73798,27 @@ "objCls" : "Chemical", "id" : "PA450657", "name" : "nortriptyline", - "version" : 7 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104998", "name" : "Annotation of CPIC Guideline for nortriptyline and CYP2D6", - "version" : 54 + "version" : 135 }, "text" : { - "id" : 1452060802, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a tricyclic antidepressant is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Utilize therapeutic drug monitoring to guide dose adjustments.

\n", + "id" : 1452060870, + "html" : "

Avoid tricyclic use due to potential for side effects. Consider alternative drug not metabolized by CYP2D6. If a tricyclic antidepressant is warranted, consider a 50% reduction of recommended starting dose. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of tricyclic antidepressants for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298213", - "name" : "Recommendation PA166298213", - "alternateDrugAvailable" : true, + "id" : "PA166298259", + "name" : "Recommendation PA166298259", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, "parents" : [], @@ -72810,11 +73828,11 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2D6: Increased metabolism of tricyclic antidepressants to less active compounds compared to normal metabolizers. Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure." + "CYP2D6: Normal metabolism of tricyclic antidepressants" ], - "lookupKey" : {"CYP2D6": "≥3.5"}, + "lookupKey" : {"CYP2D6": "2.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -72822,27 +73840,27 @@ "objCls" : "Chemical", "id" : "PA450657", "name" : "nortriptyline", - "version" : 7 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104998", "name" : "Annotation of CPIC Guideline for nortriptyline and CYP2D6", - "version" : 54 + "version" : 135 }, "text" : { - "id" : 1452060815, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a tricyclic antidepressant is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Utilize therapeutic drug monitoring to guide dose adjustments.

\n", + "id" : 1452060861, + "html" : "

Initiate therapy with recommended starting dose

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298256", - "name" : "Recommendation PA166298256", - "alternateDrugAvailable" : true, + "id" : "PA166298260", + "name" : "Recommendation PA166298260", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, "parents" : [], @@ -72852,11 +73870,11 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2D6: Increased metabolism of tricyclic antidepressants to less active compounds compared to normal metabolizers. Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure." + "CYP2D6: Normal metabolism of tricyclic antidepressants" ], - "lookupKey" : {"CYP2D6": "3.0"}, + "lookupKey" : {"CYP2D6": "1.75"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -72864,41 +73882,41 @@ "objCls" : "Chemical", "id" : "PA450657", "name" : "nortriptyline", - "version" : 7 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104998", "name" : "Annotation of CPIC Guideline for nortriptyline and CYP2D6", - "version" : 54 + "version" : 135 }, "text" : { - "id" : 1452060858, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a tricyclic antidepressant is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Utilize therapeutic drug monitoring to guide dose adjustments.

\n", + "id" : 1452060862, + "html" : "

Initiate therapy with recommended starting dose

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298269", - "name" : "Recommendation PA166298269", + "id" : "PA166298261", + "name" : "Recommendation PA166298261", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: n/a" + "CYP2D6: Normal metabolism of tricyclic antidepressants" ], - "lookupKey" : {"CYP2D6": "n/a"}, + "lookupKey" : {"CYP2D6": "1.5"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -72906,27 +73924,27 @@ "objCls" : "Chemical", "id" : "PA450657", "name" : "nortriptyline", - "version" : 7 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104998", "name" : "Annotation of CPIC Guideline for nortriptyline and CYP2D6", - "version" : 54 + "version" : 135 }, "text" : { - "id" : 1452060871, - "html" : "

No recommendation

\n

Other Considerations

\n

Because CYP2D6 phenotype could not be assigned based on genotyping performed, therapuetic monitoring should be considered. If therapuetic monitoring cannot be performed, monitor closely for toxicity and/or efficacy.

\n", + "id" : 1452060863, + "html" : "

Initiate therapy with recommended starting dose

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298252", - "name" : "Recommendation PA166298252", - "alternateDrugAvailable" : true, + "id" : "PA166298262", + "name" : "Recommendation PA166298262", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, "parents" : [], @@ -72936,11 +73954,53 @@ "valid" : true, "version" : 0 }, + "dosingInformation" : false, + "implications" : [ + "CYP2D6: Normal metabolism of tricyclic antidepressants" + ], + "lookupKey" : {"CYP2D6": "1.25"}, + "otherPrescribingGuidance" : false, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA450657", + "name" : "nortriptyline", + "version" : 36 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104998", + "name" : "Annotation of CPIC Guideline for nortriptyline and CYP2D6", + "version" : 135 + }, + "text" : { + "id" : 1452060864, + "html" : "

Initiate therapy with recommended starting dose

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "version" : 0 + }, + "version" : 1 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166298264", + "name" : "Recommendation PA166298264", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 981565059, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", + "valid" : true, + "version" : 0 + }, "dosingInformation" : true, "implications" : [ - "CYP2D6: Increased metabolism of tricyclic antidepressants to less active compounds compared to normal metabolizers. Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure." + "CYP2D6: Reduced metabolism of tricyclic antidepressants to less active compounds compared to normal metabolizers. Higher plasma concentrations of active drug will increase the probability of side effects." ], - "lookupKey" : {"CYP2D6": "≥3.25"}, + "lookupKey" : {"CYP2D6": "1.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -72948,21 +74008,21 @@ "objCls" : "Chemical", "id" : "PA450657", "name" : "nortriptyline", - "version" : 7 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104998", "name" : "Annotation of CPIC Guideline for nortriptyline and CYP2D6", - "version" : 54 + "version" : 135 }, "text" : { - "id" : 1452060854, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a tricyclic antidepressant is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Utilize therapeutic drug monitoring to guide dose adjustments.

\n", + "id" : 1452060866, + "html" : "

Consider a 25% reduction of recommended starting dose. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of tricyclic antidepressants for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -72990,105 +74050,21 @@ "objCls" : "Chemical", "id" : "PA450657", "name" : "nortriptyline", - "version" : 7 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104998", "name" : "Annotation of CPIC Guideline for nortriptyline and CYP2D6", - "version" : 54 + "version" : 135 }, "text" : { "id" : 1452060867, "html" : "

Consider a 25% reduction of recommended starting dose. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of tricyclic antidepressants for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166298258", - "name" : "Recommendation PA166298258", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 981501930, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "CYP2D6: Normal metabolism of tricyclic antidepressants" - ], - "lookupKey" : {"CYP2D6": "2.25"}, - "otherPrescribingGuidance" : false, - "population" : "general", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA450657", - "name" : "nortriptyline", - "version" : 7 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166104998", - "name" : "Annotation of CPIC Guideline for nortriptyline and CYP2D6", - "version" : 54 - }, - "text" : { - "id" : 1452060860, - "html" : "

Initiate therapy with recommended starting dose

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166298249", - "name" : "Recommendation PA166298249", - "alternateDrugAvailable" : true, - "classification" : { - "id" : 981501930, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : true, - "implications" : [ - "CYP2D6: Increased metabolism of tricyclic antidepressants to less active compounds compared to normal metabolizers. Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure." - ], - "lookupKey" : {"CYP2D6": "≥6.0"}, - "otherPrescribingGuidance" : false, - "population" : "general", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA450657", - "name" : "nortriptyline", - "version" : 7 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166104998", - "name" : "Annotation of CPIC Guideline for nortriptyline and CYP2D6", - "version" : 54 - }, - "text" : { - "id" : 1452060851, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a tricyclic antidepressant is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Utilize therapeutic drug monitoring to guide dose adjustments.

\n", - "version" : 0 - }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -73116,41 +74092,41 @@ "objCls" : "Chemical", "id" : "PA450657", "name" : "nortriptyline", - "version" : 7 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104998", "name" : "Annotation of CPIC Guideline for nortriptyline and CYP2D6", - "version" : 54 + "version" : 135 }, "text" : { "id" : 1452060868, "html" : "

Consider a 25% reduction of recommended starting dose. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of tricyclic antidepressants for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298257", - "name" : "Recommendation PA166298257", - "alternateDrugAvailable" : true, + "id" : "PA166298267", + "name" : "Recommendation PA166298267", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2D6: Increased metabolism of tricyclic antidepressants to less active compounds compared to normal metabolizers. Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure." + "CYP2D6: Reduced metabolism of tricyclic antidepressants to less active compounds compared to normal metabolizers. Higher plasma concentrations of active drug will increase the probability of side effects." ], - "lookupKey" : {"CYP2D6": "2.5"}, + "lookupKey" : {"CYP2D6": "0.25"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -73158,41 +74134,41 @@ "objCls" : "Chemical", "id" : "PA450657", "name" : "nortriptyline", - "version" : 7 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104998", "name" : "Annotation of CPIC Guideline for nortriptyline and CYP2D6", - "version" : 54 + "version" : 135 }, "text" : { - "id" : 1452060859, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a tricyclic antidepressant is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Utilize therapeutic drug monitoring to guide dose adjustments.

\n", + "id" : 1452060869, + "html" : "

Consider a 25% reduction of recommended starting dose. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of tricyclic antidepressants for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298262", - "name" : "Recommendation PA166298262", + "id" : "PA166298269", + "name" : "Recommendation PA166298269", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Normal metabolism of tricyclic antidepressants" + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "1.25"}, + "lookupKey" : {"CYP2D6": "n/a"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -73200,26 +74176,26 @@ "objCls" : "Chemical", "id" : "PA450657", "name" : "nortriptyline", - "version" : 7 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104998", "name" : "Annotation of CPIC Guideline for nortriptyline and CYP2D6", - "version" : 54 + "version" : 135 }, "text" : { - "id" : 1452060864, - "html" : "

Initiate therapy with recommended starting dose

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452060871, + "html" : "

No recommendation

\n

Other Considerations

\n

Because CYP2D6 phenotype could not be assigned based on genotyping performed, therapuetic monitoring should be considered. If therapuetic monitoring cannot be performed, monitor closely for toxicity and/or efficacy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298253", - "name" : "Recommendation PA166298253", + "id" : "PA166298255", + "name" : "Recommendation PA166298255", "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, @@ -73234,7 +74210,7 @@ "implications" : [ "CYP2D6: Increased metabolism of tricyclic antidepressants to less active compounds compared to normal metabolizers. Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure." ], - "lookupKey" : {"CYP2D6": "≥3.0"}, + "lookupKey" : {"CYP2D6": "2.75"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -73242,21 +74218,21 @@ "objCls" : "Chemical", "id" : "PA450657", "name" : "nortriptyline", - "version" : 7 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104998", "name" : "Annotation of CPIC Guideline for nortriptyline and CYP2D6", - "version" : 54 + "version" : 135 }, "text" : { - "id" : 1452060855, + "id" : 1452060857, "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a tricyclic antidepressant is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Utilize therapeutic drug monitoring to guide dose adjustments.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166104998" @@ -73427,7 +74403,7 @@ "objCls" : "Chemical", "id" : "PA450705", "name" : "ondansetron", - "version" : 9 + "version" : 44 } ], "relatedGenes" : [ @@ -73436,7 +74412,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "CPIC", @@ -73449,73 +74425,61 @@ "textMarkdown" : { "id" : 1451433671, "html" : "

This annotation is based on the CPIC® guideline for ondansetron and tropisetron and CYP2D6.

\n

October 2019 Update

\n

CYP2D6 genotype to phenotype translation changes: Up until August 2019, there were a few inconsistencies in the translation of CYP2D6 genotype to phenotype translation across guidelines (i.e. CPIC and DPWG) and between clinical genetic testing laboratories. CPIC recently conducted a modified-Delphi project to obtain consensus for a uniform system for translating CYP2D6 genotype to phenotype among a panel of international CYP2D6 experts more information. Modifications to CPIC’s prior system include downgrading the value assigned to the CYP2D6*10 allele for activity score calculation from 0.5 to 0.25 and changing the phenotype assignment for an activity score of 1 from normal metabolizer to intermediate metabolizer (table of all previous and new phenotype groupings).

\n

As a result, the following changes have been made in the CYP2D6 allele functionality table, CYP2D6 genotype to phenotype table (access tables below):

\n\n

December 2016

\n\n

Table 1: Dosing recommendations for ondansetron based on CYP2D6 phenotype/genotype

\n

Adapted from Tables 1 and 2 of the 2016 guideline manuscript.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
CYP2D6 PhenotypeActivity scoreCYP2D6 GenotypesaExamples of diplotypesImplicationsTherapeutic recommendationsClassification of RecommendationsbConsideration for alternative 5-HT3 receptor antagonists antiemeticsc
Ultrarapid metabolizer>2.0An individual carrying duplications of function alleles*1/*1xN, *1/*2xN, *2/*2xNdIncreased metabolism to less active compounds when compared to normal metabolizers and is associated with decreased response to ondansetron and tropisetron (i.e. vomiting).Select and alternative drug not predominantly metabolized by CYP2D6 (i.e. granisetron).eModerateDolasetron, palonosetron, and ramosetron are also metabolized by CYP2D6. Limited evidence is available regarding the utilization of CYP2D6 genetic variation to guide use of these drugs.
Normal metabolizer2.0-1.0fAn individual carrying two normal function alleles, or two decreased function alleles, or one normal function and one no function allele, or one normal function and one decreased function allele, or combinations of duplicated alleles that result in an activity score of 1.0-2.0*1/*1, *1/*2, *1/*4, *1/*5, *1/*9, *1/*41, *2/*2,*41/*41Normal metabolismInitiate therapy with recommended starting dose.Strong
Intermediate metabolizer0.5An individual carrying one decreased function and one no function allele*4/*10,*4/*41, *5/*9Very limited data available for CYP2D6 intermediate metabolizersInsufficient evidence demonstrating clinical impact based on CYP2D6 genotype. Initiate therapy with recommended starting dose.No recommendation
Poor metabolizer0An individual carrying no functional alleles*3/*4,*4/*4, *5/*5, *5/*6Very limited data available for CYP2D6 poor metabolizersInsufficient evidence demonstrating clinical impact based on CYP2D6 genotype. Initiate therapy with recommended starting dose.No recommendation
\n

a Assignment of allele function and citations for allele function can be found on PharmGKB: CYP2D6 Allele Definition Table and CYP2D6 Allele Functionality Table.

\n

b Rating scheme is described in the 2016 Supplement

\n

c CPIC strength of recommendation: No Recommendation. See rating scheme described in the Supplement.

\n

d Where xN represents the number of CYP2D6 gene copies. For individuals with CYP2D6 duplications or multiplications, see supplemental data for additional information on how to translate diplotypes into phenotypes.

\n

e Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy.

\n

f Patients with an activity score of 1.0 may be classified as intermediate metabolizers by some reference laboratories.

\n", - "version" : 1 + "version" : 2 }, "userId" : "carrillo", - "version" : 33 + "version" : 89 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166298294", - "name" : "Recommendation PA166298294", - "alternateDrugAvailable" : true, - "classification" : { - "id" : 981501931, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", - "valid" : true, - "version" : 0 - }, + "id" : "PA166301326", + "name" : "Recommendation Annotation PA166301326", + "alternateDrugAvailable" : false, "dosingInformation" : false, - "implications" : [ - "CYP2D6: Increased metabolism to less active compounds when compared to normal metabolizers and is associated with decreased response to ondansetron and tropisetron (i.e. vomiting)." - ], - "lookupKey" : {"CYP2D6": "≥3.75"}, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations"}, "otherPrescribingGuidance" : false, - "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450705", "name" : "ondansetron", - "version" : 9 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161954", "name" : "Annotation of CPIC Guideline for ondansetron and CYP2D6", - "version" : 33 + "version" : 89 }, "text" : { - "id" : 1452060896, - "html" : "

Select alternative drug not predominantly metabolized by CYP2D6 (i.e., granisetron).

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy. Dolasetron, palonosetron, and ramosetron are also metabolized by CYP2D6. Limited evidence is available regarding the utilization of CYP2D6 genetic variation to guide use of these drugs.

\n", + "id" : 1452095645, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298312", - "name" : "Recommendation PA166298312", + "id" : "PA166298305", + "name" : "Recommendation PA166298305", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Very limited data available for CYP2D6 poor metabolizers" + "CYP2D6: Normal metabolism" ], - "lookupKey" : {"CYP2D6": "0.0"}, + "lookupKey" : {"CYP2D6": "1.75"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -73523,26 +74487,26 @@ "objCls" : "Chemical", "id" : "PA450705", "name" : "ondansetron", - "version" : 9 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161954", "name" : "Annotation of CPIC Guideline for ondansetron and CYP2D6", - "version" : 33 + "version" : 89 }, "text" : { - "id" : 1452060914, - "html" : "

Insufficient evidence demonstrating clinical impact based on CYP2D6 genotype. Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy.

\n", + "id" : 1452060907, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298303", - "name" : "Recommendation PA166298303", + "id" : "PA166298304", + "name" : "Recommendation PA166298304", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -73557,7 +74521,7 @@ "implications" : [ "CYP2D6: Normal metabolism" ], - "lookupKey" : {"CYP2D6": "2.25"}, + "lookupKey" : {"CYP2D6": "2.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -73565,41 +74529,41 @@ "objCls" : "Chemical", "id" : "PA450705", "name" : "ondansetron", - "version" : 9 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161954", "name" : "Annotation of CPIC Guideline for ondansetron and CYP2D6", - "version" : 33 + "version" : 89 }, "text" : { - "id" : 1452060905, + "id" : 1452060906, "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298298", - "name" : "Recommendation PA166298298", - "alternateDrugAvailable" : true, + "id" : "PA166298306", + "name" : "Recommendation PA166298306", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Increased metabolism to less active compounds when compared to normal metabolizers and is associated with decreased response to ondansetron and tropisetron (i.e. vomiting)." + "CYP2D6: Normal metabolism" ], - "lookupKey" : {"CYP2D6": "≥3.0"}, + "lookupKey" : {"CYP2D6": "1.5"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -73607,41 +74571,41 @@ "objCls" : "Chemical", "id" : "PA450705", "name" : "ondansetron", - "version" : 9 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161954", "name" : "Annotation of CPIC Guideline for ondansetron and CYP2D6", - "version" : 33 + "version" : 89 }, "text" : { - "id" : 1452060900, - "html" : "

Select alternative drug not predominantly metabolized by CYP2D6 (i.e., granisetron).

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy. Dolasetron, palonosetron, and ramosetron are also metabolized by CYP2D6. Limited evidence is available regarding the utilization of CYP2D6 genetic variation to guide use of these drugs.

\n", + "id" : 1452060908, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298307", - "name" : "Recommendation PA166298307", - "alternateDrugAvailable" : false, + "id" : "PA166298292", + "name" : "Recommendation PA166298292", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Normal metabolism" + "CYP2D6: Increased metabolism to less active compounds when compared to normal metabolizers and is associated with decreased response to ondansetron and tropisetron (i.e. vomiting)." ], - "lookupKey" : {"CYP2D6": "1.25"}, + "lookupKey" : {"CYP2D6": "≥6.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -73649,26 +74613,26 @@ "objCls" : "Chemical", "id" : "PA450705", "name" : "ondansetron", - "version" : 9 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161954", "name" : "Annotation of CPIC Guideline for ondansetron and CYP2D6", - "version" : 33 + "version" : 89 }, "text" : { - "id" : 1452060909, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy.

\n", + "id" : 1452060894, + "html" : "

Select alternative drug not predominantly metabolized by CYP2D6 (i.e., granisetron).

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy. Dolasetron, palonosetron, and ramosetron are also metabolized by CYP2D6. Limited evidence is available regarding the utilization of CYP2D6 genetic variation to guide use of these drugs.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298300", - "name" : "Recommendation PA166298300", + "id" : "PA166298293", + "name" : "Recommendation PA166298293", "alternateDrugAvailable" : true, "classification" : { "id" : 981501931, @@ -73683,7 +74647,7 @@ "implications" : [ "CYP2D6: Increased metabolism to less active compounds when compared to normal metabolizers and is associated with decreased response to ondansetron and tropisetron (i.e. vomiting)." ], - "lookupKey" : {"CYP2D6": "2.75"}, + "lookupKey" : {"CYP2D6": "≥5.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -73691,17 +74655,17 @@ "objCls" : "Chemical", "id" : "PA450705", "name" : "ondansetron", - "version" : 9 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161954", "name" : "Annotation of CPIC Guideline for ondansetron and CYP2D6", - "version" : 33 + "version" : 89 }, "text" : { - "id" : 1452060902, + "id" : 1452060895, "html" : "

Select alternative drug not predominantly metabolized by CYP2D6 (i.e., granisetron).

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy. Dolasetron, palonosetron, and ramosetron are also metabolized by CYP2D6. Limited evidence is available regarding the utilization of CYP2D6 genetic variation to guide use of these drugs.

\n", "version" : 0 }, @@ -73733,14 +74697,14 @@ "objCls" : "Chemical", "id" : "PA450705", "name" : "ondansetron", - "version" : 9 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161954", "name" : "Annotation of CPIC Guideline for ondansetron and CYP2D6", - "version" : 33 + "version" : 89 }, "text" : { "id" : 1452060897, @@ -73751,23 +74715,23 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298313", - "name" : "Recommendation PA166298313", - "alternateDrugAvailable" : false, + "id" : "PA166298296", + "name" : "Recommendation PA166298296", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: n/a" + "CYP2D6: Increased metabolism to less active compounds when compared to normal metabolizers and is associated with decreased response to ondansetron and tropisetron (i.e. vomiting)." ], - "lookupKey" : {"CYP2D6": "n/a"}, + "lookupKey" : {"CYP2D6": "≥3.5"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -73775,41 +74739,41 @@ "objCls" : "Chemical", "id" : "PA450705", "name" : "ondansetron", - "version" : 9 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161954", "name" : "Annotation of CPIC Guideline for ondansetron and CYP2D6", - "version" : 33 + "version" : 89 }, "text" : { - "id" : 1452060915, - "html" : "

No recommendation

\n", + "id" : 1452060898, + "html" : "

Select alternative drug not predominantly metabolized by CYP2D6 (i.e., granisetron).

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy. Dolasetron, palonosetron, and ramosetron are also metabolized by CYP2D6. Limited evidence is available regarding the utilization of CYP2D6 genetic variation to guide use of these drugs.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298308", - "name" : "Recommendation PA166298308", - "alternateDrugAvailable" : false, + "id" : "PA166298297", + "name" : "Recommendation PA166298297", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Very limited data available for CYP2D6 intermediate metabolizers" + "CYP2D6: Increased metabolism to less active compounds when compared to normal metabolizers and is associated with decreased response to ondansetron and tropisetron (i.e. vomiting)." ], - "lookupKey" : {"CYP2D6": "1.0"}, + "lookupKey" : {"CYP2D6": "≥3.25"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -73817,41 +74781,41 @@ "objCls" : "Chemical", "id" : "PA450705", "name" : "ondansetron", - "version" : 9 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161954", "name" : "Annotation of CPIC Guideline for ondansetron and CYP2D6", - "version" : 33 + "version" : 89 }, "text" : { - "id" : 1452060910, - "html" : "

Insufficient evidence demonstrating clinical impact based on CYP2D6 genotype. Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy.

\n", + "id" : 1452060899, + "html" : "

Select alternative drug not predominantly metabolized by CYP2D6 (i.e., granisetron).

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy. Dolasetron, palonosetron, and ramosetron are also metabolized by CYP2D6. Limited evidence is available regarding the utilization of CYP2D6 genetic variation to guide use of these drugs.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298304", - "name" : "Recommendation PA166298304", - "alternateDrugAvailable" : false, + "id" : "PA166298298", + "name" : "Recommendation PA166298298", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Normal metabolism" + "CYP2D6: Increased metabolism to less active compounds when compared to normal metabolizers and is associated with decreased response to ondansetron and tropisetron (i.e. vomiting)." ], - "lookupKey" : {"CYP2D6": "2.0"}, + "lookupKey" : {"CYP2D6": "≥3.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -73859,18 +74823,18 @@ "objCls" : "Chemical", "id" : "PA450705", "name" : "ondansetron", - "version" : 9 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161954", "name" : "Annotation of CPIC Guideline for ondansetron and CYP2D6", - "version" : 33 + "version" : 89 }, "text" : { - "id" : 1452060906, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy.

\n", + "id" : 1452060900, + "html" : "

Select alternative drug not predominantly metabolized by CYP2D6 (i.e., granisetron).

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy. Dolasetron, palonosetron, and ramosetron are also metabolized by CYP2D6. Limited evidence is available regarding the utilization of CYP2D6 genetic variation to guide use of these drugs.

\n", "version" : 0 }, "version" : 0 @@ -73901,14 +74865,14 @@ "objCls" : "Chemical", "id" : "PA450705", "name" : "ondansetron", - "version" : 9 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161954", "name" : "Annotation of CPIC Guideline for ondansetron and CYP2D6", - "version" : 33 + "version" : 89 }, "text" : { "id" : 1452060901, @@ -73943,14 +74907,14 @@ "objCls" : "Chemical", "id" : "PA450705", "name" : "ondansetron", - "version" : 9 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161954", "name" : "Annotation of CPIC Guideline for ondansetron and CYP2D6", - "version" : 33 + "version" : 89 }, "text" : { "id" : 1452060903, @@ -73961,8 +74925,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298296", - "name" : "Recommendation PA166298296", + "id" : "PA166298302", + "name" : "Recommendation PA166298302", "alternateDrugAvailable" : true, "classification" : { "id" : 981501931, @@ -73977,7 +74941,7 @@ "implications" : [ "CYP2D6: Increased metabolism to less active compounds when compared to normal metabolizers and is associated with decreased response to ondansetron and tropisetron (i.e. vomiting)." ], - "lookupKey" : {"CYP2D6": "≥3.5"}, + "lookupKey" : {"CYP2D6": "2.5"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -73985,17 +74949,17 @@ "objCls" : "Chemical", "id" : "PA450705", "name" : "ondansetron", - "version" : 9 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161954", "name" : "Annotation of CPIC Guideline for ondansetron and CYP2D6", - "version" : 33 + "version" : 89 }, "text" : { - "id" : 1452060898, + "id" : 1452060904, "html" : "

Select alternative drug not predominantly metabolized by CYP2D6 (i.e., granisetron).

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy. Dolasetron, palonosetron, and ramosetron are also metabolized by CYP2D6. Limited evidence is available regarding the utilization of CYP2D6 genetic variation to guide use of these drugs.

\n", "version" : 0 }, @@ -74003,23 +74967,23 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298292", - "name" : "Recommendation PA166298292", - "alternateDrugAvailable" : true, + "id" : "PA166298303", + "name" : "Recommendation PA166298303", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Increased metabolism to less active compounds when compared to normal metabolizers and is associated with decreased response to ondansetron and tropisetron (i.e. vomiting)." + "CYP2D6: Normal metabolism" ], - "lookupKey" : {"CYP2D6": "≥6.0"}, + "lookupKey" : {"CYP2D6": "2.25"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -74027,41 +74991,41 @@ "objCls" : "Chemical", "id" : "PA450705", "name" : "ondansetron", - "version" : 9 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161954", "name" : "Annotation of CPIC Guideline for ondansetron and CYP2D6", - "version" : 33 + "version" : 89 }, "text" : { - "id" : 1452060894, - "html" : "

Select alternative drug not predominantly metabolized by CYP2D6 (i.e., granisetron).

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy. Dolasetron, palonosetron, and ramosetron are also metabolized by CYP2D6. Limited evidence is available regarding the utilization of CYP2D6 genetic variation to guide use of these drugs.

\n", + "id" : 1452060905, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298310", - "name" : "Recommendation PA166298310", - "alternateDrugAvailable" : false, + "id" : "PA166298294", + "name" : "Recommendation PA166298294", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Very limited data available for CYP2D6 intermediate metabolizers" + "CYP2D6: Increased metabolism to less active compounds when compared to normal metabolizers and is associated with decreased response to ondansetron and tropisetron (i.e. vomiting)." ], - "lookupKey" : {"CYP2D6": "0.5"}, + "lookupKey" : {"CYP2D6": "≥3.75"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -74069,41 +75033,41 @@ "objCls" : "Chemical", "id" : "PA450705", "name" : "ondansetron", - "version" : 9 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161954", "name" : "Annotation of CPIC Guideline for ondansetron and CYP2D6", - "version" : 33 + "version" : 89 }, "text" : { - "id" : 1452060912, - "html" : "

Insufficient evidence demonstrating clinical impact based on CYP2D6 genotype. Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy.

\n", + "id" : 1452060896, + "html" : "

Select alternative drug not predominantly metabolized by CYP2D6 (i.e., granisetron).

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy. Dolasetron, palonosetron, and ramosetron are also metabolized by CYP2D6. Limited evidence is available regarding the utilization of CYP2D6 genetic variation to guide use of these drugs.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298309", - "name" : "Recommendation PA166298309", - "alternateDrugAvailable" : false, + "id" : "PA166298300", + "name" : "Recommendation PA166298300", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Very limited data available for CYP2D6 intermediate metabolizers" + "CYP2D6: Increased metabolism to less active compounds when compared to normal metabolizers and is associated with decreased response to ondansetron and tropisetron (i.e. vomiting)." ], - "lookupKey" : {"CYP2D6": "0.75"}, + "lookupKey" : {"CYP2D6": "2.75"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -74111,26 +75075,26 @@ "objCls" : "Chemical", "id" : "PA450705", "name" : "ondansetron", - "version" : 9 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161954", "name" : "Annotation of CPIC Guideline for ondansetron and CYP2D6", - "version" : 33 + "version" : 89 }, "text" : { - "id" : 1452060911, - "html" : "

Insufficient evidence demonstrating clinical impact based on CYP2D6 genotype. Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy.

\n", + "id" : 1452060902, + "html" : "

Select alternative drug not predominantly metabolized by CYP2D6 (i.e., granisetron).

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy. Dolasetron, palonosetron, and ramosetron are also metabolized by CYP2D6. Limited evidence is available regarding the utilization of CYP2D6 genetic variation to guide use of these drugs.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298305", - "name" : "Recommendation PA166298305", + "id" : "PA166298307", + "name" : "Recommendation PA166298307", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -74145,7 +75109,7 @@ "implications" : [ "CYP2D6: Normal metabolism" ], - "lookupKey" : {"CYP2D6": "1.75"}, + "lookupKey" : {"CYP2D6": "1.25"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -74153,26 +75117,26 @@ "objCls" : "Chemical", "id" : "PA450705", "name" : "ondansetron", - "version" : 9 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161954", "name" : "Annotation of CPIC Guideline for ondansetron and CYP2D6", - "version" : 33 + "version" : 89 }, "text" : { - "id" : 1452060907, + "id" : 1452060909, "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298311", - "name" : "Recommendation PA166298311", + "id" : "PA166298308", + "name" : "Recommendation PA166298308", "alternateDrugAvailable" : false, "classification" : { "id" : 1448526251, @@ -74187,7 +75151,7 @@ "implications" : [ "CYP2D6: Very limited data available for CYP2D6 intermediate metabolizers" ], - "lookupKey" : {"CYP2D6": "0.25"}, + "lookupKey" : {"CYP2D6": "1.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -74195,71 +75159,83 @@ "objCls" : "Chemical", "id" : "PA450705", "name" : "ondansetron", - "version" : 9 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161954", "name" : "Annotation of CPIC Guideline for ondansetron and CYP2D6", - "version" : 33 + "version" : 89 }, "text" : { - "id" : 1452060913, + "id" : 1452060910, "html" : "

Insufficient evidence demonstrating clinical impact based on CYP2D6 genotype. Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301326", - "name" : "Recommendation Annotation PA166301326", + "id" : "PA166298309", + "name" : "Recommendation PA166298309", "alternateDrugAvailable" : false, + "classification" : { + "id" : 1448526251, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", + "valid" : true, + "version" : 0 + }, "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations"}, + "implications" : [ + "CYP2D6: Very limited data available for CYP2D6 intermediate metabolizers" + ], + "lookupKey" : {"CYP2D6": "0.75"}, "otherPrescribingGuidance" : false, + "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450705", "name" : "ondansetron", - "version" : 9 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161954", "name" : "Annotation of CPIC Guideline for ondansetron and CYP2D6", - "version" : 33 + "version" : 89 }, "text" : { - "id" : 1452095645, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "id" : 1452060911, + "html" : "

Insufficient evidence demonstrating clinical impact based on CYP2D6 genotype. Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298302", - "name" : "Recommendation PA166298302", - "alternateDrugAvailable" : true, + "id" : "PA166298310", + "name" : "Recommendation PA166298310", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Increased metabolism to less active compounds when compared to normal metabolizers and is associated with decreased response to ondansetron and tropisetron (i.e. vomiting)." + "CYP2D6: Very limited data available for CYP2D6 intermediate metabolizers" ], - "lookupKey" : {"CYP2D6": "2.5"}, + "lookupKey" : {"CYP2D6": "0.5"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -74267,41 +75243,41 @@ "objCls" : "Chemical", "id" : "PA450705", "name" : "ondansetron", - "version" : 9 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161954", "name" : "Annotation of CPIC Guideline for ondansetron and CYP2D6", - "version" : 33 + "version" : 89 }, "text" : { - "id" : 1452060904, - "html" : "

Select alternative drug not predominantly metabolized by CYP2D6 (i.e., granisetron).

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy. Dolasetron, palonosetron, and ramosetron are also metabolized by CYP2D6. Limited evidence is available regarding the utilization of CYP2D6 genetic variation to guide use of these drugs.

\n", + "id" : 1452060912, + "html" : "

Insufficient evidence demonstrating clinical impact based on CYP2D6 genotype. Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298297", - "name" : "Recommendation PA166298297", - "alternateDrugAvailable" : true, + "id" : "PA166298311", + "name" : "Recommendation PA166298311", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Increased metabolism to less active compounds when compared to normal metabolizers and is associated with decreased response to ondansetron and tropisetron (i.e. vomiting)." + "CYP2D6: Very limited data available for CYP2D6 intermediate metabolizers" ], - "lookupKey" : {"CYP2D6": "≥3.25"}, + "lookupKey" : {"CYP2D6": "0.25"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -74309,41 +75285,41 @@ "objCls" : "Chemical", "id" : "PA450705", "name" : "ondansetron", - "version" : 9 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161954", "name" : "Annotation of CPIC Guideline for ondansetron and CYP2D6", - "version" : 33 + "version" : 89 }, "text" : { - "id" : 1452060899, - "html" : "

Select alternative drug not predominantly metabolized by CYP2D6 (i.e., granisetron).

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy. Dolasetron, palonosetron, and ramosetron are also metabolized by CYP2D6. Limited evidence is available regarding the utilization of CYP2D6 genetic variation to guide use of these drugs.

\n", + "id" : 1452060913, + "html" : "

Insufficient evidence demonstrating clinical impact based on CYP2D6 genotype. Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298293", - "name" : "Recommendation PA166298293", - "alternateDrugAvailable" : true, + "id" : "PA166298312", + "name" : "Recommendation PA166298312", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Increased metabolism to less active compounds when compared to normal metabolizers and is associated with decreased response to ondansetron and tropisetron (i.e. vomiting)." + "CYP2D6: Very limited data available for CYP2D6 poor metabolizers" ], - "lookupKey" : {"CYP2D6": "≥5.0"}, + "lookupKey" : {"CYP2D6": "0.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -74351,41 +75327,41 @@ "objCls" : "Chemical", "id" : "PA450705", "name" : "ondansetron", - "version" : 9 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161954", "name" : "Annotation of CPIC Guideline for ondansetron and CYP2D6", - "version" : 33 + "version" : 89 }, "text" : { - "id" : 1452060895, - "html" : "

Select alternative drug not predominantly metabolized by CYP2D6 (i.e., granisetron).

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy. Dolasetron, palonosetron, and ramosetron are also metabolized by CYP2D6. Limited evidence is available regarding the utilization of CYP2D6 genetic variation to guide use of these drugs.

\n", + "id" : 1452060914, + "html" : "

Insufficient evidence demonstrating clinical impact based on CYP2D6 genotype. Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298306", - "name" : "Recommendation PA166298306", + "id" : "PA166298313", + "name" : "Recommendation PA166298313", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Normal metabolism" + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "1.5"}, + "lookupKey" : {"CYP2D6": "n/a"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -74393,21 +75369,21 @@ "objCls" : "Chemical", "id" : "PA450705", "name" : "ondansetron", - "version" : 9 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161954", "name" : "Annotation of CPIC Guideline for ondansetron and CYP2D6", - "version" : 33 + "version" : 89 }, "text" : { - "id" : 1452060908, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy.

\n", + "id" : 1452060915, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166161954" @@ -74548,7 +75524,7 @@ "id" : "PA165954769", "symbol" : "HLA-B*15:02", "name" : "*15:02", - "version" : 5 + "version" : 21 } ], "relatedChemicals" : [ @@ -74556,7 +75532,7 @@ "objCls" : "Chemical", "id" : "PA450732", "name" : "oxcarbazepine", - "version" : 9 + "version" : 27 } ], "relatedGenes" : [ @@ -74565,14 +75541,14 @@ "id" : "PA35056", "symbol" : "HLA-B", "name" : "major histocompatibility complex, class I, B", - "version" : 40 + "version" : 2920 } ], "source" : "CPIC", "summaryMarkdown" : { "id" : 1449163680, "html" : "

The CPIC Dosing Guideline for oxcarbazepine recommends an alternative drug for oxcarbazepine-naive patients carrying at least one copy of HLA-B*15:02 due to the association of this allele with an increased risk of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).

\n", - "version" : 0 + "version" : 1 }, "terms" : [], "textMarkdown" : { @@ -74581,14 +75557,14 @@ "version" : 2 }, "userId" : "whaleyr", - "version" : 19 + "version" : 35 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166298338", - "name" : "Recommendation PA166298338", - "alternateDrugAvailable" : true, + "id" : "PA166298337", + "name" : "Recommendation PA166298337", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, "parents" : [], @@ -74600,9 +75576,9 @@ }, "dosingInformation" : false, "implications" : [ - "HLA-B: Greater risk of oxcarbazepine-induced SJS/TEN" + "HLA-B: Normal risk of oxcarbazepine-induced SJS/TEN" ], - "lookupKey" : {"HLA-B": "*15:02 positive"}, + "lookupKey" : {"HLA-B": "*15:02 negative"}, "otherPrescribingGuidance" : false, "population" : "OXC naive", "relatedChemicals" : [ @@ -74610,27 +75586,27 @@ "objCls" : "Chemical", "id" : "PA450732", "name" : "oxcarbazepine", - "version" : 9 + "version" : 27 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166176623", "name" : "Annotation of CPIC Guideline for oxcarbazepine and HLA-B", - "version" : 19 + "version" : 35 }, "text" : { - "id" : 1452060940, - "html" : "

If patient is oxcarbazepine-naïve, do not use oxcarbazepine.

\n

Other Considerations

\n

Other aromatic anticonvulsants have weaker evidence linking SJS/TEN with the HLA-B*15:02 allele; however, caution should still be used in choosing an alternative agent. Aromatic anticonvulsants include carbamazepine, oxcarbazepine, eslicarbazepine, lamotrigine, phenytoin, fosphenytoin, and phenobarbital.

\n", + "id" : 1452060939, + "html" : "

Use oxcarbazepine per standard dosing guidelines.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298339", - "name" : "Recommendation PA166298339", - "alternateDrugAvailable" : false, + "id" : "PA166298338", + "name" : "Recommendation PA166298338", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, "parents" : [], @@ -74642,115 +75618,115 @@ }, "dosingInformation" : false, "implications" : [ - "HLA-B: Normal risk of oxcarbazepine-induced SJS/TEN" + "HLA-B: Greater risk of oxcarbazepine-induced SJS/TEN" ], - "lookupKey" : {"HLA-B": "*15:02 negative"}, + "lookupKey" : {"HLA-B": "*15:02 positive"}, "otherPrescribingGuidance" : false, - "population" : "OXC use >3 mos", + "population" : "OXC naive", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450732", "name" : "oxcarbazepine", - "version" : 9 + "version" : 27 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166176623", "name" : "Annotation of CPIC Guideline for oxcarbazepine and HLA-B", - "version" : 19 + "version" : 35 }, "text" : { - "id" : 1452060941, - "html" : "

Use oxcarbazepine per standard dosing guidelines.

\n", + "id" : 1452060940, + "html" : "

If patient is oxcarbazepine-naïve, do not use oxcarbazepine.

\n

Other Considerations

\n

Other aromatic anticonvulsants have weaker evidence linking SJS/TEN with the HLA-B*15:02 allele; however, caution should still be used in choosing an alternative agent. Aromatic anticonvulsants include carbamazepine, oxcarbazepine, eslicarbazepine, lamotrigine, phenytoin, fosphenytoin, and phenobarbital.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298340", - "name" : "Recommendation PA166298340", + "id" : "PA166298339", + "name" : "Recommendation PA166298339", "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "HLA-B: Greater risk of oxcarbazepine-induced SJS/TEN" + "HLA-B: Normal risk of oxcarbazepine-induced SJS/TEN" ], - "lookupKey" : {"HLA-B": "*15:02 positive"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"HLA-B": "*15:02 negative"}, + "otherPrescribingGuidance" : false, "population" : "OXC use >3 mos", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450732", "name" : "oxcarbazepine", - "version" : 9 + "version" : 27 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166176623", "name" : "Annotation of CPIC Guideline for oxcarbazepine and HLA-B", - "version" : 19 + "version" : 35 }, "text" : { - "id" : 1452060942, - "html" : "

The latency period for drug-induced SJS/TEN is short with continuous dosing and adherence to therapy (~4-28 days), and cases usually occur within three months of dosing; therefore, if the patient has previously used oxcarbazepine consistently for longer than three months without incidence of cutaneous adverse reactions, cautiously consider use of oxcarbazepine in the future.

\n

Other Considerations

\n

Previous tolerance of oxcarbazepine is not indicative of tolerance to other aromatic anticonvulsants. Aromatic anticonvulsants include carbamazepine, oxcarbazepine, eslicarbazepine, lamotrigine, phenytoin, fosphenytoin, and phenobarbital.

\n", + "id" : 1452060941, + "html" : "

Use oxcarbazepine per standard dosing guidelines.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298337", - "name" : "Recommendation PA166298337", + "id" : "PA166298340", + "name" : "Recommendation PA166298340", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "HLA-B: Normal risk of oxcarbazepine-induced SJS/TEN" + "HLA-B: Greater risk of oxcarbazepine-induced SJS/TEN" ], - "lookupKey" : {"HLA-B": "*15:02 negative"}, - "otherPrescribingGuidance" : false, - "population" : "OXC naive", + "lookupKey" : {"HLA-B": "*15:02 positive"}, + "otherPrescribingGuidance" : true, + "population" : "OXC use >3 mos", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450732", "name" : "oxcarbazepine", - "version" : 9 + "version" : 27 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166176623", "name" : "Annotation of CPIC Guideline for oxcarbazepine and HLA-B", - "version" : 19 + "version" : 35 }, "text" : { - "id" : 1452060939, - "html" : "

Use oxcarbazepine per standard dosing guidelines.

\n", + "id" : 1452060942, + "html" : "

The latency period for drug-induced SJS/TEN is short with continuous dosing and adherence to therapy (~4-28 days), and cases usually occur within three months of dosing; therefore, if the patient has previously used oxcarbazepine consistently for longer than three months without incidence of cutaneous adverse reactions, cautiously consider use of oxcarbazepine in the future.

\n

Other Considerations

\n

Previous tolerance of oxcarbazepine is not indicative of tolerance to other aromatic anticonvulsants. Aromatic anticonvulsants include carbamazepine, oxcarbazepine, eslicarbazepine, lamotrigine, phenytoin, fosphenytoin, and phenobarbital.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166176623" @@ -74914,6 +75890,7 @@ "version" : 1 } ], + "descriptiveVideoId" : "nAyXCBn3ZHI", "dosingInformation" : true, "hasTestingInfo" : false, "history" : [ @@ -74972,6 +75949,13 @@ "description" : "added CPIC guideline publication", "type" : "Update", "version" : 0 + }, + { + "id" : 1452508440, + "date" : "2024-06-26T03:38:00.482-07:00", + "description" : "Added video", + "type" : "Update", + "version" : 0 } ], "literature" : [ @@ -74983,7 +75967,7 @@ "pediatricMarkdown" : { "id" : 1451266624, "html" : "

Guideline excerpt: "Therefore, the generalizability of other recommendations to pediatric patients needs to be established. As such, clinicians treating children and adolescents should determine their applicability to younger patients while considering the unique and more limited evidence base for these medications in youth, as well as pediatric-specific differences in tolerability (e.g., activation)and disorder-specific response trajectory. Because CYP2D6, CYP2C19, and CYP2B6 activity reach adult levels by early childhood, it may be appropriate to extrapolate genotype-guided recommendations for antidepressants related to CYP2D6, CYP2C19 and CYP2B6 to adolescents or possibly younger children with close monitoring."

\n", - "version" : 1 + "version" : 3 }, "recommendation" : true, "relatedAlleles" : [], @@ -74992,7 +75976,7 @@ "objCls" : "Chemical", "id" : "PA450801", "name" : "paroxetine", - "version" : 15 + "version" : 47 } ], "relatedGenes" : [ @@ -75001,29 +75985,29 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "CPIC", "summaryMarkdown" : { "id" : 1447982281, "html" : "

The CPIC Dosing Guideline for the selective serotonin reuptake inhibitor paroxetine recommends an alternative drug not predominantly metabolized by CYP2D6 for CYP2D6 ultrarapid metabolizers. For CYP2D6 poor metabolizers, consider a 50% reduction in recommended starting dose, slower titration schedule, and a 50% lower maintenance dose.

\n", - "version" : 1 + "version" : 2 }, "terms" : [], "textMarkdown" : { "id" : 1451433659, "html" : "

This annotation is based on the CPIC® guideline for CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A Genotypes and Serotonin Reuptake Inhibitor Antidepressants. This is an update to the previous CPIC® guideline for Selective Serotonin Reuptake Inhibitors and CYP2D6 and CYP2C19.

\n

February 2023

\n\n

Table 1: Dosing recommendations for paroxetine based on CYP2D6 phenotype

\n

Adapted from Tables 1 and 2a of the guideline.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
PhenotypeActivity score
range		Activity scoreExamplesImplicationsTherapeutic
Recommendations		Classification of
recommendationa		Considerations
CYP2D6 ultrarapid metabolizer>2.25>2.25*1/*1xN, *1/*2xN, *2/*2xNcIncreased metabolism of paroxetine to less active compounds when compared to CYP2D6 normal metabolizers. Lower plasma concentrations decrease the probability of clinical benefit. The extent to which ultrarapid metabolizers phenoconvert to normal, intermediate, or poor metabolizers due to paroxetine autoinhibition of CYP2D6 is unclear.Select alternative drug not predominantly metabolized by CYP2D6.ModerateDrug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when selecting an alternative therapy.
CYP2D6 normal metabolizer1.25 <= x <= 2.251.25
1.5
1.75
2.0
2.25		*1/*10
*1/*41, *1/*9
*10/*41x3
*1/*1, *1/*2
*2x2/*10		Normal metabolism of paroxetine to less active compounds. Paroxetine-associated phenoconversion of normal metabolizers to intermediate or poor metabolizers due to CYP2D6 autoinhibition may occur and is dose-dependent and greater at steady state concentrations.Initiate therapy with recommended starting dose.Strong
CYP2D6 intermediate metabolizer0 < x < 1.250.25
0.5
0.75
1.0		*4/*10
*4/*41, *10/*10
*10/*41
*41/*41, *1/*5		Reduced metabolism of paroxetine to less active compounds when compared to CYP2D6 normal metabolizers when starting treatment or at lower doses. Higher plasma concentrations may increase the probability of side effects. Paroxetine-associated phenoconversion of intermediate metabolizers to poor metabolizers due to CYP2D6 autoinhibition may occur and is dose-dependent and greater at steady state concentrations.Consider a lower starting dose and slower titration schedule as compared to normal metabolizers.OptionalDrug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when adjusting dose or selecting an alternative therapy.
CYP2D6 poor metabolizer00*3/*4, *4/*4, *5/*5, *5/*6Greatly reduced metabolism when compared to CYP2D6 normal metabolizers. Higher plasma concentrations may increase the probability of side effects. The impact of paroxetine-associated autoinhibition of CYP2D6 is minimal in poor metabolizers.Consider a 50% reduction in recommended starting dose, slower titration schedule, and a 50% lower maintenance dose as compared to normal metabolizers.ModerateDrug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when adjusting dose or selecting an alternative therapy.
CYP2D6 Indeterminaten/aAn individual carrying one or two unknown or uncertain function alleles*1/*22, *1/*25, *22/*25No recommendationNo recommendation
\n

a Rating scheme described in Supplemental Materials.

\n

October 2019 Update

\n

CYP2D6 genotype to phenotype translation changes: Up until August 2019, there were a few inconsistencies in the translation of CYP2D6 genotype to phenotype translation across guidelines (i.e. CPIC and DPWG) and between clinical genetic testing laboratories. CPIC recently conducted a modified-Delphi project to obtain consensus for a uniform system for translating CYP2D6 genotype to phenotype among a panel of international CYP2D6 experts more information. Modifications to CPIC’s prior system include downgrading the value assigned to the CYP2D6*10 allele for activity score calculation from 0.5 to 0.25 and changing the phenotype assignment for an activity score of 1 from normal metabolizer to intermediate metabolizer (table of all previous and new phenotype groupings).

\n

As a result, the following changes have been made in the CYP2D6 allele functionality table, CYP2D6 genotype to phenotype table (access tables below):

\n\n

August 2015

\n

Advanced online publication May 2015

\n\n

Table 1: Dosing recommendations for paroxetine based on CYP2D6 phenotype:

\n

Adapted from Tables 1 and 2a of the 2015 guideline manuscript.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Likely phenotypeActivity ScoreGenotypesExamples of CYP2D6 diplotypesImplications for paroxetine metabolismTherapeutic RecommendationsClassification of recommendations a
Ultrarapid metabolizer (~1-2% of patients)b> 2.0An individual carrying duplications of functional alleles*1/*1xN, *1/*2xN, *2/*2xN cIncreased metabolism to less active compounds when compared to extensive metabolizers. Lower/undetectable plasma concentrations may increase probability of pharmacotherapy failure.Select alternative drug not predominantly metabolized by CYP2D6.dStrong
Extensive metabolizer (~77-92% of patients)2.0-1.0 eAn individual carrying two normal function alleles or two decreased function alleles or one normal function and one no function allele or one normal function and one decreased function allele*1/*1, *1/*2, *1/*4, *1/*5, *1/*9, *1/*41, *2/*2,*41/*41Normal metabolismInitiate therapy with recommended starting dose.Strong
Intermediate metabolizer (~2-11% of patients)0.5An individual carrying one decreased function and one no function allele*4/*10,*4/*41, *5/*9Reduced metabolism when compared to extensive metabolizers. Higher plasma concentrations may increase the probability of side effects.Initiate therapy with recommended starting dose.Moderate
Poor metabolizers (~5-10% of patients)0An individual carrying only no functional alleles*3/*4,*4/*4, *5/*5, *5/*6Greatly reduced metabolism when compared to extensive metabolizers. Higher plasma concentrations may increase the probability of side effects.Select alternative drug not predominantly metabolized by CYP2D6 d or if paroxetine use warranted, consider a 50% reduction of recommended starting dose and titrate to response.Optional
\n

a Rating scheme described in Supplement.

\n

b CYP2D6 metabolizer status frequencies are based on data from Caucasians and may differ from other ethnicities. See Supplemental note for information on the chances of observing specific diplotypes in different major race/ethnic groups.

\n

c Where xN represents the number of CYP2D6 gene copies. For individuals with CYP2D6 duplications or multiplications, see supplemental data for additional information on how to translate diplotypes into phenotypes.

\n

d Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when selecting an alternative therapy.

\n

e Patients with an activity score of 1.0 may be classified as intermediate metabolizers by some reference laboratories.

\n", - "version" : 1 + "version" : 5 }, "userId" : "whaleyr", - "version" : 50 + "version" : 141 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166298347", - "name" : "Recommendation PA166298347", + "id" : "PA166300883", + "name" : "Recommendation PA166300883", "alternateDrugAvailable" : true, "classification" : { "id" : 981501931, @@ -75038,7 +76022,7 @@ "implications" : [ "CYP2D6: Increased metabolism of paroxetine to less active compounds when compared to CYP2D6 normal metabolizers. Lower plasma concentrations decrease the probability of clinical benefit. The extent to which ultrarapid metabolizers phenoconvert to normal, intermediate, or poor metabolizers due to paroxetine autoinhibition of CYP2D6 is unclear." ], - "lookupKey" : {"CYP2D6": "2.5"}, + "lookupKey" : {"CYP2D6": "≥3.75"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -75046,26 +76030,26 @@ "objCls" : "Chemical", "id" : "PA450801", "name" : "paroxetine", - "version" : 15 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127636", "name" : "Annotation of CPIC Guideline for paroxetine and CYP2D6", - "version" : 50 + "version" : 141 }, "text" : { - "id" : 1452093851, + "id" : 1452093843, "html" : "

Select alternative drug not predominantly metabolized by CYP2D6.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when selecting an alternative therapy.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300883", - "name" : "Recommendation PA166300883", + "id" : "PA166300884", + "name" : "Recommendation PA166300884", "alternateDrugAvailable" : true, "classification" : { "id" : 981501931, @@ -75080,7 +76064,7 @@ "implications" : [ "CYP2D6: Increased metabolism of paroxetine to less active compounds when compared to CYP2D6 normal metabolizers. Lower plasma concentrations decrease the probability of clinical benefit. The extent to which ultrarapid metabolizers phenoconvert to normal, intermediate, or poor metabolizers due to paroxetine autoinhibition of CYP2D6 is unclear." ], - "lookupKey" : {"CYP2D6": "≥3.75"}, + "lookupKey" : {"CYP2D6": "2.75"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -75088,26 +76072,26 @@ "objCls" : "Chemical", "id" : "PA450801", "name" : "paroxetine", - "version" : 15 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127636", "name" : "Annotation of CPIC Guideline for paroxetine and CYP2D6", - "version" : 50 + "version" : 141 }, "text" : { - "id" : 1452093843, + "id" : 1452093849, "html" : "

Select alternative drug not predominantly metabolized by CYP2D6.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when selecting an alternative therapy.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298343", - "name" : "Recommendation PA166298343", + "id" : "PA166298346", + "name" : "Recommendation PA166298346", "alternateDrugAvailable" : true, "classification" : { "id" : 981501931, @@ -75122,7 +76106,7 @@ "implications" : [ "CYP2D6: Increased metabolism of paroxetine to less active compounds when compared to CYP2D6 normal metabolizers. Lower plasma concentrations decrease the probability of clinical benefit. The extent to which ultrarapid metabolizers phenoconvert to normal, intermediate, or poor metabolizers due to paroxetine autoinhibition of CYP2D6 is unclear." ], - "lookupKey" : {"CYP2D6": "≥3.0"}, + "lookupKey" : {"CYP2D6": "3.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -75130,41 +76114,41 @@ "objCls" : "Chemical", "id" : "PA450801", "name" : "paroxetine", - "version" : 15 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127636", "name" : "Annotation of CPIC Guideline for paroxetine and CYP2D6", - "version" : 50 + "version" : 141 }, "text" : { - "id" : 1452093847, + "id" : 1452093850, "html" : "

Select alternative drug not predominantly metabolized by CYP2D6.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when selecting an alternative therapy.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298356", - "name" : "Recommendation PA166298356", - "alternateDrugAvailable" : false, + "id" : "PA166298073", + "name" : "Recommendation PA166298073", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981565059, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2D6: Reduced metabolism of paroxetine to less active compounds when compared to CYP2D6 normal metabolizers when starting treatment or at lower doses. Higher plasma concentrations may increase the probability of side\neffects. Paroxetine-associated phenoconversion of intermediate metabolizers to poor metabolizers due to CYP2D6 autoinhibition may occur and is dose-dependent and greater at steady state concentrations." + "CYP2D6: Increased metabolism of paroxetine to less active compounds when compared to CYP2D6 normal metabolizers. Lower plasma concentrations decrease the probability of clinical benefit. The extent to which ultrarapid metabolizers phenoconvert to normal, intermediate, or poor metabolizers due to paroxetine autoinhibition of CYP2D6 is unclear." ], - "lookupKey" : {"CYP2D6": "0.25"}, + "lookupKey" : {"CYP2D6": "≥6.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -75172,41 +76156,41 @@ "objCls" : "Chemical", "id" : "PA450801", "name" : "paroxetine", - "version" : 15 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127636", "name" : "Annotation of CPIC Guideline for paroxetine and CYP2D6", - "version" : 50 + "version" : 141 }, "text" : { - "id" : 1452093860, - "html" : "

Consider a lower starting dose and slower titration schedule as compared to normal metabolizers.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when adjusting dose or selecting an alternative therapy.

\n", + "id" : 1452093841, + "html" : "

Select alternative drug not predominantly metabolized by CYP2D6.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when selecting an alternative therapy.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298351", - "name" : "Recommendation PA166298351", - "alternateDrugAvailable" : false, + "id" : "PA166298341", + "name" : "Recommendation PA166298341", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Normal metabolism of paroxetine to less active compounds. Paroxetine-associated phenoconversion of normal metabolizers to intermediate or poor metabolizers due to CYP2D6 autoinhibition may occur and is dose-dependent and greater at steady state concentrations." + "CYP2D6: Increased metabolism of paroxetine to less active compounds when compared to CYP2D6 normal metabolizers. Lower plasma concentrations decrease the probability of clinical benefit. The extent to which ultrarapid metabolizers phenoconvert to normal, intermediate, or poor metabolizers due to paroxetine autoinhibition of CYP2D6 is unclear." ], - "lookupKey" : {"CYP2D6": "1.5"}, + "lookupKey" : {"CYP2D6": "≥3.5"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -75214,21 +76198,21 @@ "objCls" : "Chemical", "id" : "PA450801", "name" : "paroxetine", - "version" : 15 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127636", "name" : "Annotation of CPIC Guideline for paroxetine and CYP2D6", - "version" : 50 + "version" : 141 }, "text" : { - "id" : 1452093855, - "html" : "

Initiate therapy with recommended starting dose

\n", + "id" : 1452093845, + "html" : "

Select alternative drug not predominantly metabolized by CYP2D6.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when selecting an alternative therapy.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", @@ -75256,26 +76240,26 @@ "objCls" : "Chemical", "id" : "PA450801", "name" : "paroxetine", - "version" : 15 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127636", "name" : "Annotation of CPIC Guideline for paroxetine and CYP2D6", - "version" : 50 + "version" : 141 }, "text" : { "id" : 1452093846, "html" : "

Select alternative drug not predominantly metabolized by CYP2D6.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when selecting an alternative therapy.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300884", - "name" : "Recommendation PA166300884", + "id" : "PA166298343", + "name" : "Recommendation PA166298343", "alternateDrugAvailable" : true, "classification" : { "id" : 981501931, @@ -75290,7 +76274,7 @@ "implications" : [ "CYP2D6: Increased metabolism of paroxetine to less active compounds when compared to CYP2D6 normal metabolizers. Lower plasma concentrations decrease the probability of clinical benefit. The extent to which ultrarapid metabolizers phenoconvert to normal, intermediate, or poor metabolizers due to paroxetine autoinhibition of CYP2D6 is unclear." ], - "lookupKey" : {"CYP2D6": "2.75"}, + "lookupKey" : {"CYP2D6": "≥3.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -75298,63 +76282,21 @@ "objCls" : "Chemical", "id" : "PA450801", "name" : "paroxetine", - "version" : 15 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127636", "name" : "Annotation of CPIC Guideline for paroxetine and CYP2D6", - "version" : 50 + "version" : 141 }, "text" : { - "id" : 1452093849, + "id" : 1452093847, "html" : "

Select alternative drug not predominantly metabolized by CYP2D6.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when selecting an alternative therapy.

\n", "version" : 0 }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166298348", - "name" : "Recommendation PA166298348", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 981501930, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "CYP2D6: Normal metabolism of paroxetine to less active compounds. Paroxetine-associated phenoconversion of normal metabolizers to intermediate or poor metabolizers due to CYP2D6 autoinhibition may occur and is dose-dependent and greater at steady state concentrations." - ], - "lookupKey" : {"CYP2D6": "2.25"}, - "otherPrescribingGuidance" : false, - "population" : "general", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA450801", - "name" : "paroxetine", - "version" : 15 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166127636", - "name" : "Annotation of CPIC Guideline for paroxetine and CYP2D6", - "version" : 50 - }, - "text" : { - "id" : 1452093852, - "html" : "

Initiate therapy with recommended starting dose

\n", - "version" : 0 - }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", @@ -75382,27 +76324,27 @@ "objCls" : "Chemical", "id" : "PA450801", "name" : "paroxetine", - "version" : 15 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127636", "name" : "Annotation of CPIC Guideline for paroxetine and CYP2D6", - "version" : 50 + "version" : 141 }, "text" : { "id" : 1452093848, "html" : "

Select alternative drug not predominantly metabolized by CYP2D6.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when selecting an alternative therapy.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298357", - "name" : "Recommendation PA166298357", - "alternateDrugAvailable" : false, + "id" : "PA166298347", + "name" : "Recommendation PA166298347", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501931, "parents" : [], @@ -75412,11 +76354,11 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2D6: Greatly reduced metabolism when compared to CYP2D6 normal metabolizers. Higher plasma concentrations may increase the probability of side effects. The impact of paroxetine-associated autoinhibition of CYP2D6 is minimal in poor metabolizers." + "CYP2D6: Increased metabolism of paroxetine to less active compounds when compared to CYP2D6 normal metabolizers. Lower plasma concentrations decrease the probability of clinical benefit. The extent to which ultrarapid metabolizers phenoconvert to normal, intermediate, or poor metabolizers due to paroxetine autoinhibition of CYP2D6 is unclear." ], - "lookupKey" : {"CYP2D6": "0.0"}, + "lookupKey" : {"CYP2D6": "2.5"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -75424,26 +76366,26 @@ "objCls" : "Chemical", "id" : "PA450801", "name" : "paroxetine", - "version" : 15 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127636", "name" : "Annotation of CPIC Guideline for paroxetine and CYP2D6", - "version" : 50 + "version" : 141 }, "text" : { - "id" : 1452093861, - "html" : "

Consider a 50% reduction in recommended starting dose, slower titration schedule, and a 50% lower maintenance dose as compared to normal metabolizers.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when adjusting dose or selecting an alternative therapy.

\n", + "id" : 1452093851, + "html" : "

Select alternative drug not predominantly metabolized by CYP2D6.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when selecting an alternative therapy.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298352", - "name" : "Recommendation PA166298352", + "id" : "PA166298348", + "name" : "Recommendation PA166298348", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -75458,7 +76400,7 @@ "implications" : [ "CYP2D6: Normal metabolism of paroxetine to less active compounds. Paroxetine-associated phenoconversion of normal metabolizers to intermediate or poor metabolizers due to CYP2D6 autoinhibition may occur and is dose-dependent and greater at steady state concentrations." ], - "lookupKey" : {"CYP2D6": "1.25"}, + "lookupKey" : {"CYP2D6": "2.25"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -75466,56 +76408,68 @@ "objCls" : "Chemical", "id" : "PA450801", "name" : "paroxetine", - "version" : 15 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127636", "name" : "Annotation of CPIC Guideline for paroxetine and CYP2D6", - "version" : 50 + "version" : 141 }, "text" : { - "id" : 1452093856, + "id" : 1452093852, "html" : "

Initiate therapy with recommended starting dose

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301327", - "name" : "Recommendation Annotation PA166301327", + "id" : "PA166298349", + "name" : "Recommendation PA166298349", "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501930, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", + "valid" : true, + "version" : 0 + }, "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations"}, + "implications" : [ + "CYP2D6: Normal metabolism of paroxetine to less active compounds. Paroxetine-associated phenoconversion of normal metabolizers to intermediate or poor metabolizers due to CYP2D6 autoinhibition may occur and is dose-dependent and greater at steady state concentrations." + ], + "lookupKey" : {"CYP2D6": "2.0"}, "otherPrescribingGuidance" : false, + "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450801", "name" : "paroxetine", - "version" : 15 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127636", "name" : "Annotation of CPIC Guideline for paroxetine and CYP2D6", - "version" : 50 + "version" : 141 }, "text" : { - "id" : 1452095646, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "id" : 1452093853, + "html" : "

Initiate therapy with recommended starting dose

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298349", - "name" : "Recommendation PA166298349", + "id" : "PA166298350", + "name" : "Recommendation PA166298350", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -75530,7 +76484,7 @@ "implications" : [ "CYP2D6: Normal metabolism of paroxetine to less active compounds. Paroxetine-associated phenoconversion of normal metabolizers to intermediate or poor metabolizers due to CYP2D6 autoinhibition may occur and is dose-dependent and greater at steady state concentrations." ], - "lookupKey" : {"CYP2D6": "2.0"}, + "lookupKey" : {"CYP2D6": "1.75"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -75538,41 +76492,41 @@ "objCls" : "Chemical", "id" : "PA450801", "name" : "paroxetine", - "version" : 15 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127636", "name" : "Annotation of CPIC Guideline for paroxetine and CYP2D6", - "version" : 50 + "version" : 141 }, "text" : { - "id" : 1452093853, + "id" : 1452093854, "html" : "

Initiate therapy with recommended starting dose

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298314", - "name" : "Recommendation PA166298314", - "alternateDrugAvailable" : true, + "id" : "PA166298351", + "name" : "Recommendation PA166298351", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Increased metabolism of paroxetine to less active compounds when compared to CYP2D6 normal metabolizers. Lower plasma concentrations decrease the probability of clinical benefit. The extent to which ultrarapid metabolizers phenoconvert to normal, intermediate, or poor metabolizers due to paroxetine autoinhibition of CYP2D6 is unclear." + "CYP2D6: Normal metabolism of paroxetine to less active compounds. Paroxetine-associated phenoconversion of normal metabolizers to intermediate or poor metabolizers due to CYP2D6 autoinhibition may occur and is dose-dependent and greater at steady state concentrations." ], - "lookupKey" : {"CYP2D6": "≥4.0"}, + "lookupKey" : {"CYP2D6": "1.5"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -75580,41 +76534,41 @@ "objCls" : "Chemical", "id" : "PA450801", "name" : "paroxetine", - "version" : 15 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127636", "name" : "Annotation of CPIC Guideline for paroxetine and CYP2D6", - "version" : 50 + "version" : 141 }, "text" : { - "id" : 1452093844, - "html" : "

Select alternative drug not predominantly metabolized by CYP2D6.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when selecting an alternative therapy.

\n", + "id" : 1452093855, + "html" : "

Initiate therapy with recommended starting dose

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298358", - "name" : "Recommendation PA166298358", + "id" : "PA166298352", + "name" : "Recommendation PA166298352", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: n/a" + "CYP2D6: Normal metabolism of paroxetine to less active compounds. Paroxetine-associated phenoconversion of normal metabolizers to intermediate or poor metabolizers due to CYP2D6 autoinhibition may occur and is dose-dependent and greater at steady state concentrations." ], - "lookupKey" : {"CYP2D6": "n/a"}, + "lookupKey" : {"CYP2D6": "1.25"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -75622,21 +76576,21 @@ "objCls" : "Chemical", "id" : "PA450801", "name" : "paroxetine", - "version" : 15 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127636", "name" : "Annotation of CPIC Guideline for paroxetine and CYP2D6", - "version" : 50 + "version" : 141 }, "text" : { - "id" : 1452093862, - "html" : "

No recommendation

\n", + "id" : 1452093856, + "html" : "

Initiate therapy with recommended starting dose

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", @@ -75664,41 +76618,41 @@ "objCls" : "Chemical", "id" : "PA450801", "name" : "paroxetine", - "version" : 15 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127636", "name" : "Annotation of CPIC Guideline for paroxetine and CYP2D6", - "version" : 50 + "version" : 141 }, "text" : { "id" : 1452093857, "html" : "

Consider a lower starting dose and slower titration schedule as compared to normal metabolizers.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when adjusting dose or selecting an alternative therapy.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298073", - "name" : "Recommendation PA166298073", - "alternateDrugAvailable" : true, + "id" : "PA166298354", + "name" : "Recommendation PA166298354", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2D6: Increased metabolism of paroxetine to less active compounds when compared to CYP2D6 normal metabolizers. Lower plasma concentrations decrease the probability of clinical benefit. The extent to which ultrarapid metabolizers phenoconvert to normal, intermediate, or poor metabolizers due to paroxetine autoinhibition of CYP2D6 is unclear." + "CYP2D6: Reduced metabolism of paroxetine to less active compounds when compared to CYP2D6 normal metabolizers when starting treatment or at lower doses. Higher plasma concentrations may increase the probability of side\neffects. Paroxetine-associated phenoconversion of intermediate metabolizers to poor metabolizers due to CYP2D6 autoinhibition may occur and is dose-dependent and greater at steady state concentrations." ], - "lookupKey" : {"CYP2D6": "≥6.0"}, + "lookupKey" : {"CYP2D6": "0.75"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -75706,21 +76660,21 @@ "objCls" : "Chemical", "id" : "PA450801", "name" : "paroxetine", - "version" : 15 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127636", "name" : "Annotation of CPIC Guideline for paroxetine and CYP2D6", - "version" : 50 + "version" : 141 }, "text" : { - "id" : 1452093841, - "html" : "

Select alternative drug not predominantly metabolized by CYP2D6.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when selecting an alternative therapy.

\n", + "id" : 1452093858, + "html" : "

Consider a lower starting dose and slower titration schedule as compared to normal metabolizers.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when adjusting dose or selecting an alternative therapy.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", @@ -75748,41 +76702,41 @@ "objCls" : "Chemical", "id" : "PA450801", "name" : "paroxetine", - "version" : 15 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127636", "name" : "Annotation of CPIC Guideline for paroxetine and CYP2D6", - "version" : 50 + "version" : 141 }, "text" : { "id" : 1452093859, "html" : "

Consider a lower starting dose and slower titration schedule as compared to normal metabolizers.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when adjusting dose or selecting an alternative therapy.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298346", - "name" : "Recommendation PA166298346", - "alternateDrugAvailable" : true, + "id" : "PA166298356", + "name" : "Recommendation PA166298356", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2D6: Increased metabolism of paroxetine to less active compounds when compared to CYP2D6 normal metabolizers. Lower plasma concentrations decrease the probability of clinical benefit. The extent to which ultrarapid metabolizers phenoconvert to normal, intermediate, or poor metabolizers due to paroxetine autoinhibition of CYP2D6 is unclear." + "CYP2D6: Reduced metabolism of paroxetine to less active compounds when compared to CYP2D6 normal metabolizers when starting treatment or at lower doses. Higher plasma concentrations may increase the probability of side\neffects. Paroxetine-associated phenoconversion of intermediate metabolizers to poor metabolizers due to CYP2D6 autoinhibition may occur and is dose-dependent and greater at steady state concentrations." ], - "lookupKey" : {"CYP2D6": "3.0"}, + "lookupKey" : {"CYP2D6": "0.25"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -75790,27 +76744,27 @@ "objCls" : "Chemical", "id" : "PA450801", "name" : "paroxetine", - "version" : 15 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127636", "name" : "Annotation of CPIC Guideline for paroxetine and CYP2D6", - "version" : 50 + "version" : 141 }, "text" : { - "id" : 1452093850, - "html" : "

Select alternative drug not predominantly metabolized by CYP2D6.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when selecting an alternative therapy.

\n", + "id" : 1452093860, + "html" : "

Consider a lower starting dose and slower titration schedule as compared to normal metabolizers.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when adjusting dose or selecting an alternative therapy.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298231", - "name" : "Recommendation PA166298231", - "alternateDrugAvailable" : true, + "id" : "PA166298357", + "name" : "Recommendation PA166298357", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, "parents" : [], @@ -75820,11 +76774,11 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2D6: Increased metabolism of paroxetine to less active compounds when compared to CYP2D6 normal metabolizers. Lower plasma concentrations decrease the probability of clinical benefit. The extent to which ultrarapid metabolizers phenoconvert to normal, intermediate, or poor metabolizers due to paroxetine autoinhibition of CYP2D6 is unclear." + "CYP2D6: Greatly reduced metabolism when compared to CYP2D6 normal metabolizers. Higher plasma concentrations may increase the probability of side effects. The impact of paroxetine-associated autoinhibition of CYP2D6 is minimal in poor metabolizers." ], - "lookupKey" : {"CYP2D6": "≥5.0"}, + "lookupKey" : {"CYP2D6": "0.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -75832,41 +76786,41 @@ "objCls" : "Chemical", "id" : "PA450801", "name" : "paroxetine", - "version" : 15 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127636", "name" : "Annotation of CPIC Guideline for paroxetine and CYP2D6", - "version" : 50 + "version" : 141 }, "text" : { - "id" : 1452093842, - "html" : "

Select alternative drug not predominantly metabolized by CYP2D6.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when selecting an alternative therapy.

\n", + "id" : 1452093861, + "html" : "

Consider a 50% reduction in recommended starting dose, slower titration schedule, and a 50% lower maintenance dose as compared to normal metabolizers.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when adjusting dose or selecting an alternative therapy.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298341", - "name" : "Recommendation PA166298341", - "alternateDrugAvailable" : true, + "id" : "PA166298358", + "name" : "Recommendation PA166298358", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Increased metabolism of paroxetine to less active compounds when compared to CYP2D6 normal metabolizers. Lower plasma concentrations decrease the probability of clinical benefit. The extent to which ultrarapid metabolizers phenoconvert to normal, intermediate, or poor metabolizers due to paroxetine autoinhibition of CYP2D6 is unclear." + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "≥3.5"}, + "lookupKey" : {"CYP2D6": "n/a"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -75874,41 +76828,71 @@ "objCls" : "Chemical", "id" : "PA450801", "name" : "paroxetine", - "version" : 15 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127636", "name" : "Annotation of CPIC Guideline for paroxetine and CYP2D6", - "version" : 50 + "version" : 141 }, "text" : { - "id" : 1452093845, - "html" : "

Select alternative drug not predominantly metabolized by CYP2D6.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when selecting an alternative therapy.

\n", + "id" : 1452093862, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298354", - "name" : "Recommendation PA166298354", + "id" : "PA166301327", + "name" : "Recommendation Annotation PA166301327", "alternateDrugAvailable" : false, + "dosingInformation" : false, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA450801", + "name" : "paroxetine", + "version" : 47 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166127636", + "name" : "Annotation of CPIC Guideline for paroxetine and CYP2D6", + "version" : 141 + }, + "text" : { + "id" : 1452095646, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166298231", + "name" : "Recommendation PA166298231", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981565059, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2D6: Reduced metabolism of paroxetine to less active compounds when compared to CYP2D6 normal metabolizers when starting treatment or at lower doses. Higher plasma concentrations may increase the probability of side\neffects. Paroxetine-associated phenoconversion of intermediate metabolizers to poor metabolizers due to CYP2D6 autoinhibition may occur and is dose-dependent and greater at steady state concentrations." + "CYP2D6: Increased metabolism of paroxetine to less active compounds when compared to CYP2D6 normal metabolizers. Lower plasma concentrations decrease the probability of clinical benefit. The extent to which ultrarapid metabolizers phenoconvert to normal, intermediate, or poor metabolizers due to paroxetine autoinhibition of CYP2D6 is unclear." ], - "lookupKey" : {"CYP2D6": "0.75"}, + "lookupKey" : {"CYP2D6": "≥5.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -75916,41 +76900,41 @@ "objCls" : "Chemical", "id" : "PA450801", "name" : "paroxetine", - "version" : 15 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127636", "name" : "Annotation of CPIC Guideline for paroxetine and CYP2D6", - "version" : 50 + "version" : 141 }, "text" : { - "id" : 1452093858, - "html" : "

Consider a lower starting dose and slower titration schedule as compared to normal metabolizers.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when adjusting dose or selecting an alternative therapy.

\n", + "id" : 1452093842, + "html" : "

Select alternative drug not predominantly metabolized by CYP2D6.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when selecting an alternative therapy.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298350", - "name" : "Recommendation PA166298350", - "alternateDrugAvailable" : false, + "id" : "PA166298314", + "name" : "Recommendation PA166298314", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Normal metabolism of paroxetine to less active compounds. Paroxetine-associated phenoconversion of normal metabolizers to intermediate or poor metabolizers due to CYP2D6 autoinhibition may occur and is dose-dependent and greater at steady state concentrations." + "CYP2D6: Increased metabolism of paroxetine to less active compounds when compared to CYP2D6 normal metabolizers. Lower plasma concentrations decrease the probability of clinical benefit. The extent to which ultrarapid metabolizers phenoconvert to normal, intermediate, or poor metabolizers due to paroxetine autoinhibition of CYP2D6 is unclear." ], - "lookupKey" : {"CYP2D6": "1.75"}, + "lookupKey" : {"CYP2D6": "≥4.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -75958,21 +76942,21 @@ "objCls" : "Chemical", "id" : "PA450801", "name" : "paroxetine", - "version" : 15 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127636", "name" : "Annotation of CPIC Guideline for paroxetine and CYP2D6", - "version" : 50 + "version" : 141 }, "text" : { - "id" : 1452093854, - "html" : "

Initiate therapy with recommended starting dose

\n", + "id" : 1452093844, + "html" : "

Select alternative drug not predominantly metabolized by CYP2D6.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when selecting an alternative therapy.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166127636" @@ -76124,19 +77108,19 @@ "objCls" : "Chemical", "id" : "PA164749390", "name" : "peginterferon alfa-2a", - "version" : 6 + "version" : 16 }, { "objCls" : "Chemical", "id" : "PA164784024", "name" : "peginterferon alfa-2b", - "version" : 6 + "version" : 19 }, { "objCls" : "Chemical", "id" : "PA451241", "name" : "ribavirin", - "version" : 10 + "version" : 40 } ], "relatedGenes" : [ @@ -76145,14 +77129,14 @@ "id" : "PA134952671", "symbol" : "IFNL3", "name" : "interferon lambda 3", - "version" : 8 + "version" : 35 } ], "source" : "CPIC", "summaryMarkdown" : { "id" : 1447981876, "html" : "

IFNL3 (IL28B) variation (rs12979860) is the strongest baseline predictor of response to PEG-interferon-alpha-containing regimens in HCV genotype 1 patients. Patients with the favorable response genotype (rs12979860 CC) have increased likelihood of response (higher SVR rate) to PEG-interferon-alpha-containing regimens as compared to patients with unfavorable response genotype (rs12979860 CT or TT). Consider implications before initiating PEG-IFN alpha and RBV containing regimens.

\n", - "version" : 10 + "version" : 13 }, "terms" : [], "textMarkdown" : { @@ -76161,7 +77145,7 @@ "version" : 0 }, "userId" : "whaleyr", - "version" : 47 + "version" : 103 }, "recommendations" : [], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166110235" @@ -76500,7 +77484,7 @@ "objCls" : "Chemical", "id" : "PA450985", "name" : "piroxicam", - "version" : 13 + "version" : 31 } ], "relatedGenes" : [ @@ -76509,14 +77493,14 @@ "id" : "PA126", "symbol" : "CYP2C9", "name" : "cytochrome P450 family 2 subfamily C member 9", - "version" : 7877 + "version" : 7952 } ], "source" : "CPIC", "summaryMarkdown" : { "id" : 1450986503, "html" : "

The CPIC Dosing Guideline for piroxicam recommends that CYP2C9 poor metabolizers and intermediate metabolizers with activity score of 1 should choose an alternative therapy not metabolized by CYP2C9 or not significantly impacted by CYP2C9 genetic variants in vivo or choose an NSAID metabolized by CYP2C9 but with a shorter half-life. See full guideline for further details and supporting evidence.

\n", - "version" : 0 + "version" : 1 }, "terms" : [], "textMarkdown" : { @@ -76525,28 +77509,28 @@ "version" : 1 }, "userId" : "lgong", - "version" : 9 + "version" : 97 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166298444", - "name" : "Recommendation PA166298444", + "id" : "PA166298448", + "name" : "Recommendation PA166298448", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2C9: Mildly reduced metabolism" + "CYP2C9: n/a" ], - "lookupKey" : {"CYP2C9": "1.5"}, + "lookupKey" : {"CYP2C9": "n/a"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -76554,41 +77538,41 @@ "objCls" : "Chemical", "id" : "PA450985", "name" : "piroxicam", - "version" : 13 + "version" : 31 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166192321", "name" : "Annotation of CPIC Guideline for piroxicam and CYP2C9", - "version" : 9 + "version" : 97 }, "text" : { - "id" : 1452061046, - "html" : "

Initiate therapy with recommended starting dose. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals.

\n

Other Considerations

\n

IMs might have a higher than normal risk of adverse events especially in individuals with other factors affecting clearance of these drugs such as hepatic impairment or advanced age.

\n", + "id" : 1452061050, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298448", - "name" : "Recommendation PA166298448", + "id" : "PA166298443", + "name" : "Recommendation PA166298443", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2C9: n/a" + "CYP2C9: Normal metabolism" ], - "lookupKey" : {"CYP2C9": "n/a"}, + "lookupKey" : {"CYP2C9": "2.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -76596,26 +77580,26 @@ "objCls" : "Chemical", "id" : "PA450985", "name" : "piroxicam", - "version" : 13 + "version" : 31 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166192321", "name" : "Annotation of CPIC Guideline for piroxicam and CYP2C9", - "version" : 9 + "version" : 97 }, "text" : { - "id" : 1452061050, - "html" : "

No recommendation

\n", + "id" : 1452061045, + "html" : "

Initiate therapy with recommended starting dose. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298445", - "name" : "Recommendation PA166298445", + "id" : "PA166298446", + "name" : "Recommendation PA166298446", "alternateDrugAvailable" : true, "classification" : { "id" : 981501931, @@ -76628,9 +77612,9 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2C9: Moderately reduced metabolism; higher plasma concentrations may increase probability of toxicities" + "CYP2C9: Significantly reduced metabolism and prolonged half-life; higher plasma concentrations may increase probability and/or severity of toxicities" ], - "lookupKey" : {"CYP2C9": "1.0"}, + "lookupKey" : {"CYP2C9": "0.5"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -76638,17 +77622,17 @@ "objCls" : "Chemical", "id" : "PA450985", "name" : "piroxicam", - "version" : 13 + "version" : 31 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166192321", "name" : "Annotation of CPIC Guideline for piroxicam and CYP2C9", - "version" : 9 + "version" : 97 }, "text" : { - "id" : 1452061047, + "id" : 1452061048, "html" : "

Choose an alternative therapy not metabolized by CYP2C9 or not significantly impacted by CYP2C9 genetic variants in vivo or choose an NSAID metabolized by CYP2C9 but with a shorter half-life (see CPIC THERAPEUTIC RECOMMENDATIONS FOR CELECOXIB, FLURBIPROFEN, LORNOXICAM, AND IBUPROFEN BASED ON CYP2C9 PHENOTYPE).

\n

Other Considerations

\n

Alternative therapies not primarily metabolized by CYP2C9 include aspirin, ketorolac, naproxen and sulindac. Selection of therapy will depend on individual patient treatment goals and risks for toxicity.

\n", "version" : 0 }, @@ -76656,8 +77640,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298446", - "name" : "Recommendation PA166298446", + "id" : "PA166298447", + "name" : "Recommendation PA166298447", "alternateDrugAvailable" : true, "classification" : { "id" : 981501931, @@ -76672,7 +77656,7 @@ "implications" : [ "CYP2C9: Significantly reduced metabolism and prolonged half-life; higher plasma concentrations may increase probability and/or severity of toxicities" ], - "lookupKey" : {"CYP2C9": "0.5"}, + "lookupKey" : {"CYP2C9": "0.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -76680,17 +77664,17 @@ "objCls" : "Chemical", "id" : "PA450985", "name" : "piroxicam", - "version" : 13 + "version" : 31 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166192321", "name" : "Annotation of CPIC Guideline for piroxicam and CYP2C9", - "version" : 9 + "version" : 97 }, "text" : { - "id" : 1452061048, + "id" : 1452061049, "html" : "

Choose an alternative therapy not metabolized by CYP2C9 or not significantly impacted by CYP2C9 genetic variants in vivo or choose an NSAID metabolized by CYP2C9 but with a shorter half-life (see CPIC THERAPEUTIC RECOMMENDATIONS FOR CELECOXIB, FLURBIPROFEN, LORNOXICAM, AND IBUPROFEN BASED ON CYP2C9 PHENOTYPE).

\n

Other Considerations

\n

Alternative therapies not primarily metabolized by CYP2C9 include aspirin, ketorolac, naproxen and sulindac. Selection of therapy will depend on individual patient treatment goals and risks for toxicity.

\n", "version" : 0 }, @@ -76698,9 +77682,9 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298447", - "name" : "Recommendation PA166298447", - "alternateDrugAvailable" : true, + "id" : "PA166298444", + "name" : "Recommendation PA166298444", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, "parents" : [], @@ -76712,9 +77696,9 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2C9: Significantly reduced metabolism and prolonged half-life; higher plasma concentrations may increase probability and/or severity of toxicities" + "CYP2C9: Mildly reduced metabolism" ], - "lookupKey" : {"CYP2C9": "0.0"}, + "lookupKey" : {"CYP2C9": "1.5"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -76722,41 +77706,41 @@ "objCls" : "Chemical", "id" : "PA450985", "name" : "piroxicam", - "version" : 13 + "version" : 31 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166192321", "name" : "Annotation of CPIC Guideline for piroxicam and CYP2C9", - "version" : 9 + "version" : 97 }, "text" : { - "id" : 1452061049, - "html" : "

Choose an alternative therapy not metabolized by CYP2C9 or not significantly impacted by CYP2C9 genetic variants in vivo or choose an NSAID metabolized by CYP2C9 but with a shorter half-life (see CPIC THERAPEUTIC RECOMMENDATIONS FOR CELECOXIB, FLURBIPROFEN, LORNOXICAM, AND IBUPROFEN BASED ON CYP2C9 PHENOTYPE).

\n

Other Considerations

\n

Alternative therapies not primarily metabolized by CYP2C9 include aspirin, ketorolac, naproxen and sulindac. Selection of therapy will depend on individual patient treatment goals and risks for toxicity.

\n", + "id" : 1452061046, + "html" : "

Initiate therapy with recommended starting dose. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals.

\n

Other Considerations

\n

IMs might have a higher than normal risk of adverse events especially in individuals with other factors affecting clearance of these drugs such as hepatic impairment or advanced age.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298443", - "name" : "Recommendation PA166298443", - "alternateDrugAvailable" : false, + "id" : "PA166298445", + "name" : "Recommendation PA166298445", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2C9: Normal metabolism" + "CYP2C9: Moderately reduced metabolism; higher plasma concentrations may increase probability of toxicities" ], - "lookupKey" : {"CYP2C9": "2.0"}, + "lookupKey" : {"CYP2C9": "1.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -76764,21 +77748,21 @@ "objCls" : "Chemical", "id" : "PA450985", "name" : "piroxicam", - "version" : 13 + "version" : 31 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166192321", "name" : "Annotation of CPIC Guideline for piroxicam and CYP2C9", - "version" : 9 + "version" : 97 }, "text" : { - "id" : 1452061045, - "html" : "

Initiate therapy with recommended starting dose. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals.

\n", + "id" : 1452061047, + "html" : "

Choose an alternative therapy not metabolized by CYP2C9 or not significantly impacted by CYP2C9 genetic variants in vivo or choose an NSAID metabolized by CYP2C9 but with a shorter half-life (see CPIC THERAPEUTIC RECOMMENDATIONS FOR CELECOXIB, FLURBIPROFEN, LORNOXICAM, AND IBUPROFEN BASED ON CYP2C9 PHENOTYPE).

\n

Other Considerations

\n

Alternative therapies not primarily metabolized by CYP2C9 include aspirin, ketorolac, naproxen and sulindac. Selection of therapy will depend on individual patient treatment goals and risks for toxicity.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166192321" @@ -76940,14 +77924,14 @@ "id" : "PA165819265", "symbol" : "SLCO1B1*15", "name" : "*15", - "version" : 23 + "version" : 39 }, { "objCls" : "Haplotype", "id" : "PA165819255", "symbol" : "SLCO1B1*5", "name" : "*5", - "version" : 23 + "version" : 39 } ], "relatedChemicals" : [ @@ -76955,7 +77939,7 @@ "objCls" : "Chemical", "id" : "PA142650384", "name" : "pitavastatin", - "version" : 4 + "version" : 14 } ], "relatedGenes" : [ @@ -76964,7 +77948,7 @@ "id" : "PA134865839", "symbol" : "SLCO1B1", "name" : "solute carrier organic anion transporter family member 1B1", - "version" : 49 + "version" : 109 } ], "source" : "CPIC", @@ -76977,100 +77961,16 @@ "textMarkdown" : { "id" : 1451668801, "html" : "

This annotation is based on the CPIC® guideline for SLCO1B1, ABCG2, and CYP2C9 and statin-associated musculoskeletal symptoms.

\n

February 2022

\n\n\n

Adapted from Table 1 and 2 of the 2022 guideline update manuscript.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
PhenotypeGenotypeExamples of diplotypes aImplications for pitavastatinDosing recommendations for pitavastatin b,cClassification of recommendations d
Normal functionAn individual carrying two normal function alleles or one normal plus one increased function allele*1/*1, *1/*14Typical myopathy risk and statin exposurePrescribe desired starting dose and adjust doses based on disease-specific guidelines.Strong
Increased functionAn individual carrying two increased function alleles*14/*14Typical myopathy risk and statin exposurePrescribe desired starting dose and adjust doses based on disease-specific guidelines.Strong
Decreased functionAn individual carrying one normal or increased function allele plus one no function allele*1/*5, *1/*15Increased pitavastatin exposure as compared to normal function which may translate to increased myopathy riskPrescribe ≤ 2mg as a starting dose and adjust doses of pitavastatin based on disease-specific guidelines. Prescriber should be aware of possible increased risk for myopathy especially for doses >1mg. If dose >2mg needed for desired efficacy, consider an alternative statin (see Figure 1 for recommendations for alternative statins) or combination therapy (i.e. pitavastatin plus non-statin guideline directed medical therapy).Moderate
Possible decreased functionAn individual carrying one no function allele plus one uncertain/unknown function allele*5/*6, *15/*10, *5/*43Increased pitavastatin exposure as compared to normal function which may translate to increased myopathy riskPrescribe ≤ 2mg as a starting dose and adjust doses of pitavastatin based on disease-specific guidelines. Prescriber should be aware of possible increased risk for myopathy especially for doses >1mg. If dose >2mg needed for desired efficacy, consider an alternative statin (see Figure 1 for recommendations for alternative statins) or combination therapy (i.e. pitavastatin plus non-statin guideline directed medical therapy).Moderate
Poor functionAn individual carrying two no function alleles*5/*5, *5/*15, *15/*15Increased pitavastatin exposure as compared to normal and decreased function which may translate to increased myopathy risk.Prescribe ≤1mg as a starting dose and adjust doses of pitavastatin based on disease-specific guidelines. If dose >1mg needed for desired efficacy, consider an alternative statin (see Figure 1 for recommendations for alternative statins) or combination therapy (i.e. pitavastatin plus non-statin guideline directed medical therapy)(3).Moderate
IndeterminateAn individual carrying one normal function allele plus one uncertain or unknown function allele OR allele combinations with uncertain and/or unknown function alleles*1/*7, *1/*10, *7/*10n/aNo recommendation.No recommendation.
\n

Figure 1 : SLCO1B1 recommendations with intensity and statin dose stratified by SLCO1B1 phenotype; all doses assume adult dosing.

\n

Adapted from Figure 1 of the 2022 guideline manuscript

\n

\"Fig1\"

\n\n", - "version" : 3 + "version" : 7 }, "userId" : "lgong", - "version" : 6 + "version" : 22 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166298453", - "name" : "Recommendation PA166298453", - "alternateDrugAvailable" : true, - "classification" : { - "id" : 981501931, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : true, - "implications" : [ - "SLCO1B1: Increased pitavastatin exposure as compared to normal and decreased function which may translate to increased myopathy risk." - ], - "lookupKey" : {"SLCO1B1": "Poor Function"}, - "otherPrescribingGuidance" : false, - "population" : "general", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA142650384", - "name" : "pitavastatin", - "version" : 4 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166262261", - "name" : "Annotation of CPIC Guideline for pitavastatin and SLCO1B1", - "version" : 6 - }, - "text" : { - "id" : 1452061055, - "html" : "

Prescribe ≤1mg as a starting dose and adjust doses of pitavastatin based on disease-specific guidelines. If dose >1mg needed for desired efficacy, consider an alternative statin (see Figure 1 of PMID: 35152405 for recommendations for alternative statins) or combination therapy (i.e. pitavastatin plus non-statin guideline directed medical therapy)(PMID: 30423391).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166298454", - "name" : "Recommendation PA166298454", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 1448526251, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "SLCO1B1: n/a" - ], - "lookupKey" : {"SLCO1B1": "Indeterminate"}, - "otherPrescribingGuidance" : false, - "population" : "general", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA142650384", - "name" : "pitavastatin", - "version" : 4 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166262261", - "name" : "Annotation of CPIC Guideline for pitavastatin and SLCO1B1", - "version" : 6 - }, - "text" : { - "id" : 1452061056, - "html" : "

No recommendation

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166298449", - "name" : "Recommendation PA166298449", + "id" : "PA166298450", + "name" : "Recommendation PA166298450", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -77085,7 +77985,7 @@ "implications" : [ "SLCO1B1: Typical myopathy risk and statin exposure" ], - "lookupKey" : {"SLCO1B1": "Increased Function"}, + "lookupKey" : {"SLCO1B1": "Normal Function"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -77093,41 +77993,41 @@ "objCls" : "Chemical", "id" : "PA142650384", "name" : "pitavastatin", - "version" : 4 + "version" : 14 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262261", "name" : "Annotation of CPIC Guideline for pitavastatin and SLCO1B1", - "version" : 6 + "version" : 22 }, "text" : { - "id" : 1452061051, + "id" : 1452061052, "html" : "

Prescribe desired starting dose and adjust doses based on disease-specific guidelines.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and ancestry should be evaluated prior to initiating a statin.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298450", - "name" : "Recommendation PA166298450", - "alternateDrugAvailable" : false, + "id" : "PA166298451", + "name" : "Recommendation PA166298451", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "SLCO1B1: Typical myopathy risk and statin exposure" + "SLCO1B1: Increased pitavastatin exposure as compared to normal function which may translate to increased myopathy risk" ], - "lookupKey" : {"SLCO1B1": "Normal Function"}, + "lookupKey" : {"SLCO1B1": "Possible Decreased Function"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -77135,21 +78035,21 @@ "objCls" : "Chemical", "id" : "PA142650384", "name" : "pitavastatin", - "version" : 4 + "version" : 14 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262261", "name" : "Annotation of CPIC Guideline for pitavastatin and SLCO1B1", - "version" : 6 + "version" : 22 }, "text" : { - "id" : 1452061052, - "html" : "

Prescribe desired starting dose and adjust doses based on disease-specific guidelines.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and ancestry should be evaluated prior to initiating a statin.

\n", + "id" : 1452061053, + "html" : "

Prescribe ≤ 2mg as a starting dose and adjust doses of pitavastatin based on disease-specific guidelines. Prescriber should be aware of possible increased risk for myopathy especially for doses >1mg. If dose >2mg needed for desired efficacy, consider an alternative statin (see Figure 1 of PMID: 35152405 for recommendations for alternative statins) or combination therapy (i.e. pitavastatin plus non-statin guideline directed medical therapy) (PMID: 30423391).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -77177,26 +78077,26 @@ "objCls" : "Chemical", "id" : "PA142650384", "name" : "pitavastatin", - "version" : 4 + "version" : 14 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262261", "name" : "Annotation of CPIC Guideline for pitavastatin and SLCO1B1", - "version" : 6 + "version" : 22 }, "text" : { "id" : 1452061054, "html" : "

Prescribe ≤ 2mg as a starting dose and adjust doses of pitavastatin based on disease-specific guidelines. Prescriber should be aware of possible increased risk for myopathy especially for doses >1mg. If dose >2mg needed for desired efficacy, consider an alternative statin (see Figure 1 of PMID: 35152405 for recommendations for alternative statins) or combination therapy (i.e. pitavastatin plus non-statin guideline directed medical therapy) (PMID: 30423391).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298451", - "name" : "Recommendation PA166298451", + "id" : "PA166298453", + "name" : "Recommendation PA166298453", "alternateDrugAvailable" : true, "classification" : { "id" : 981501931, @@ -77209,9 +78109,9 @@ }, "dosingInformation" : true, "implications" : [ - "SLCO1B1: Increased pitavastatin exposure as compared to normal function which may translate to increased myopathy risk" + "SLCO1B1: Increased pitavastatin exposure as compared to normal and decreased function which may translate to increased myopathy risk." ], - "lookupKey" : {"SLCO1B1": "Possible Decreased Function"}, + "lookupKey" : {"SLCO1B1": "Poor Function"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -77219,21 +78119,105 @@ "objCls" : "Chemical", "id" : "PA142650384", "name" : "pitavastatin", - "version" : 4 + "version" : 14 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262261", "name" : "Annotation of CPIC Guideline for pitavastatin and SLCO1B1", - "version" : 6 + "version" : 22 }, "text" : { - "id" : 1452061053, - "html" : "

Prescribe ≤ 2mg as a starting dose and adjust doses of pitavastatin based on disease-specific guidelines. Prescriber should be aware of possible increased risk for myopathy especially for doses >1mg. If dose >2mg needed for desired efficacy, consider an alternative statin (see Figure 1 of PMID: 35152405 for recommendations for alternative statins) or combination therapy (i.e. pitavastatin plus non-statin guideline directed medical therapy) (PMID: 30423391).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452061055, + "html" : "

Prescribe ≤1mg as a starting dose and adjust doses of pitavastatin based on disease-specific guidelines. If dose >1mg needed for desired efficacy, consider an alternative statin (see Figure 1 of PMID: 35152405 for recommendations for alternative statins) or combination therapy (i.e. pitavastatin plus non-statin guideline directed medical therapy)(PMID: 30423391).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166298454", + "name" : "Recommendation PA166298454", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 1448526251, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : false, + "implications" : [ + "SLCO1B1: n/a" + ], + "lookupKey" : {"SLCO1B1": "Indeterminate"}, + "otherPrescribingGuidance" : false, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA142650384", + "name" : "pitavastatin", + "version" : 14 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166262261", + "name" : "Annotation of CPIC Guideline for pitavastatin and SLCO1B1", + "version" : 22 + }, + "text" : { + "id" : 1452061056, + "html" : "

No recommendation

\n", + "version" : 0 + }, + "version" : 1 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166298449", + "name" : "Recommendation PA166298449", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501930, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : false, + "implications" : [ + "SLCO1B1: Typical myopathy risk and statin exposure" + ], + "lookupKey" : {"SLCO1B1": "Increased Function"}, + "otherPrescribingGuidance" : false, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA142650384", + "name" : "pitavastatin", + "version" : 14 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166262261", + "name" : "Annotation of CPIC Guideline for pitavastatin and SLCO1B1", + "version" : 22 + }, + "text" : { + "id" : 1452061051, + "html" : "

Prescribe desired starting dose and adjust doses based on disease-specific guidelines.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and ancestry should be evaluated prior to initiating a statin.

\n", + "version" : 0 + }, + "version" : 1 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166262261" @@ -77395,14 +78379,14 @@ "id" : "PA165819265", "symbol" : "SLCO1B1*15", "name" : "*15", - "version" : 23 + "version" : 39 }, { "objCls" : "Haplotype", "id" : "PA165819255", "symbol" : "SLCO1B1*5", "name" : "*5", - "version" : 23 + "version" : 39 } ], "relatedChemicals" : [ @@ -77410,7 +78394,7 @@ "objCls" : "Chemical", "id" : "PA451089", "name" : "pravastatin", - "version" : 21 + "version" : 47 } ], "relatedGenes" : [ @@ -77419,7 +78403,7 @@ "id" : "PA134865839", "symbol" : "SLCO1B1", "name" : "solute carrier organic anion transporter family member 1B1", - "version" : 49 + "version" : 109 } ], "source" : "CPIC", @@ -77432,115 +78416,115 @@ "textMarkdown" : { "id" : 1451668821, "html" : "

This annotation is based on the CPIC® guideline for SLCO1B1, ABCG2, and CYP2C9 and statin-associated musculoskeletal symptoms.

\n

February 2022

\n\n\n

Adapted from Table 1 and 2 of the 2022 guideline update manuscript.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
PhenotypeGenotypeExamples of diplotypes aImplications for pravastatinDosing recommendations for pravastatin b,cClassification of recommendations d
Normal functionAn individual carrying two normal function alleles or one normal plus one increased function allele*1/*1, *1/*14Typical myopathy risk and statin exposurePrescribe desired starting dose and adjust doses based on disease-specific guidelines.Strong
Increased functionAn individual carrying two increased function alleles*14/*14Typical myopathy risk and statin exposurePrescribe desired starting dose and adjust doses based on disease-specific guidelines.Strong
Decreased functionAn individual carrying one normal or increased function allele plus one no function allele*1/*5, *1/*15Increased pravastatin exposure as compared to normal function; Typical myopathy risk with doses ≤40 mg.Prescribe desired starting dose and adjust doses of pravastatin based on disease-specific guidelines. Prescriber should be aware of possible increased risk for myopathy with pravastatin especially with doses >40mg per day.Moderate
Possible decreased functionAn individual carrying one no function allele plus one uncertain/unknown function allele*5/*6, *15/*10, *5/*43Increased pravastatin exposure as compared to normal function; Typical myopathy risk with doses ≤40 mg.Prescribe desired starting dose and adjust doses of pravastatin based on disease-specific guidelines. Prescriber should be aware of possible increased risk for myopathy with pravastatin especially with doses >40mg per day.Moderate
Poor functionAn individual carrying two no function alleles*5/*5, *5/*15, *15/*15Increased pravastatin statin exposure as compared to normal and decreased function; Typical myopathy risk with doses ≤40 mg.Prescribe ≤40mg as a starting dose and adjust doses of pravastatin based on disease-specific guidelines. If patient is tolerating 40mg dose but higher potency is needed, a higher dose (>40mg) or an alternative statin (see Figure 1 for recommendations for alternative statins) or combination therapy (i.e. pravastatin plus non-statin guideline directed medical therapy) could be considered. Prescriber should be aware of possible increased risk for myopathy especially with pravastatin doses >40mg.Moderate
IndeterminateAn individual carrying one normal function allele plus one uncertain or unknown function allele OR allele combinations with uncertain and/or unknown function alleles*1/*7, *1/*10, *7/*10n/aNo recommendation.No recommendation.
\n

Figure 1 : SLCO1B1 recommendations with intensity and statin dose stratified by SLCO1B1 phenotype; all doses assume adult dosing.

\n

Adapted from Figure 1 of the 2022 guideline manuscript

\n

\"Fig1\"

\n\n", - "version" : 2 + "version" : 8 }, "userId" : "lgong", - "version" : 4 + "version" : 19 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166298457", - "name" : "Recommendation PA166298457", + "id" : "PA166298455", + "name" : "Recommendation PA166298455", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "SLCO1B1: Increased pravastatin exposure as compared to normal function; Typical myopathy risk with doses ≤40 mg." + "SLCO1B1: Typical myopathy risk and statin exposure" ], - "lookupKey" : {"SLCO1B1": "Possible Decreased Function"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"SLCO1B1": "Increased Function"}, + "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451089", "name" : "pravastatin", - "version" : 21 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262281", "name" : "Annotation of CPIC Guideline for pravastatin and SLCO1B1", - "version" : 4 + "version" : 19 }, "text" : { - "id" : 1452061059, - "html" : "

Prescribe desired starting dose and adjust doses of pravastatin based on disease-specific guidelines. Prescriber should be aware of possible increased risk for myopathy with pravastatin especially with doses >40mg per day.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452061057, + "html" : "

Prescribe desired starting dose and adjust doses based on disease-specific guidelines.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and ancestry should be evaluated prior to initiating a statin.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298458", - "name" : "Recommendation PA166298458", + "id" : "PA166298456", + "name" : "Recommendation PA166298456", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "SLCO1B1: Increased pravastatin exposure as compared to normal function; Typical myopathy risk with doses ≤40 mg." + "SLCO1B1: Typical myopathy risk and statin exposure" ], - "lookupKey" : {"SLCO1B1": "Decreased Function"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"SLCO1B1": "Normal Function"}, + "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451089", "name" : "pravastatin", - "version" : 21 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262281", "name" : "Annotation of CPIC Guideline for pravastatin and SLCO1B1", - "version" : 4 + "version" : 19 }, "text" : { - "id" : 1452061060, - "html" : "

Prescribe desired starting dose and adjust doses of pravastatin based on disease-specific guidelines. Prescriber should be aware of possible increased risk for myopathy with pravastatin especially with doses >40mg per day.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452061058, + "html" : "

Prescribe desired starting dose and adjust doses based on disease-specific guidelines.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and ancestry should be evaluated prior to initiating a statin.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298459", - "name" : "Recommendation PA166298459", - "alternateDrugAvailable" : true, + "id" : "PA166298460", + "name" : "Recommendation PA166298460", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "SLCO1B1: Increased pravastatin statin exposure as compared to normal and decreased function; Typical myopathy risk with doses ≤40 mg." + "SLCO1B1: n/a" ], - "lookupKey" : {"SLCO1B1": "Poor Function"}, + "lookupKey" : {"SLCO1B1": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -77548,125 +78532,125 @@ "objCls" : "Chemical", "id" : "PA451089", "name" : "pravastatin", - "version" : 21 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262281", "name" : "Annotation of CPIC Guideline for pravastatin and SLCO1B1", - "version" : 4 + "version" : 19 }, "text" : { - "id" : 1452061061, - "html" : "

Prescribe ≤40mg as a starting dose and adjust doses of pravastatin based on disease-specific guidelines. If patient is tolerating 40mg dose but higher potency is needed, a higher dose (>40mg) or an alternative statin (see Figure 1 of of PMID: 35152405 for recommendations for alternative statins) or combination therapy (i.e. pravastatin plus non-statin guideline directed medical therapy)(PMID: 30423391) could be considered. Prescriber should be aware of possible increased risk for myopathy especially with pravastatin doses >40mg.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452061062, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298455", - "name" : "Recommendation PA166298455", + "id" : "PA166298458", + "name" : "Recommendation PA166298458", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "SLCO1B1: Typical myopathy risk and statin exposure" + "SLCO1B1: Increased pravastatin exposure as compared to normal function; Typical myopathy risk with doses ≤40 mg." ], - "lookupKey" : {"SLCO1B1": "Increased Function"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"SLCO1B1": "Decreased Function"}, + "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451089", "name" : "pravastatin", - "version" : 21 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262281", "name" : "Annotation of CPIC Guideline for pravastatin and SLCO1B1", - "version" : 4 + "version" : 19 }, "text" : { - "id" : 1452061057, - "html" : "

Prescribe desired starting dose and adjust doses based on disease-specific guidelines.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and ancestry should be evaluated prior to initiating a statin.

\n", + "id" : 1452061060, + "html" : "

Prescribe desired starting dose and adjust doses of pravastatin based on disease-specific guidelines. Prescriber should be aware of possible increased risk for myopathy with pravastatin especially with doses >40mg per day.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, - "version" : 0 + "version" : 4 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298456", - "name" : "Recommendation PA166298456", + "id" : "PA166298457", + "name" : "Recommendation PA166298457", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "SLCO1B1: Typical myopathy risk and statin exposure" + "SLCO1B1: Increased pravastatin exposure as compared to normal function; Typical myopathy risk with doses ≤40 mg." ], - "lookupKey" : {"SLCO1B1": "Normal Function"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"SLCO1B1": "Possible Decreased Function"}, + "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451089", "name" : "pravastatin", - "version" : 21 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262281", "name" : "Annotation of CPIC Guideline for pravastatin and SLCO1B1", - "version" : 4 + "version" : 19 }, "text" : { - "id" : 1452061058, - "html" : "

Prescribe desired starting dose and adjust doses based on disease-specific guidelines.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and ancestry should be evaluated prior to initiating a statin.

\n", + "id" : 1452061059, + "html" : "

Prescribe desired starting dose and adjust doses of pravastatin based on disease-specific guidelines. Prescriber should be aware of possible increased risk for myopathy with pravastatin especially with doses >40mg per day.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298460", - "name" : "Recommendation PA166298460", - "alternateDrugAvailable" : false, + "id" : "PA166298459", + "name" : "Recommendation PA166298459", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "SLCO1B1: n/a" + "SLCO1B1: Increased pravastatin statin exposure as compared to normal and decreased function; Typical myopathy risk with doses ≤40 mg." ], - "lookupKey" : {"SLCO1B1": "Indeterminate"}, + "lookupKey" : {"SLCO1B1": "Poor Function"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -77674,21 +78658,21 @@ "objCls" : "Chemical", "id" : "PA451089", "name" : "pravastatin", - "version" : 21 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262281", "name" : "Annotation of CPIC Guideline for pravastatin and SLCO1B1", - "version" : 4 + "version" : 19 }, "text" : { - "id" : 1452061062, - "html" : "

No recommendation

\n", + "id" : 1452061061, + "html" : "

Prescribe ≤40mg as a starting dose and adjust doses of pravastatin based on disease-specific guidelines. If patient is tolerating 40mg dose but higher potency is needed, a higher dose (>40mg) or an alternative statin (see Figure 1 of of PMID: 35152405 for recommendations for alternative statins) or combination therapy (i.e. pravastatin plus non-statin guideline directed medical therapy)(PMID: 30423391) could be considered. Prescriber should be aware of possible increased risk for myopathy especially with pravastatin doses >40mg.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166262281" @@ -77794,7 +78778,7 @@ "objCls" : "Chemical", "id" : "PA451103", "name" : "primaquine", - "version" : 7 + "version" : 35 } ], "relatedGenes" : [ @@ -77803,30 +78787,30 @@ "id" : "PA28469", "symbol" : "G6PD", "name" : "glucose-6-phosphate dehydrogenase", - "version" : 135 + "version" : 1326 } ], "source" : "CPIC", "summaryMarkdown" : { "id" : 1451899160, "html" : "

Primaquine should be avoided in G6PD deficient patients with or without chronic non-spherocytic hemolytic anemia (CNSHA) in most cases, with some exceptions for G6PD deficient patients without CNSHA. In patients with a G6PD variable or indeterminate phenotype an enzyme activity test should be carried out before initiating drug therapy.

\n

The G6PD gene is located on the X chromosome. Therefore, some patients will only have one copy, whereas others will have two copies. See full guideline for disclaimers, further details and supporting evidence.

\n", - "version" : 0 + "version" : 2 }, "terms" : [], "textMarkdown" : { "id" : 1451899161, "html" : "

This annotation is based on the Expanded CPIC® Guideline for Medication Use in the Context of G6PD Genotype. The CPIC authors evaluated the available evidence for the use of various drugs in patients carrying G6PD variants.

\n

September 2022

\n\n\n

Adapted from Tables 1 and 4 of the guideline

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Predicted PhenotypeGenotypeaExample genotypesbImplicationsTherapeutic RecommendationsClassification of recommendationscConsiderations
NormalA person with one X chromosome carrying a non-deficient (class IV) allele
OR
A person carrying two non-deficient (class IV) alleles		B, Sao Boria, IV
 
B/B, B/Sao Boria, B/A, IV/IV		Low risk of acute hemolytic anemiaNo reason to avoid primaquine based on G6PD statusStrong
DeficientA person with one X chromosome carrying a deficient (class II-III) allele
OR
A person carrying two deficient (class II-III) alleles OR one class I allele and one class II or III allele		A-, Orissa, Kalyan-Kerala, Mediterranean, Canton, Chatham, II, III
 
A-/A-, A-/Orissa, Orissa/ Kalyan-Kerala, Mediterranean/ Mediterranean, Chatham /Mediterranean, Canton/ Viangchan, II/II, II/III, III/III, I/II, I/III		High risk of acute hemolytic anemia with standard (or higher than standard) anti-relapse dosages for Plasmodium vivax or Plasmodium ovale of 0.25-0.5 mg/kg daily for 14 daysAvoid primaquine, except in the following cases where established expert consensus guidelines for the treatment of malaria should be followed: (1) Treating Plasmodium vivax or Plasmodium ovale malaria for radical cure of liver-stage infections: 0.75 mg/kg once weekly x8 weeks (WHO) or 45 mg once weekly x8 weeks (CDC) - with close monitoring for hemolysis; (2) Treating Plasmodium falciparum malaria by using primaquine single dose as a gametocytocide at 0.25 mg/kg (WHO) - without need for monitoring for hemolysis.StrongDosing recommendations for primaquine in patients with G6PD deficiency are derived from the malaria treatment guidelines issued by the World Health Organization and the U.S. Centers for Disease Control and Prevention.
Deficient with CNSHAA person with one X chromosome carrying a deficient (class I) allele
OR
A person carrying two deficient (class I) allelesd		Bangkok, Villeurbanne, I
 
Bangkok/Bangkok, Bangkok/Villeurbanne, I/I		High risk of acute exacerbation of chronic hemolysisAvoid primaquineStrongThe strength of evidence among patients with the G6PD Deficient phenotype provides strong rationale to also avoid primaquine in the setting of the more severe G6PD Deficient with CNSHA phenotype.
VariableeA person carrying one non-deficient (class IV) allele and one deficient (class I-III) alleleB /Bangkok, B/Mediterranean, B/A-, IV/I, IV/II, IV/IIIVariable risk of acute hemolytic anemiaTo ascertain G6PD status, enzyme activity must be measured. Drug use should be guided per the recommendations based on the activity-based phenotype.ModerateDue to X-linked mosaicism, individuals with more than one X chromosome (e.g., females, individuals with Klinefelter syndrome) and heterozygous for one nondeficient (class IV) and one deficient (class I–III) allele may display a normal or a deficient phenotype; an enzyme activity test is needed to guide treatment in such cases.
IndeterminateA person carrying at least one allele with uncertain functionDagua
 
B/Dagua		Unknown risk of acute hemolytic anemiaTo ascertain G6PD status, enzyme activity must be measured. Drug use should be guided per the recommendations based on the activity-based phenotype.Moderate
\n

CNSHA: chronic non-spherocytic hemolytic anemia
\na WHO classifications from [Article:22293322], other details from [Article:4963040]. Class I alleles are extremely rare; the distinction between Class II and III alleles is not clear. Almost all patients will carry class II, III, or IV alleles.
\nb Due to the large number of G6PD alleles, other genotypes may be possible besides those given as examples here; see the G6PD Allele Definition Table for a more comprehensive list of alleles and G6PD Allele Functionality Table for their assigned function (WHO class). Note that some labs use the designation “B allele” to indicate an allele carrying no known class I-III variants. The G6PD Frequency Table can be referenced for the frequency of G6PD alleles across major biogeographical groups.
\nc Rating scheme described in the Strength of Recommendations section in the guideline supplement.
\nd Such genotypes have never been seen and are presumably exceedingly rare.
\ne Due to X-linked mosaicism, persons heterozygous (generally females) for one non-deficient (class IV) and one deficient (class I-III alleles) allele may display a normal or a deficient phenotype. It is therefore difficult to predict the phenotype of these individuals (see Supplement, G6PD Heterozygotes).

\n", - "version" : 1 + "version" : 12 }, "userId" : "rachel", - "version" : 3 + "version" : 22 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166298461", - "name" : "Recommendation PA166298461", - "alternateDrugAvailable" : false, + "id" : "PA166298462", + "name" : "Recommendation PA166298462", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, "parents" : [], @@ -77838,9 +78822,9 @@ }, "dosingInformation" : false, "implications" : [ - "G6PD: Low risk of acute hemolytic anemia" + "G6PD: High risk of acute hemolytic anemia with standard (or higher than standard) anti-relapse dosages for Plasmodium vivax or Plasmodium ovale of 0.25-0.5 mg/kg daily for 14 days" ], - "lookupKey" : {"G6PD": "Normal"}, + "lookupKey" : {"G6PD": "Deficient"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -77848,26 +78832,26 @@ "objCls" : "Chemical", "id" : "PA451103", "name" : "primaquine", - "version" : 7 + "version" : 35 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166279621", "name" : "Annotation of CPIC Guideline for primaquine and G6PD", - "version" : 3 + "version" : 22 }, "text" : { - "id" : 1452061063, - "html" : "

No reason to avoid based on G6PD status

\n", + "id" : 1452061064, + "html" : "

Avoid primaquine, except in the following cases where established expert consensus guidelines for the treatment of malaria should be followed: (1) Treating Plasmodium vivax or Plasmodium ovale malaria for radical cure of liver-stage infections: 0.75 mg/kg once weekly x8 weeks (WHO) or 45 mg once weekly x8 weeks (CDC) - with close monitoring for hemolysis; (2) Treating Plasmodium falciparum malaria by using primaquine single dose as a gametocytocide at 0.25 mg/kg (WHO) - without need for monitoring for hemolysis.

\n

Other Considerations

\n

Dosing recommendations for primaquine in patients with G6PD deficiency are derived from the malaria treatment guidelines issued by the World Health Organization and the U.S. Centers for Disease Control and Prevention.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298462", - "name" : "Recommendation PA166298462", + "id" : "PA166298463", + "name" : "Recommendation PA166298463", "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, @@ -77880,9 +78864,9 @@ }, "dosingInformation" : false, "implications" : [ - "G6PD: High risk of acute hemolytic anemia with standard (or higher than standard) anti-relapse dosages for Plasmodium vivax or Plasmodium ovale of 0.25-0.5 mg/kg daily for 14 days" + "G6PD: High risk of acute of acute exacerbation of chronic hemolysis" ], - "lookupKey" : {"G6PD": "Deficient"}, + "lookupKey" : {"G6PD": "Deficient with CNSHA"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -77890,27 +78874,27 @@ "objCls" : "Chemical", "id" : "PA451103", "name" : "primaquine", - "version" : 7 + "version" : 35 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166279621", "name" : "Annotation of CPIC Guideline for primaquine and G6PD", - "version" : 3 + "version" : 22 }, "text" : { - "id" : 1452061064, - "html" : "

Avoid primaquine, except in the following cases where established expert consensus guidelines for the treatment of malaria should be followed: (1) Treating Plasmodium vivax or Plasmodium ovale malaria for radical cure of liver-stage infections: 0.75 mg/kg once weekly x8 weeks (WHO) or 45 mg once weekly x8 weeks (CDC) - with close monitoring for hemolysis; (2) Treating Plasmodium falciparum malaria by using primaquine single dose as a gametocytocide at 0.25 mg/kg (WHO) - without need for monitoring for hemolysis.

\n

Other Considerations

\n

Dosing recommendations for primaquine in patients with G6PD deficiency are derived from the malaria treatment guidelines issued by the World Health Organization and the U.S. Centers for Disease Control and Prevention.

\n", + "id" : 1452061065, + "html" : "

Avoid primaquine

\n

Other Considerations

\n

The strength of evidence among patients with the G6PD Deficient phenotype provides strong rationale to also avoid primaquine in the setting of the more severe G6PD Deficient with CNSHA phenotype.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298463", - "name" : "Recommendation PA166298463", - "alternateDrugAvailable" : true, + "id" : "PA166298461", + "name" : "Recommendation PA166298461", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, "parents" : [], @@ -77922,9 +78906,9 @@ }, "dosingInformation" : false, "implications" : [ - "G6PD: High risk of acute of acute exacerbation of chronic hemolysis" + "G6PD: Low risk of acute hemolytic anemia" ], - "lookupKey" : {"G6PD": "Deficient with CNSHA"}, + "lookupKey" : {"G6PD": "Normal"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -77932,21 +78916,21 @@ "objCls" : "Chemical", "id" : "PA451103", "name" : "primaquine", - "version" : 7 + "version" : 35 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166279621", "name" : "Annotation of CPIC Guideline for primaquine and G6PD", - "version" : 3 + "version" : 22 }, "text" : { - "id" : 1452061065, - "html" : "

Avoid primaquine

\n

Other Considerations

\n

The strength of evidence among patients with the G6PD Deficient phenotype provides strong rationale to also avoid primaquine in the setting of the more severe G6PD Deficient with CNSHA phenotype.

\n", + "id" : 1452061063, + "html" : "

No reason to avoid based on G6PD status

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -77974,21 +78958,21 @@ "objCls" : "Chemical", "id" : "PA451103", "name" : "primaquine", - "version" : 7 + "version" : 35 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166279621", "name" : "Annotation of CPIC Guideline for primaquine and G6PD", - "version" : 3 + "version" : 22 }, "text" : { "id" : 1452061017, "html" : "

To ascertain G6PD status, enzyme activity must be measured. Drug use should be guided per the recommendations based on the activity-based phenotype.

\n

Other Considerations

\n

Due to X-linked mosaicism, individuals with more than one X chromosome (e.g., females, individuals with Klinefelter syndrome) and heterozygous for one nondeficient (class IV) and one deficient (class I–III) allele may display a normal or a deficient phenotype; an enzyme activity test is needed to guide treatment in such cases.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -78016,21 +79000,21 @@ "objCls" : "Chemical", "id" : "PA451103", "name" : "primaquine", - "version" : 7 + "version" : 35 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166279621", "name" : "Annotation of CPIC Guideline for primaquine and G6PD", - "version" : 3 + "version" : 22 }, "text" : { "id" : 1452061030, "html" : "

To ascertain G6PD status, enzyme activity must be measured. Drug use should be guided per the recommendations based on the activity-based phenotype.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166279621" @@ -78185,7 +79169,7 @@ "id" : "PA166156544", "symbol" : "rs2231142", "name" : "rs2231142", - "version" : 4 + "version" : 7 }, { "objCls" : "Variant", @@ -78199,14 +79183,14 @@ "id" : "PA165819265", "symbol" : "SLCO1B1*15", "name" : "*15", - "version" : 23 + "version" : 39 }, { "objCls" : "Haplotype", "id" : "PA165819255", "symbol" : "SLCO1B1*5", "name" : "*5", - "version" : 23 + "version" : 39 } ], "relatedChemicals" : [ @@ -78214,7 +79198,7 @@ "objCls" : "Chemical", "id" : "PA134308647", "name" : "rosuvastatin", - "version" : 21 + "version" : 40 } ], "relatedGenes" : [ @@ -78223,52 +79207,52 @@ "id" : "PA390", "symbol" : "ABCG2", "name" : "ATP binding cassette subfamily G member 2 (Junior blood group)", - "version" : 3596 + "version" : 3672 }, { "objCls" : "Gene", "id" : "PA134865839", "symbol" : "SLCO1B1", "name" : "solute carrier organic anion transporter family member 1B1", - "version" : 49 + "version" : 109 } ], "source" : "CPIC", "summaryMarkdown" : { "id" : 1451672600, "html" : "

Prescribe ≤20mg as a starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines for patients who are SLCO1B1 or ABCG2 poor function phenotype. If dose >20mg needed for desired efficacy, consider combination therapy (i.e. rosuvastatin plus non-statin guideline directed medical therapy). Patients with both ABCG2 poor function and SLCO1B1 poor/decreased function should be prescribed ≤10mg as a starting dose.

\n", - "version" : 0 + "version" : 1 }, "terms" : [], "textMarkdown" : { "id" : 1451672601, "html" : "

This annotation is based on the CPIC® guideline for SLCO1B1, ABCG2, and CYP2C9 and statin-associated musculoskeletal symptoms.

\n

February 2022

\n\n\n

Adapted from Table 1 and 2 of the 2022 guideline update manuscript.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
PhenotypeGenotypeExamples of diplotypes aImplications for rosuvastatinDosing recommendations for rosuvastatin b,cClassification of recommendations d
Normal functionAn individual carrying two normal function alleles or one normal plus one increased function allele*1/*1, *1/*14Typical myopathy risk and statin exposurePrescribe desired starting dose and adjust doses based on disease-specific guidelines.Strong
Increased functionAn individual carrying two increased function alleles*14/*14Typical myopathy risk and statin exposurePrescribe desired starting dose and adjust doses based on disease-specific guidelines.Strong
Decreased functionAn individual carrying one normal or increased function allele plus one no function allele*1/*5, *1/*15Increased rosuvastatin exposure as compared to normal function; Typical myopathy risk with doses ≤20 mg.Prescribe desired starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines. Prescriber should be aware of possible increased risk for myopathy especially for doses >20mg.Strong
Possible decreased functionAn individual carrying one no function allele plus one uncertain/unknown function allele*5/*6, *15/*10, *5/*43Increased rosuvastatin exposure as compared to normal function; Typical myopathy risk with doses ≤20 mg.Prescribe desired starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines. Prescriber should be aware of possible increased risk for myopathy especially for doses >20mg.Strong
Poor functionAn individual carrying two no function alleles*5/*5, *5/*15, *15/*15Increased rosuvastatin exposure as compared to normal function and decreased function; Typical myopathy risk with doses ≤20 mg.Prescribe ≤20mg as a starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines If dose >20mg needed for desired efficacy, consider combination therapy (i.e. rosuvastatin plus non-statin guideline directed medical therapy).Moderate
IndeterminateAn individual carrying one normal function allele plus one uncertain or unknown function allele OR allele combinations with uncertain and/or unknown function alleles*1/*7, *1/*10, *7/*10n/aNo recommendation.No recommendation.
\n\n

Adapted from Table 3 of the 2022 guideline update manuscript.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
PhenotypeGenotypeExamples of diplotypes aImplications for rosuvastatinDosing recommendations for rosuvastatin b,cClassification of recommendations d
Normal functionAn individual carrying two normal function allelesc.421 C/C (rs2231142)Typical myopathy risk and rosuvastatin exposurePrescribe desired starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines.Strong
Decreased functionAn individual carrying one normal function allele plus one decreased function allelec.421 C/A (rs2231142)Increased rosuvastatin exposure as compared to normal function; unknown risk for myopathy.Prescribe desired starting dose and adjust doses of rosuvastatin based on disease-specific guidelines and specific population guidelines.Moderate
Poor functionAn individual carrying two decreased function allelesc.421 A/A (rs2231142)Increased rosuvastatin exposure compared to normal and decreased function; unknown myopathy risk; increased lipid-lowering effects.Prescribe ≤20mg as a starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines. If dose >20mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., rosuvastatin plus non-statin guideline directed medical therapy).Moderate
\n\n

Adapted from Table 5 of the 2022 guideline update manuscript.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
PhenotypeABCG2 normal functionABCG2 decreased functionABCG2 poor function
SLCO1B1 normal functionPrescribe desired starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines. STRONGPrescribe desired starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines. MODERATEPrescribe ≤20mg as a starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines. If dose >20mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., rosuvastatin plus non-statin guideline directed medical therapy). OPTIONAL
SLCO1B1 increased functionPrescribe desired starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines. STRONGPrescribe desired starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines. MODERATEPrescribe ≤20mg as a starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines. If dose >20mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., rosuvastatin plus non-statin guideline directed medical therapy). OPTIONAL
SLCO1B1 decreased functionPrescribe desired starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines. Prescriber should be aware of possible increased risk for myopathy especially for doses >20mg. STRONGPrescribe desired starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines. Prescriber should be aware of possible increased risk for myopathy especially for doses >20mg. MODERATEPrescribe ≤10mg as a starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines. If dose >10mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., rosuvastatin plus non-statin guideline directed medical therapy). OPTIONAL
SLCO1B1 possible decreased functionPrescribe desired starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines. Prescriber should be aware of possible increased risk for myopathy especially for doses >20mg. STRONGPrescribe desired starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines. Prescriber should be aware of possible increased risk for myopathy especially for doses >20mg. MODERATEPrescribe ≤10mg as a starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines. If dose >10mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., rosuvastatin plus non-statin guideline directed medical therapy). OPTIONAL
SLCO1B1 poor functionPrescribe ≤20mg as a starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines. If dose > 20mg needed for desired efficacy, consider combination therapy (i.e., rosuvastatin plus non-statin guideline directed medical therapy).MODERATEPrescribe ≤20mg as a starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines. If dose >20mg needed for desired efficacy, consider combination therapy (i.e., rosuvastatin plus non-statin guideline directed medical therapy). MODERATEPrescribe ≤10mg as a starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines. If dose >10mg needed for desired efficacy, consider combination therapy (i.e., rosuvastatin plus non-statin guideline directed medical therapy). OPTIONAL
\n

Figure 1 : SLCO1B1 recommendations with intensity and statin dose stratified by SLCO1B1 phenotype; all doses assume adult dosing.

\n

Adapted from Figure 1 of the 2022 guideline manuscript

\n

\"Fig1\"

\n\n", - "version" : 2 + "version" : 14 }, "userId" : "lgong", - "version" : 4 + "version" : 26 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166298488", - "name" : "Recommendation PA166298488", - "alternateDrugAvailable" : false, + "id" : "PA166298465", + "name" : "Recommendation PA166298465", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "ABCG2: Typical myopathy risk and rosuvastatin exposure", - "SLCO1B1: n/a" + "ABCG2: Increased rosuvastatin exposure compared to normal and decreased function; unknown myopathy risk; increased lipid-lowering effects", + "SLCO1B1: Increased rosuvastatin exposure as compared to normal function; Typical myopathy risk with doses ≤20 mg." ], - "lookupKey" : {"ABCG2": "Normal Function", "SLCO1B1": "No Result"}, + "lookupKey" : {"ABCG2": "Poor Function", "SLCO1B1": "Decreased Function"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -78276,18 +79260,18 @@ "objCls" : "Chemical", "id" : "PA134308647", "name" : "rosuvastatin", - "version" : 21 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262321", "name" : "Annotation of CPIC Guideline for rosuvastatin and ABCG2, SLCO1B1", - "version" : 4 + "version" : 26 }, "text" : { - "id" : 1452061090, - "html" : "

Based on ABCG2 status, prescribe desired starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines. SLCO1B1 genotype result is not available.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and Asian ancestry should be evaluated prior to initiating rosuvastatin.

\n", + "id" : 1452061067, + "html" : "

Prescribe ≤10mg as a starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines. If dose >10mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., rosuvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and Asian ancestry should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

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Prescribe desired starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines. Prescriber should be aware of possible increased risk for myopathy especially for doses >20mg.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and Asian ancestry should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452061071, + "html" : "

Prescribe ≤20mg as a starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines. If dose >20mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., rosuvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and Asian ancestry should be evaluated prior to initiating rosuvastatin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298474", - "name" : "Recommendation PA166298474", - "alternateDrugAvailable" : false, + "id" : "PA166298470", + "name" : "Recommendation PA166298470", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "ABCG2: Typical myopathy risk and rosuvastatin exposure", + "ABCG2: Increased rosuvastatin exposure compared to normal and decreased function; unknown myopathy risk; increased lipid-lowering effects", "SLCO1B1: Typical myopathy risk and statin exposure" ], - "lookupKey" : {"ABCG2": "Normal Function", "SLCO1B1": "Increased Function"}, + "lookupKey" : {"ABCG2": "Poor Function", "SLCO1B1": "Normal Function"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -78405,27 +79389,27 @@ "objCls" : "Chemical", "id" : "PA134308647", "name" : "rosuvastatin", - "version" : 21 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262321", "name" : "Annotation of CPIC Guideline for rosuvastatin and ABCG2, SLCO1B1", - "version" : 4 + "version" : 26 }, "text" : { - "id" : 1452061076, - "html" : "

Prescribe desired starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and Asian ancestry should be evaluated prior to initiating rosuvastatin.

\n", + "id" : 1452061072, + "html" : "

Prescribe ≤20mg as a starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines. If dose >20mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., rosuvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and Asian ancestry should be evaluated prior to initiating rosuvastatin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298487", - "name" : "Recommendation PA166298487", - "alternateDrugAvailable" : false, + "id" : "PA166298489", + "name" : "Recommendation PA166298489", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501931, "parents" : [], @@ -78435,12 +79419,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "ABCG2: Increased rosuvastatin exposure as compared to normal function; unknown risk for myopathy; increased lipid lowering effects", + "ABCG2: Increased rosuvastatin exposure compared to normal and decreased function; unknown myopathy risk; increased lipid-lowering effects", "SLCO1B1: n/a" ], - "lookupKey" : {"ABCG2": "Decreased Function", "SLCO1B1": "No Result"}, + "lookupKey" : {"ABCG2": "Poor Function", "SLCO1B1": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -78448,18 +79432,18 @@ "objCls" : "Chemical", "id" : "PA134308647", "name" : "rosuvastatin", - "version" : 21 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262321", "name" : "Annotation of CPIC Guideline for rosuvastatin and ABCG2, SLCO1B1", - "version" : 4 + "version" : 26 }, "text" : { - "id" : 1452061089, - "html" : "

Based on ABCG2 status, prescribe desired starting dose and adjust doses of rosuvastatin based on disease-specific guidelines and specific population guidelines. SLCO1B1 genotype result is not available.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and Asian ancestry should be evaluated prior to initiating rosuvastatin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452061091, + "html" : "

Based on ABCG2 status, prescribe ≤20mg as a starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines. If dose >20mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., rosuvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391). SLCO1B1 genotype result is not available.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and Asian ancestry should be evaluated prior to initiating rosuvastatin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, "version" : 0 @@ -78491,27 +79475,27 @@ "objCls" : "Chemical", "id" : "PA134308647", "name" : "rosuvastatin", - "version" : 21 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262321", "name" : "Annotation of CPIC Guideline for rosuvastatin and ABCG2, SLCO1B1", - "version" : 4 + "version" : 26 }, "text" : { "id" : 1452061094, "html" : "

Based on SLCO1B1 status, prescribe desired starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines. Prescriber should be aware of possible increased risk for myopathy especially for doses >20mg. ABCG2 genotype result is not available.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and Asian ancestry should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298470", - "name" : "Recommendation PA166298470", - "alternateDrugAvailable" : true, + "id" : "PA166298467", + "name" : "Recommendation PA166298467", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -78524,9 +79508,9 @@ "dosingInformation" : true, "implications" : [ "ABCG2: Increased rosuvastatin exposure compared to normal and decreased function; unknown myopathy risk; increased lipid-lowering effects", - "SLCO1B1: Typical myopathy risk and statin exposure" + "SLCO1B1: Increased rosuvastatin exposure as compared to normal function and decreased function; Typical myopathy risk with doses ≤20 mg." ], - "lookupKey" : {"ABCG2": "Poor Function", "SLCO1B1": "Normal Function"}, + "lookupKey" : {"ABCG2": "Poor Function", "SLCO1B1": "Poor Function"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -78534,26 +79518,26 @@ "objCls" : "Chemical", "id" : "PA134308647", "name" : "rosuvastatin", - "version" : 21 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262321", "name" : "Annotation of CPIC Guideline for rosuvastatin and ABCG2, SLCO1B1", - "version" : 4 + "version" : 26 }, "text" : { - "id" : 1452061072, - "html" : "

Prescribe ≤20mg as a starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines. If dose >20mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., rosuvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and Asian ancestry should be evaluated prior to initiating rosuvastatin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452061069, + "html" : "

Prescribe ≤10mg as a starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines. If dose >10mg needed for desired efficacy, consider combination therapy (i.e., rosuvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and Asian ancestry should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298483", - "name" : "Recommendation PA166298483", + "id" : "PA166298468", + "name" : "Recommendation PA166298468", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -78564,12 +79548,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "ABCG2: Increased rosuvastatin exposure as compared to normal function; unknown risk for myopathy; increased lipid lowering effects", - "SLCO1B1: n/a" + "ABCG2: Typical myopathy risk and rosuvastatin exposure", + "SLCO1B1: Increased rosuvastatin exposure as compared to normal function and decreased function; Typical myopathy risk with doses ≤20 mg." ], - "lookupKey" : {"ABCG2": "Decreased Function", "SLCO1B1": "Indeterminate"}, + "lookupKey" : {"ABCG2": "Normal Function", "SLCO1B1": "Poor Function"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -78577,26 +79561,26 @@ "objCls" : "Chemical", "id" : "PA134308647", "name" : "rosuvastatin", - "version" : 21 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262321", "name" : "Annotation of CPIC Guideline for rosuvastatin and ABCG2, SLCO1B1", - "version" : 4 + "version" : 26 }, "text" : { - "id" : 1452061085, - "html" : "

Based on ABCG2 status, prescribe desired starting dose and adjust doses of rosuvastatin based on disease-specific guidelines and specific population guidelines. SLCO1B1 phenotype could not be assigned based on genotyping.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and Asian ancestry should be evaluated prior to initiating rosuvastatin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452061070, + "html" : "

Prescribe ≤20mg as a starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines. If dose > 20mg needed for desired efficacy, consider combination therapy (i.e., rosuvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and Asian ancestry should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298476", - "name" : "Recommendation PA166298476", + "id" : "PA166298472", + "name" : "Recommendation PA166298472", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -78609,10 +79593,10 @@ }, "dosingInformation" : false, "implications" : [ - "ABCG2: Typical myopathy risk and rosuvastatin exposure", + "ABCG2: n/a", "SLCO1B1: Typical myopathy risk and statin exposure" ], - "lookupKey" : {"ABCG2": "Normal Function", "SLCO1B1": "Normal Function"}, + "lookupKey" : {"ABCG2": "No Result", "SLCO1B1": "Increased Function"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -78620,27 +79604,27 @@ "objCls" : "Chemical", "id" : "PA134308647", "name" : "rosuvastatin", - "version" : 21 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262321", "name" : "Annotation of CPIC Guideline for rosuvastatin and ABCG2, SLCO1B1", - "version" : 4 + "version" : 26 }, "text" : { - "id" : 1452061078, - "html" : "

Prescribe desired starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and Asian ancestry should be evaluated prior to initiating rosuvastatin.

\n", + "id" : 1452061074, + "html" : "

Based on SLCO1B1 status, prescribe desired starting dose and adjust doses based on disease-specific guidelines. ABCG2 genotype result is not available.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and ancestry should be evaluated prior to initiating a statin.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298489", - "name" : "Recommendation PA166298489", - "alternateDrugAvailable" : true, + "id" : "PA166298473", + "name" : "Recommendation PA166298473", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, "parents" : [], @@ -78650,12 +79634,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "ABCG2: Increased rosuvastatin exposure compared to normal and decreased function; unknown myopathy risk; increased lipid-lowering effects", - "SLCO1B1: n/a" + "ABCG2: Increased rosuvastatin exposure as compared to normal function; unknown risk for myopathy; increased lipid lowering effects", + "SLCO1B1: Typical myopathy risk and statin exposure" ], - "lookupKey" : {"ABCG2": "Poor Function", "SLCO1B1": "No Result"}, + "lookupKey" : {"ABCG2": "Decreased Function", "SLCO1B1": "Increased Function"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -78663,42 +79647,42 @@ "objCls" : "Chemical", "id" : "PA134308647", "name" : "rosuvastatin", - "version" : 21 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262321", "name" : "Annotation of CPIC Guideline for rosuvastatin and ABCG2, SLCO1B1", - "version" : 4 + "version" : 26 }, "text" : { - "id" : 1452061091, - "html" : "

Based on ABCG2 status, prescribe ≤20mg as a starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines. If dose >20mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., rosuvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391). SLCO1B1 genotype result is not available.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and Asian ancestry should be evaluated prior to initiating rosuvastatin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452061075, + "html" : "

Prescribe desired starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and Asian ancestry should be evaluated prior to initiating rosuvastatin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298467", - "name" : "Recommendation PA166298467", + "id" : "PA166298474", + "name" : "Recommendation PA166298474", "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "ABCG2: Increased rosuvastatin exposure compared to normal and decreased function; unknown myopathy risk; increased lipid-lowering effects", - "SLCO1B1: Increased rosuvastatin exposure as compared to normal function and decreased function; Typical myopathy risk with doses ≤20 mg." + "ABCG2: Typical myopathy risk and rosuvastatin exposure", + "SLCO1B1: Typical myopathy risk and statin exposure" ], - "lookupKey" : {"ABCG2": "Poor Function", "SLCO1B1": "Poor Function"}, + "lookupKey" : {"ABCG2": "Normal Function", "SLCO1B1": "Increased Function"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -78706,43 +79690,42 @@ "objCls" : "Chemical", "id" : "PA134308647", "name" : "rosuvastatin", - "version" : 21 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262321", "name" : "Annotation of CPIC Guideline for rosuvastatin and ABCG2, SLCO1B1", - "version" : 4 + "version" : 26 }, "text" : { - "id" : 1452061069, - "html" : "

Prescribe ≤10mg as a starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines. If dose >10mg needed for desired efficacy, consider combination therapy (i.e., rosuvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and Asian ancestry should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452061076, + "html" : "

Prescribe desired starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and Asian ancestry should be evaluated prior to initiating rosuvastatin.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298484", - "name" : "Recommendation PA166298484", + "id" : "PA166298475", + "name" : "Recommendation PA166298475", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, - "version" : 1 + "version" : 0 }, "dosingInformation" : false, "implications" : [ - "ABCG2: n/a", - "SLCO1B1: n/a" + "ABCG2: Increased rosuvastatin exposure as compared to normal function; unknown risk for myopathy; increased lipid lowering effects", + "SLCO1B1: Typical myopathy risk and statin exposure" ], - "lookupKey" : {"ABCG2": "No Result", "SLCO1B1": "Indeterminate"}, + "lookupKey" : {"ABCG2": "Decreased Function", "SLCO1B1": "Normal Function"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -78750,42 +79733,42 @@ "objCls" : "Chemical", "id" : "PA134308647", "name" : "rosuvastatin", - "version" : 21 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262321", "name" : "Annotation of CPIC Guideline for rosuvastatin and ABCG2, SLCO1B1", - "version" : 4 + "version" : 26 }, "text" : { - "id" : 1452061086, - "html" : "

n/a

\n", + "id" : 1452061077, + "html" : "

Prescribe desired starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and Asian ancestry should be evaluated prior to initiating rosuvastatin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298475", - "name" : "Recommendation PA166298475", + "id" : "PA166298476", + "name" : "Recommendation PA166298476", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "ABCG2: Increased rosuvastatin exposure as compared to normal function; unknown risk for myopathy; increased lipid lowering effects", + "ABCG2: Typical myopathy risk and rosuvastatin exposure", "SLCO1B1: Typical myopathy risk and statin exposure" ], - "lookupKey" : {"ABCG2": "Decreased Function", "SLCO1B1": "Normal Function"}, + "lookupKey" : {"ABCG2": "Normal Function", "SLCO1B1": "Normal Function"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -78793,42 +79776,42 @@ "objCls" : "Chemical", "id" : "PA134308647", "name" : "rosuvastatin", - "version" : 21 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262321", "name" : "Annotation of CPIC Guideline for rosuvastatin and ABCG2, SLCO1B1", - "version" : 4 + "version" : 26 }, "text" : { - "id" : 1452061077, - "html" : "

Prescribe desired starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and Asian ancestry should be evaluated prior to initiating rosuvastatin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452061078, + "html" : "

Prescribe desired starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and Asian ancestry should be evaluated prior to initiating rosuvastatin.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298480", - "name" : "Recommendation PA166298480", + "id" : "PA166298477", + "name" : "Recommendation PA166298477", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "ABCG2: Typical myopathy risk and rosuvastatin exposure", + "ABCG2: Increased rosuvastatin exposure as compared to normal function; unknown risk for myopathy; increased lipid lowering effects", "SLCO1B1: Increased rosuvastatin exposure as compared to normal function; Typical myopathy risk with doses ≤20 mg." ], - "lookupKey" : {"ABCG2": "Normal Function", "SLCO1B1": "Possible Decreased Function"}, + "lookupKey" : {"ABCG2": "Decreased Function", "SLCO1B1": "Decreased Function"}, "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ @@ -78836,26 +79819,26 @@ "objCls" : "Chemical", "id" : "PA134308647", "name" : "rosuvastatin", - "version" : 21 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262321", "name" : "Annotation of CPIC Guideline for rosuvastatin and ABCG2, SLCO1B1", - "version" : 4 + "version" : 26 }, "text" : { - "id" : 1452061082, - "html" : "

Prescribe desired starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines. Prescriber should be aware of possible increased risk for myopathy especially for doses >20mg.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and Asian ancestry should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452061079, + "html" : "

Prescribe desired starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines. Prescriber should be aware of possible increased risk for myopathy especially for doses >20mg.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and Asian ancestry should be evaluated prior to initiating rosuvastatin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298471", - "name" : "Recommendation PA166298471", + "id" : "PA166298478", + "name" : "Recommendation PA166298478", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -78866,82 +79849,125 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ "ABCG2: Increased rosuvastatin exposure as compared to normal function; unknown risk for myopathy; increased lipid lowering effects", - "SLCO1B1: Increased rosuvastatin exposure as compared to normal function and decreased function; Typical myopathy risk with doses ≤20 mg." + "SLCO1B1: Increased rosuvastatin exposure as compared to normal function; Typical myopathy risk with doses ≤20 mg." ], - "lookupKey" : {"ABCG2": "Decreased Function", "SLCO1B1": "Poor Function"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"ABCG2": "Decreased Function", "SLCO1B1": "Possible Decreased Function"}, + "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA134308647", "name" : "rosuvastatin", - "version" : 21 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262321", "name" : "Annotation of CPIC Guideline for rosuvastatin and ABCG2, SLCO1B1", - "version" : 4 + "version" : 26 }, "text" : { - "id" : 1452061073, - "html" : "

Prescribe ≤20mg as a starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines. If dose >20mg needed for desired efficacy, consider combination therapy (i.e., rosuvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and Asian ancestry should be evaluated prior to initiating rosuvastatin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452061080, + "html" : "

Prescribe desired starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines. Prescriber should be aware of possible increased risk for myopathy especially for doses >20mg.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and Asian ancestry should be evaluated prior to initiating rosuvastatin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298468", - "name" : "Recommendation PA166298468", + "id" : "PA166298479", + "name" : "Recommendation PA166298479", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ "ABCG2: Typical myopathy risk and rosuvastatin exposure", - "SLCO1B1: Increased rosuvastatin exposure as compared to normal function and decreased function; Typical myopathy risk with doses ≤20 mg." + "SLCO1B1: Increased rosuvastatin exposure as compared to normal function; Typical myopathy risk with doses ≤20 mg." ], - "lookupKey" : {"ABCG2": "Normal Function", "SLCO1B1": "Poor Function"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"ABCG2": "Normal Function", "SLCO1B1": "Decreased Function"}, + "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA134308647", "name" : "rosuvastatin", - "version" : 21 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262321", "name" : "Annotation of CPIC Guideline for rosuvastatin and ABCG2, SLCO1B1", - "version" : 4 + "version" : 26 }, "text" : { - "id" : 1452061070, - "html" : "

Prescribe ≤20mg as a starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines. If dose > 20mg needed for desired efficacy, consider combination therapy (i.e., rosuvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and Asian ancestry should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452061081, + "html" : "

Prescribe desired starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines. Prescriber should be aware of possible increased risk for myopathy especially for doses >20mg.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and Asian ancestry should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298490", - "name" : "Recommendation PA166298490", + "id" : "PA166298480", + "name" : "Recommendation PA166298480", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501930, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : false, + "implications" : [ + "ABCG2: Typical myopathy risk and rosuvastatin exposure", + "SLCO1B1: Increased rosuvastatin exposure as compared to normal function; Typical myopathy risk with doses ≤20 mg." + ], + "lookupKey" : {"ABCG2": "Normal Function", "SLCO1B1": "Possible Decreased Function"}, + "otherPrescribingGuidance" : true, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA134308647", + "name" : "rosuvastatin", + "version" : 40 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166262321", + "name" : "Annotation of CPIC Guideline for rosuvastatin and ABCG2, SLCO1B1", + "version" : 26 + }, + "text" : { + "id" : 1452061082, + "html" : "

Prescribe desired starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines. Prescriber should be aware of possible increased risk for myopathy especially for doses >20mg.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and Asian ancestry should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "version" : 0 + }, + "version" : 1 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166298481", + "name" : "Recommendation PA166298481", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -78955,36 +79981,36 @@ "dosingInformation" : false, "implications" : [ "ABCG2: n/a", - "SLCO1B1: Typical myopathy risk and statin exposure" + "SLCO1B1: Increased rosuvastatin exposure as compared to normal function; Typical myopathy risk with doses ≤20 mg." ], - "lookupKey" : {"ABCG2": "No Result", "SLCO1B1": "Normal Function"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"ABCG2": "No Result", "SLCO1B1": "Decreased Function"}, + "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA134308647", "name" : "rosuvastatin", - "version" : 21 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262321", "name" : "Annotation of CPIC Guideline for rosuvastatin and ABCG2, SLCO1B1", - "version" : 4 + "version" : 26 }, "text" : { - "id" : 1452061092, - "html" : "

Based on SLCO1B1 status, prescribe desired starting dose and adjust doses based on disease-specific guidelines. ABCG2 genotype result is not available.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and ancestry should be evaluated prior to initiating a statin.

\n", + "id" : 1452061083, + "html" : "

Based on SLCO1B1 status, prescribe desired starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines. Prescriber should be aware of possible increased risk for myopathy especially for doses >20mg. ABCG2 genotype result is not available.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and Asian ancestry should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298477", - "name" : "Recommendation PA166298477", + "id" : "PA166298483", + "name" : "Recommendation PA166298483", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -78998,52 +80024,53 @@ "dosingInformation" : false, "implications" : [ "ABCG2: Increased rosuvastatin exposure as compared to normal function; unknown risk for myopathy; increased lipid lowering effects", - "SLCO1B1: Increased rosuvastatin exposure as compared to normal function; Typical myopathy risk with doses ≤20 mg." + "SLCO1B1: n/a" ], - "lookupKey" : {"ABCG2": "Decreased Function", "SLCO1B1": "Decreased Function"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"ABCG2": "Decreased Function", "SLCO1B1": "Indeterminate"}, + "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA134308647", "name" : "rosuvastatin", - "version" : 21 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262321", "name" : "Annotation of CPIC Guideline for rosuvastatin and ABCG2, SLCO1B1", - "version" : 4 + "version" : 26 }, "text" : { - "id" : 1452061079, - "html" : "

Prescribe desired starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines. Prescriber should be aware of possible increased risk for myopathy especially for doses >20mg.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and Asian ancestry should be evaluated prior to initiating rosuvastatin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452061085, + "html" : "

Based on ABCG2 status, prescribe desired starting dose and adjust doses of rosuvastatin based on disease-specific guidelines and specific population guidelines. SLCO1B1 phenotype could not be assigned based on genotyping.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and Asian ancestry should be evaluated prior to initiating rosuvastatin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298472", - "name" : "Recommendation PA166298472", + "id" : "PA166298484", + "name" : "Recommendation PA166298484", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, "dosingInformation" : false, "implications" : [ "ABCG2: n/a", - "SLCO1B1: Typical myopathy risk and statin exposure" + "SLCO1B1: n/a" ], - "lookupKey" : {"ABCG2": "No Result", "SLCO1B1": "Increased Function"}, + "lookupKey" : {"ABCG2": "No Result", "SLCO1B1": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -79051,21 +80078,21 @@ "objCls" : "Chemical", "id" : "PA134308647", "name" : "rosuvastatin", - "version" : 21 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262321", "name" : "Annotation of CPIC Guideline for rosuvastatin and ABCG2, SLCO1B1", - "version" : 4 + "version" : 26 }, "text" : { - "id" : 1452061074, - "html" : "

Based on SLCO1B1 status, prescribe desired starting dose and adjust doses based on disease-specific guidelines. ABCG2 genotype result is not available.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and ancestry should be evaluated prior to initiating a statin.

\n", + "id" : 1452061086, + "html" : "

n/a

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -79094,85 +80121,42 @@ "objCls" : "Chemical", "id" : "PA134308647", "name" : "rosuvastatin", - "version" : 21 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262321", "name" : "Annotation of CPIC Guideline for rosuvastatin and ABCG2, SLCO1B1", - "version" : 4 + "version" : 26 }, "text" : { "id" : 1452061087, "html" : "

Based on ABCG2 status, prescribe desired starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines. SLCO1B1 phenotype could not be assigned based on genotyping.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and Asian ancestry should be evaluated prior to initiating rosuvastatin.

\n", "version" : 0 }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166298481", - "name" : "Recommendation PA166298481", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 981501930, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "ABCG2: n/a", - "SLCO1B1: Increased rosuvastatin exposure as compared to normal function; Typical myopathy risk with doses ≤20 mg." - ], - "lookupKey" : {"ABCG2": "No Result", "SLCO1B1": "Decreased Function"}, - "otherPrescribingGuidance" : true, - "population" : "general", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA134308647", - "name" : "rosuvastatin", - "version" : 21 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166262321", - "name" : "Annotation of CPIC Guideline for rosuvastatin and ABCG2, SLCO1B1", - "version" : 4 - }, - "text" : { - "id" : 1452061083, - "html" : "

Based on SLCO1B1 status, prescribe desired starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines. Prescriber should be aware of possible increased risk for myopathy especially for doses >20mg. ABCG2 genotype result is not available.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and Asian ancestry should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", - "version" : 0 - }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298469", - "name" : "Recommendation PA166298469", + "id" : "PA166298486", + "name" : "Recommendation PA166298486", "alternateDrugAvailable" : true, "classification" : { - "id" : 981565059, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ "ABCG2: Increased rosuvastatin exposure compared to normal and decreased function; unknown myopathy risk; increased lipid-lowering effects", - "SLCO1B1: Typical myopathy risk and statin exposure" + "SLCO1B1: n/a" ], - "lookupKey" : {"ABCG2": "Poor Function", "SLCO1B1": "Increased Function"}, + "lookupKey" : {"ABCG2": "Poor Function", "SLCO1B1": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -79180,26 +80164,26 @@ "objCls" : "Chemical", "id" : "PA134308647", "name" : "rosuvastatin", - "version" : 21 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262321", "name" : "Annotation of CPIC Guideline for rosuvastatin and ABCG2, SLCO1B1", - "version" : 4 + "version" : 26 }, "text" : { - "id" : 1452061071, - "html" : "

Prescribe ≤20mg as a starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines. If dose >20mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., rosuvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and Asian ancestry should be evaluated prior to initiating rosuvastatin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452061088, + "html" : "

Based on ABCG2 status, prescribe ≤20mg as a starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines. If dose >20mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., rosuvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391). SLCO1B1 phenotype could not be assigned based on genotyping.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and Asian ancestry should be evaluated prior to initiating rosuvastatin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298491", - "name" : "Recommendation PA166298491", + "id" : "PA166298487", + "name" : "Recommendation PA166298487", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -79210,12 +80194,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "ABCG2: n/a", - "SLCO1B1: Increased rosuvastatin exposure as compared to normal function and decreased function; Typical myopathy risk with doses ≤20 mg." + "ABCG2: Increased rosuvastatin exposure as compared to normal function; unknown risk for myopathy; increased lipid lowering effects", + "SLCO1B1: n/a" ], - "lookupKey" : {"ABCG2": "No Result", "SLCO1B1": "Poor Function"}, + "lookupKey" : {"ABCG2": "Decreased Function", "SLCO1B1": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -79223,42 +80207,42 @@ "objCls" : "Chemical", "id" : "PA134308647", "name" : "rosuvastatin", - "version" : 21 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262321", "name" : "Annotation of CPIC Guideline for rosuvastatin and ABCG2, SLCO1B1", - "version" : 4 + "version" : 26 }, "text" : { - "id" : 1452061093, - "html" : "

Based on SLCO1B1 status, prescribe ≤20mg as a starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines If dose >20mg needed for desired efficacy, consider combination therapy (i.e. rosuvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391). ABCG2 genotype result is not available.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and Asian ancestry should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452061089, + "html" : "

Based on ABCG2 status, prescribe desired starting dose and adjust doses of rosuvastatin based on disease-specific guidelines and specific population guidelines. SLCO1B1 genotype result is not available.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and Asian ancestry should be evaluated prior to initiating rosuvastatin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298465", - "name" : "Recommendation PA166298465", - "alternateDrugAvailable" : true, + "id" : "PA166298488", + "name" : "Recommendation PA166298488", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "ABCG2: Increased rosuvastatin exposure compared to normal and decreased function; unknown myopathy risk; increased lipid-lowering effects", - "SLCO1B1: Increased rosuvastatin exposure as compared to normal function; Typical myopathy risk with doses ≤20 mg." + "ABCG2: Typical myopathy risk and rosuvastatin exposure", + "SLCO1B1: n/a" ], - "lookupKey" : {"ABCG2": "Poor Function", "SLCO1B1": "Decreased Function"}, + "lookupKey" : {"ABCG2": "Normal Function", "SLCO1B1": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -79266,69 +80250,69 @@ "objCls" : "Chemical", "id" : "PA134308647", "name" : "rosuvastatin", - "version" : 21 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262321", "name" : "Annotation of CPIC Guideline for rosuvastatin and ABCG2, SLCO1B1", - "version" : 4 + "version" : 26 }, "text" : { - "id" : 1452061067, - "html" : "

Prescribe ≤10mg as a starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines. If dose >10mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., rosuvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and Asian ancestry should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452061090, + "html" : "

Based on ABCG2 status, prescribe desired starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines. SLCO1B1 genotype result is not available.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and Asian ancestry should be evaluated prior to initiating rosuvastatin.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298478", - "name" : "Recommendation PA166298478", + "id" : "PA166298490", + "name" : "Recommendation PA166298490", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "ABCG2: Increased rosuvastatin exposure as compared to normal function; unknown risk for myopathy; increased lipid lowering effects", - "SLCO1B1: Increased rosuvastatin exposure as compared to normal function; Typical myopathy risk with doses ≤20 mg." + "ABCG2: n/a", + "SLCO1B1: Typical myopathy risk and statin exposure" ], - "lookupKey" : {"ABCG2": "Decreased Function", "SLCO1B1": "Possible Decreased Function"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"ABCG2": "No Result", "SLCO1B1": "Normal Function"}, + "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA134308647", "name" : "rosuvastatin", - "version" : 21 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262321", "name" : "Annotation of CPIC Guideline for rosuvastatin and ABCG2, SLCO1B1", - "version" : 4 + "version" : 26 }, "text" : { - "id" : 1452061080, - "html" : "

Prescribe desired starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines. Prescriber should be aware of possible increased risk for myopathy especially for doses >20mg.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and Asian ancestry should be evaluated prior to initiating rosuvastatin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452061092, + "html" : "

Based on SLCO1B1 status, prescribe desired starting dose and adjust doses based on disease-specific guidelines. ABCG2 genotype result is not available.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and ancestry should be evaluated prior to initiating a statin.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298473", - "name" : "Recommendation PA166298473", + "id" : "PA166298491", + "name" : "Recommendation PA166298491", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -79339,12 +80323,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "ABCG2: Increased rosuvastatin exposure as compared to normal function; unknown risk for myopathy; increased lipid lowering effects", - "SLCO1B1: Typical myopathy risk and statin exposure" + "ABCG2: n/a", + "SLCO1B1: Increased rosuvastatin exposure as compared to normal function and decreased function; Typical myopathy risk with doses ≤20 mg." ], - "lookupKey" : {"ABCG2": "Decreased Function", "SLCO1B1": "Increased Function"}, + "lookupKey" : {"ABCG2": "No Result", "SLCO1B1": "Poor Function"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -79352,27 +80336,27 @@ "objCls" : "Chemical", "id" : "PA134308647", "name" : "rosuvastatin", - "version" : 21 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262321", "name" : "Annotation of CPIC Guideline for rosuvastatin and ABCG2, SLCO1B1", - "version" : 4 + "version" : 26 }, "text" : { - "id" : 1452061075, - "html" : "

Prescribe desired starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and Asian ancestry should be evaluated prior to initiating rosuvastatin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452061093, + "html" : "

Based on SLCO1B1 status, prescribe ≤20mg as a starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines If dose >20mg needed for desired efficacy, consider combination therapy (i.e. rosuvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391). ABCG2 genotype result is not available.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and Asian ancestry should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298486", - "name" : "Recommendation PA166298486", - "alternateDrugAvailable" : true, + "id" : "PA166298471", + "name" : "Recommendation PA166298471", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, "parents" : [], @@ -79384,10 +80368,10 @@ }, "dosingInformation" : true, "implications" : [ - "ABCG2: Increased rosuvastatin exposure compared to normal and decreased function; unknown myopathy risk; increased lipid-lowering effects", - "SLCO1B1: n/a" + "ABCG2: Increased rosuvastatin exposure as compared to normal function; unknown risk for myopathy; increased lipid lowering effects", + "SLCO1B1: Increased rosuvastatin exposure as compared to normal function and decreased function; Typical myopathy risk with doses ≤20 mg." ], - "lookupKey" : {"ABCG2": "Poor Function", "SLCO1B1": "Indeterminate"}, + "lookupKey" : {"ABCG2": "Decreased Function", "SLCO1B1": "Poor Function"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -79395,21 +80379,21 @@ "objCls" : "Chemical", "id" : "PA134308647", "name" : "rosuvastatin", - "version" : 21 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166262321", "name" : "Annotation of CPIC Guideline for rosuvastatin and ABCG2, SLCO1B1", - "version" : 4 + "version" : 26 }, "text" : { - "id" : 1452061088, - "html" : "

Based on ABCG2 status, prescribe ≤20mg as a starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines. If dose >20mg needed for desired efficacy, consider an alternative statin or combination therapy (i.e., rosuvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391). SLCO1B1 phenotype could not be assigned based on genotyping.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and Asian ancestry should be evaluated prior to initiating rosuvastatin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452061073, + "html" : "

Prescribe ≤20mg as a starting dose and adjust doses of rosuvastatin based on disease-specific and specific population guidelines. If dose >20mg needed for desired efficacy, consider combination therapy (i.e., rosuvastatin plus non-statin guideline directed medical therapy) (PMID: 30423391).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and Asian ancestry should be evaluated prior to initiating rosuvastatin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166262321" @@ -79573,6 +80557,7 @@ "version" : 1 } ], + "descriptiveVideoId" : "J4UENwJWO5s", "dosingInformation" : true, "hasTestingInfo" : false, "history" : [ @@ -79603,6 +80588,13 @@ "description" : "added publication", "type" : "Update", "version" : 0 + }, + { + "id" : 1452508520, + "date" : "2024-06-26T04:45:44.418-07:00", + "description" : "Added video", + "type" : "Update", + "version" : 0 } ], "literature" : [ @@ -79623,7 +80615,7 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "relatedGenes" : [ @@ -79632,36 +80624,36 @@ "id" : "PA123", "symbol" : "CYP2B6", "name" : "cytochrome P450 family 2 subfamily B member 6", - "version" : 6788 + "version" : 6829 }, { "objCls" : "Gene", "id" : "PA124", "symbol" : "CYP2C19", "name" : "cytochrome P450 family 2 subfamily C member 19", - "version" : 7210 + "version" : 7266 } ], "source" : "CPIC", "summaryMarkdown" : { "id" : 1447982317, "html" : "

The CPIC Dosing Guideline for the selective serotonin reuptake inhibitor sertraline recommends to consider a 50% reduction of recommended starting dose and titrate to response or select alternative drug not predominantly metabolized by CYP2C19 for CYP2C19 poor metabolizers.

\n", - "version" : 0 + "version" : 1 }, "terms" : [], "textMarkdown" : { "id" : 1451433663, "html" : "

This annotation is based on the CPIC® guideline for CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A Genotypes and Serotonin Reuptake Inhibitor Antidepressants. This is an update to the previous CPIC® guideline for Selective Serotonin Reuptake Inhibitors and CYP2D6 and CYP2C19.

\n

February 2023

\n\n

Table 1: Dosing recommendations for sertraline based on CYP2C19 phenotype

\n

Adapted from Tables 1 and 3b of the guideline.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
PhenotypeGenotypesExamplesImplicationsTherapeutic
Recommendations		Classification of
Recommendationsa		Considerations
CYP2C19 Ultrarapid MetabolizerAn individual carrying two increased function alleles.*17/*17Small increase in metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers.Initiate therapy with recommended starting dose.StrongCYP2B6 metabolizer status, drug-drug interactions, and other patient characteristics (e.g., age, renal function, liver function) should also be considered.
CYP2C19 Rapid MetabolizerAn individual carrying one normal function allele and one increased function allele.*1/*17Small increase in metabolism of sertraline to less active compounds when compared to normal metabolizers.Initiate therapy with recommended starting dose.StrongCYP2B6 metabolizer status, drug-drug interactions, and other patient characteristics (e.g., age, renal function, liver function) should also be considered.
CYP2C19 Normal MetabolizerAn individual carrying two normal function alleles.*1/*1Normal metabolismInitiate therapy with recommended starting dose.StrongCYP2B6 metabolizer status, drug-drug interactions, and other patient characteristics (e.g., age, renal function, liver function) should also be considered.
CYP2C19 Likely Intermediate MetabolizerAn individual carrying one normal function allele and one decreased b function allele or one increased function allele and one decreased b function allele or two decreased b function alleles.*1/*9, *9/*17, *9/*9Reduced metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers.Initiate therapy with recommended starting dose. Consider a slower titration schedule and lower maintenance dose than CYP2C19 normal metabolizers.ModerateCYP2B6 metabolizer status, drug-drug interactions, and other patient characteristics (e.g., age, renal function, liver function) should also be considered.
CYP2C19 Intermediate MetabolizerAn individual carrying one normal function allele and one no function allele or one increased function allele and one no function allele.*1/*2, *1/*3, *2/*17, *3/*17Reduced metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers.Initiate therapy with recommended starting dose. Consider a slower titration schedule and lower maintenance dose than CYP2C19 normal metabolizers.ModerateCYP2B6 metabolizer status, drug-drug interactions, and other patient characteristics (e.g., age, renal function, liver function) should also be considered.
CYP2C19 Likely Poor MetabolizerAn individual carrying one decreased b function allele and one no function allele.*2/*9, *3/*9Greatly reduced metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers. Higher plasma concentrations may increase the probability of side effects.Consider a lower starting dose, slower titration schedule and 50% reduction of standard maintenance dose as compared to CYP2C19 normal metabolizers or select a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2C19.ModerateCYP2B6 metabolizer status, drug-drug interactions, and other patient characteristics (e.g., age, renal function, liver function) should be considered when adjusting dose or selecting an alternative therapy.
CYP2C19 Poor MetabolizerAn individual carrying two no function alleles.*2/*2, *2/*3, *3/*3Greatly reduced metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers. Higher plasma concentrations may increase the probability of side effects.Consider a lower starting dose, slower titration schedule and 50% reduction of standard maintenance dose as compared to CYP2C19 normal metabolizers or select a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2C19.ModerateCYP2B6 metabolizer status, drug-drug interactions, and other patient characteristics (e.g., age, renal function, liver function) should be considered when adjusting dose or selecting an alternative therapy.
IndeterminateAn individual carrying one or two uncertain function alleles.*1/*12, *2/*12, *12/*14No recommendationNo recommendation
\n

a Rating scheme described in Supplement.\nb There are limited data to characterize the function of decreased function alleles.

\n

Table 2: Dosing recommendations for sertraline based on CYP2B6 phenotype

\n

Adapted from Tables 1 and 4 of the guideline.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
CYP2B6 phenotypeGenotypesExamplesImplicationsDosing
recommendations		Classification of
recommendationsa		Considerations
CYP2B6 Ultrarapid MetabolizerAn individual carrying two increased function alleles*4/*4, *22/*22, *4/*22Increase in metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers.Initiate therapy with recommended starting dose.ModerateCYP2C19 metabolizer status, drug-drug interactions, and other patient characteristics (e.g., age, renal function, liver function) should also be considered.
CYP2B6 Rapid MetabolizerAn individual carrying one normal function allele and one increased function allele*1/*4, *1/*22Small increase in metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers.Initiate therapy with recommended starting dose.StrongCYP2C19 metabolizer status, drug-drug interactions, and other patient characteristics (e.g., age, renal function, liver function) should also be considered.
CYP2B6 Normal MetabolizerAn individual carrying two normal function alleles*1/*1Normal metabolism of sertraline to less active compounds.Initiate therapy with recommended starting dose.StrongCYP2C19 metabolizer status, drug-drug interactions, and other patient characteristics (e.g., age, renal function, liver function) should also be considered.
CYP2B6 Intermediate MetabolizerAn individual carrying one normal function allele and one decreased function allele OR one normal function allele and one no function allele OR one increased function allele and one decreased function allele OR one increased function allele and one no function allele*1/*6, *1/*18, *4/*6, *4/*18, *6/*22, *18/*22Reduced metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers.Initiate therapy with recommended starting dose. Consider a slower titration schedule and lower maintenance dose than CYP2B6 normal metabolizers.OptionalCYP2C19 metabolizer status, drug-drug interactions, and other patient characteristics (e.g., age, renal function, liver function) should be also considered.
CYP2B6 Poor MetabolizerAn individual carrying two decreased function alleles OR two no function alleles OR one decreased function allele and one no function allele*6/*6, *18/*18, *6/*18Greatly reduced metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers. Higher plasma concentrations may increase the probability of side effects.Consider a lower starting dose, slower titration schedule and 25% reduction of standard maintenance dose as compared to CYP2B6 normal metabolizers or select a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2B6.OptionalCYP2C19 metabolizer status, drug-drug interactions, and other patient characteristics (e.g., age, renal function, liver function) should be considered when adjusting dose or selecting an alternative therapy.
CYP2B6 IndeterminateAn individual carrying one or two uncertain and/or unknown function alleles*3/*6, *3/*10No recommendationNo recommendation
\n

a Rating scheme described in Supplement.

\n

Table 3: Dosing recommendations for sertraline based on CYP2C19 and CYP2B6 phenotype

\n

Adapted from Tables 5 of the guideline.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
PhenotypeCYP2B6 ultrarapid or rapid metabolizerCYP2B6 normal metabolizersCYP2B6 intermediate metabolizersCYP2B6 poor metabolizersCYP2B6 indeterminate
CYP2C19 ultrarapid or rapid metabolizersInitiate therapy with recommended starting dose. If patient does not adequately respond to recommended maintenance dosing, consider titrating to a higher maintenance dose or switching to a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2C19 or CYP2B6. Classification of recommendation: OptionalInitiate therapy with recommended starting dose. Classification of recommendation: StrongInitiate therapy with recommended starting dose. Classification of recommendation: ModerateInitiate therapy with recommended starting dose. Classification of recommendation: OptionalInitiate therapy with recommended starting dose. Classification of recommendation: Strong
CYP2C19 normal metabolizersInitiate therapy with recommended starting dose. Classification of recommendation: ModerateInitiate therapy with recommended starting dose. Classification of recommendation: StrongInitiate therapy with recommended starting dose. Consider a slower titration schedule and lower maintenance dose. Classification of recommendation: ModerateConsider a lower starting dose, slower titration schedule and 25% reduction of standard maintenance dose as compared to CYP2B6 normal metabolizers or select a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2B6. Classification of recommendation: OptionalInitiate therapy with recommended starting dose. Classification of recommendation: Strong
CYP2C19 likely intermediate or intermediate metabolizersInitiate therapy with recommended starting dose. Classification of recommendation: ModerateInitiate therapy with recommended starting dose. Consider a slower titration schedule and lower maintenance dose. Classification of recommendation: ModerateInitiate therapy with recommended starting dose. Consider a slower titration schedule and lower maintenance dose than normal metabolizers. Classification of recommendation: OptionalConsider a lower starting dose, slower titration schedule and 50% reduction of standard maintenance dose as compared to CYP2B6 normal metabolizers. Classification of recommendation: OptionalInitiate therapy with recommended starting dose. Consider a slower titration schedule and lower maintenance dose. Classification of recommendation: Moderate
CYP2C19 likely poor or poor metabolizersConsider a lower starting dose, slower titration schedule and 50% reduction of standard maintenance dose as compared to CYP2C19 normal metabolizers or select a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2C19. Classification of recommendation: OptionalConsider a lower starting dose, slower titration schedule and 50% reduction of standard maintenance dose as compared to CYP2C19 normal metabolizers or select a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2C19. Classification of recommendation: ModerateConsider a lower starting dose, slower titration schedule and 50% reduction of standard maintenance dose as compared to CYP2C19 normal metabolizers or select a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2C19. Classification of recommendation: ModerateSelect an alternative antidepressant not primarily metabolized by CYP2C19 or CYP2B6. Classification of recommendation: OptionalConsider a lower starting dose, slower titration schedule and 50% reduction of standard maintenance dose as compared to CYP2C19 normal metabolizers or select a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2C19. Classification of recommendation: Moderate
CYP2C19 indeterminateInitiate therapy with recommended starting dose. Classification of recommendation: ModerateInitiate therapy with recommended starting dose. Classification of recommendation: ModerateInitiate therapy with recommended starting dose. Consider a slower titration schedule and lower maintenance dose. Classification of recommendation: ModerateConsider a lower starting dose, slower titration schedule and 25% reduction of standard maintenance dose as compared to CYP2B6 normal metabolizers or select a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2B6. Classification of recommendation: OptionalNo recommendation.
\n

August 2015

\n

Advanced online publication May 2015

\n\n

Table 1: Dosing recommendations for sertraline based on CYP2C19 phenotype:

\n

Adapted from Tables 1 and 3b of the 2015 guideline manuscript.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Likely phenotypeGenotypesExamples of CYP2C19 diplotypesImplications for sertraline metabolismTherapeutic RecommendationsClassification of recommendations a
Ultrarapid metabolizer (~5-30% of patients) bAn individual carrying two increased function alleles or one normal function allele and one increased function allele*17/*17, *1/*17Increased metabolism when compared to extensive metabolizers.Initiate therapy with recommended starting dose. If patient does not respond to recommended maintenance dosing, consider alternative drug not predominantly metabolized by CYP2C19.cOptional
Extensive metabolizer (~35-50% of patients)An individual carrying two normal function alleles*1/*1Normal metabolismInitiate therapy with recommended starting dose.Strong
Intermediate metabolizer (~18-45% of patients)An individual carrying one normal function allele or one increased function allele and one no function allele*1/*2, *1/*3, *2/*17 dReduced metabolism when compared to extensive metabolizers.Initiate therapy with recommended starting dose.Strong
Poor metabolizer (~2-15% of patients)An individual carrying two no function alleles*2/*2, *2/*3, *3/*3Greatly reduced metabolism when compared to extensive metabolizers. Higher plasma concentrations may increase the probability of side effects.Consider a 50% reduction e of recommended starting dose and titrate to response or select alternative drug not predominantly metabolized by CYP2C19.cOptional
\n

a Rating scheme described in Supplement.

\n

b CYP2C19 metabolizer status frequencies are based on average multi-ethnic frequency.

\n

c Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when selecting an alternative therapy.

\n

d The predicted metabolizer phenotype for the*2/*17 genotypes is a provisional classification. The currently available evidence indicates that the CYP2C19*17 increased function allele is unable to completely compensate for the no function CYP2C19*2. See Supplemental Materials for a more comprehensive list of predicted metabolizer phenotypes.

\n

e Percent dose adjustments corresponding to percent difference in oral clearances have been calculated/estimated by Stingl et al. [Article:22565785].

\n", - "version" : 1 + "version" : 5 }, "userId" : "whaleyr", - "version" : 48 + "version" : 123 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166300914", - "name" : "Recommendation PA166300914", + "id" : "PA166300890", + "name" : "Recommendation PA166300890", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -79672,12 +80664,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2B6: n/a", - "CYP2C19: Reduced metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers." + "CYP2B6: Reduced metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers.", + "CYP2C19: Small increase in metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers." ], - "lookupKey" : {"CYP2B6": "No Result", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2B6": "Intermediate Metabolizer", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -79685,42 +80677,42 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127639", "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 + "version" : 123 }, "text" : { - "id" : 1452093893, - "html" : "

Initiate therapy with recommended starting dose. Consider a slower titration schedule and lower maintenance dose than CYP2C19 normal metabolizers.

\n

Other Considerations

\n

CYP2B6 metabolizer status, drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be also considered.

\n", + "id" : 1452093869, + "html" : "

Initiate therapy with recommended starting dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300896", - "name" : "Recommendation PA166300896", + "id" : "PA166300891", + "name" : "Recommendation PA166300891", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2B6: Normal metabolism of sertraline to less active compounds.", + "CYP2B6: Greatly reduced metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers. Higher plasma concentrations may increase the probability of side effects.", "CYP2C19: Small increase in metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers." ], - "lookupKey" : {"CYP2B6": "Normal Metabolizer", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2B6": "Poor Metabolizer", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -79728,42 +80720,42 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127639", "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 + "version" : 123 }, "text" : { - "id" : 1452093875, + "id" : 1452093870, "html" : "

Initiate therapy with recommended starting dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300901", - "name" : "Recommendation PA166300901", - "alternateDrugAvailable" : false, + "id" : "PA166300887", + "name" : "Recommendation PA166300887", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501931, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ "CYP2B6: Increase in metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers.", - "CYP2C19: Normal metabolism" + "CYP2C19: Small increase in metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers." ], - "lookupKey" : {"CYP2B6": "Ultrarapid Metabolizer", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2B6": "Ultrarapid Metabolizer", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -79771,42 +80763,42 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127639", "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 + "version" : 123 }, "text" : { - "id" : 1452093880, - "html" : "

Initiate therapy with recommended starting dose.

\n", + "id" : 1452093866, + "html" : "

Initiate therapy with recommended starting dose. If patient does not adequately respond to recommended maintenance dosing, consider titrating to a higher\nmaintenance dose or switching to a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2C19 or CYP2B6.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300927", - "name" : "Recommendation PA166300927", + "id" : "PA166300888", + "name" : "Recommendation PA166300888", "alternateDrugAvailable" : true, "classification" : { - "id" : 981501931, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2B6: n/a", - "CYP2C19: Greatly reduced metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers. Higher plasma concentrations may increase the probability of side effects." + "CYP2B6: Small increase in metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers.", + "CYP2C19: Small increase in metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers." ], - "lookupKey" : {"CYP2B6": "Indeterminate", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2B6": "Rapid Metabolizer", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -79814,21 +80806,21 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127639", "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 + "version" : 123 }, "text" : { - "id" : 1452093906, - "html" : "

Consider a lower starting dose, slower titration schedule and 50% reduction of standard maintenance dose as compared to CYP2C19 normal metabolizers or select a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2C19.

\n", + "id" : 1452093867, + "html" : "

Initiate therapy with recommended starting dose. If patient does not adequately respond to recommended maintenance dosing, consider titrating to a higher\nmaintenance dose or switching to a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2C19 or CYP2B6.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -79857,26 +80849,26 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127639", "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 + "version" : 123 }, "text" : { "id" : 1452093871, "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300945", - "name" : "Recommendation PA166300945", + "id" : "PA166300894", + "name" : "Recommendation PA166300894", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -79889,10 +80881,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2B6: Greatly reduced metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers. Higher plasma concentrations may increase the probability of side effects.", - "CYP2C19: n/a" + "CYP2B6: Increase in metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers.", + "CYP2C19: Small increase in metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers." ], - "lookupKey" : {"CYP2B6": "Poor Metabolizer", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2B6": "Ultrarapid Metabolizer", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -79900,42 +80892,42 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127639", "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 + "version" : 123 }, "text" : { - "id" : 1452093924, - "html" : "

Consider a lower starting dose, slower titration schedule and 25% reduction of standard maintenance dose as compared to CYP2B6 normal metabolizers or select a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2B6.

\n

Other Considerations

\n

CYPC19 metabolizer status, drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be also considered.

\n", + "id" : 1452093873, + "html" : "

Initiate therapy with recommended starting dose. If patient does not adequately respond to recommended maintenance dosing, consider titrating to a higher\nmaintenance dose or switching to a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2C19 or CYP2B6.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300932", - "name" : "Recommendation PA166300932", + "id" : "PA166300895", + "name" : "Recommendation PA166300895", "alternateDrugAvailable" : true, "classification" : { - "id" : 981501931, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2B6: Reduced metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers.", - "CYP2C19: Greatly reduced metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers. Higher plasma concentrations may increase the probability of side effects." + "CYP2B6: Small increase in metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers.", + "CYP2C19: Small increase in metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers." ], - "lookupKey" : {"CYP2B6": "Intermediate Metabolizer", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2B6": "Rapid Metabolizer", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -79943,42 +80935,42 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127639", "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 + "version" : 123 }, "text" : { - "id" : 1452093911, - "html" : "

Consider a lower starting dose, slower titration schedule and 50% reduction of standard maintenance dose as compared to CYP2C19 normal metabolizers or select a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2C19.

\n", + "id" : 1452093874, + "html" : "

Initiate therapy with recommended starting dose. If patient does not adequately respond to recommended maintenance dosing, consider titrating to a higher\nmaintenance dose or switching to a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2C19 or CYP2B6.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300936", - "name" : "Recommendation PA166300936", + "id" : "PA166300885", + "name" : "Recommendation PA166300885", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2B6: Increase in metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers.", - "CYP2C19: n/a" + "CYP2B6: n/a", + "CYP2C19: Small increase in metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers." ], - "lookupKey" : {"CYP2B6": "Ultrarapid Metabolizer", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2B6": "Indeterminate", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -79986,42 +80978,85 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127639", "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 + "version" : 123 }, "text" : { - "id" : 1452093915, + "id" : 1452093864, "html" : "

Initiate therapy with recommended starting dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300923", - "name" : "Recommendation PA166300923", - "alternateDrugAvailable" : true, + "id" : "PA166300886", + "name" : "Recommendation PA166300886", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : false, + "implications" : [ + "CYP2B6: n/a", + "CYP2C19: Small increase in metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers." + ], + "lookupKey" : {"CYP2B6": "No Result", "CYP2C19": "Ultrarapid Metabolizer"}, + "otherPrescribingGuidance" : false, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA451333", + "name" : "sertraline", + "version" : 44 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166127639", + "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", + "version" : 123 + }, + "text" : { + "id" : 1452093865, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

CYP2B6 metabolizer status, drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be also considered.

\n", + "version" : 0 + }, + "version" : 2 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166300889", + "name" : "Recommendation PA166300889", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2B6: Small increase in metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers.", - "CYP2C19: Greatly reduced metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers. Higher plasma concentrations may increase the probability of side effects." + "CYP2B6: Normal metabolism of sertraline to less active compounds.", + "CYP2C19: Small increase in metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers." ], - "lookupKey" : {"CYP2B6": "Rapid Metabolizer", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2B6": "Normal Metabolizer", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -80029,42 +81064,42 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127639", "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 + "version" : 123 }, "text" : { - "id" : 1452093902, - "html" : "

Consider a lower starting dose, slower titration schedule and 50% reduction of standard maintenance dose as compared to CYP2C19 normal metabolizers or select a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2C19.

\n", + "id" : 1452093868, + "html" : "

Initiate therapy with recommended starting dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300910", - "name" : "Recommendation PA166300910", + "id" : "PA166300893", + "name" : "Recommendation PA166300893", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2B6: Normal metabolism of sertraline to less active compounds.", - "CYP2C19: Reduced metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers." + "CYP2B6: n/a", + "CYP2C19: Small increase in metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers." ], - "lookupKey" : {"CYP2B6": "Normal Metabolizer", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2B6": "No Result", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -80072,42 +81107,42 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127639", "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 + "version" : 123 }, "text" : { - "id" : 1452093889, - "html" : "

Initiate therapy with recommended starting dose. Consider a slower titration schedule and lower maintenance dose.

\n", + "id" : 1452093872, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

CYP2B6 metabolizer status, drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be also considered.

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Initiate therapy with recommended starting dose.

\n", + "id" : 1452093897, + "html" : "

Initiate therapy with recommended starting dose. Consider a slower titration schedule and lower maintenance dose than normal metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300940", - "name" : "Recommendation PA166300940", - "alternateDrugAvailable" : true, + "id" : "PA166300919", + "name" : "Recommendation PA166300919", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -80148,9 +81183,9 @@ "dosingInformation" : true, "implications" : [ "CYP2B6: Greatly reduced metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers. Higher plasma concentrations may increase the probability of side effects.", - "CYP2C19: n/a" + "CYP2C19: Reduced metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers." ], - "lookupKey" : {"CYP2B6": "Poor Metabolizer", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2B6": "Poor Metabolizer", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -80158,27 +81193,27 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127639", "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 + "version" : 123 }, "text" : { - "id" : 1452093919, - "html" : "

Consider a lower starting dose, slower titration schedule and 25% reduction of standard maintenance dose as CYP2B6 normal metabolizers or select a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2B6.

\n", + "id" : 1452093898, + "html" : "

Consider a lower starting dose, slower titration schedule and 50% reduction of standard maintenance dose as compared to CYP2B6 normal metabolizers

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300931", - "name" : "Recommendation PA166300931", - "alternateDrugAvailable" : true, + "id" : "PA166300920", + "name" : "Recommendation PA166300920", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, "parents" : [], @@ -80190,10 +81225,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2B6: Normal metabolism of sertraline to less active compounds.", - "CYP2C19: Greatly reduced metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers. Higher plasma concentrations may increase the probability of side effects." + "CYP2B6: n/a", + "CYP2C19: Reduced metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers." ], - "lookupKey" : {"CYP2B6": "Normal Metabolizer", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2B6": "Indeterminate", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -80201,27 +81236,27 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127639", "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 + "version" : 123 }, "text" : { - "id" : 1452093910, - "html" : "

Consider a lower starting dose, slower titration schedule and 50% reduction of standard maintenance dose as compared to CYP2C19 normal metabolizers or select a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2C19.

\n", + "id" : 1452093899, + "html" : "

Initiate therapy with recommended starting dose. Consider a slower titration schedule and lower maintenance dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300918", - "name" : "Recommendation PA166300918", - "alternateDrugAvailable" : false, + "id" : "PA166300905", + "name" : "Recommendation PA166300905", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -80233,10 +81268,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2B6: Reduced metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers.", - "CYP2C19: Reduced metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers." + "CYP2B6: Greatly reduced metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers. Higher plasma concentrations may increase the probability of side effects.", + "CYP2C19: Normal metabolism" ], - "lookupKey" : {"CYP2B6": "Intermediate Metabolizer", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2B6": "Poor Metabolizer", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -80244,42 +81279,42 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127639", "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 + "version" : 123 }, "text" : { - "id" : 1452093897, - "html" : "

Initiate therapy with recommended starting dose. Consider a slower titration schedule and lower maintenance dose than normal metabolizers.

\n", + "id" : 1452093884, + "html" : "

Consider a lower starting dose, slower titration schedule and 25% reduction of standard maintenance dose as compared to CYP2B6 normal metabolizers or select a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2B6.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300905", - "name" : "Recommendation PA166300905", + "id" : "PA166300921", + "name" : "Recommendation PA166300921", "alternateDrugAvailable" : true, "classification" : { - "id" : 981565059, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2B6: Greatly reduced metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers. Higher plasma concentrations may increase the probability of side effects.", - "CYP2C19: Normal metabolism" + "CYP2B6: n/a", + "CYP2C19: Greatly reduced metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers. Higher plasma concentrations may increase the probability of side effects." ], - "lookupKey" : {"CYP2B6": "Poor Metabolizer", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2B6": "No Result", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -80287,42 +81322,42 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127639", "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 + "version" : 123 }, "text" : { - "id" : 1452093884, - "html" : "

Consider a lower starting dose, slower titration schedule and 25% reduction of standard maintenance dose as compared to CYP2B6 normal metabolizers or select a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2B6.

\n", + "id" : 1452093900, + "html" : "

Consider a lower starting dose, slower titration schedule and 50% reduction of standard maintenance dose as compared to CYP2C19 normal metabolizers or select a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2C19.

\n

Other Considerations

\n

CYP2B6 metabolizer status, drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be also considered.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300887", - "name" : "Recommendation PA166300887", - "alternateDrugAvailable" : true, + "id" : "PA166300896", + "name" : "Recommendation PA166300896", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2B6: Increase in metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers.", + "CYP2B6: Normal metabolism of sertraline to less active compounds.", "CYP2C19: Small increase in metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers." ], - "lookupKey" : {"CYP2B6": "Ultrarapid Metabolizer", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2B6": "Normal Metabolizer", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -80330,26 +81365,26 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127639", "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 + "version" : 123 }, "text" : { - "id" : 1452093866, - "html" : "

Initiate therapy with recommended starting dose. If patient does not adequately respond to recommended maintenance dosing, consider titrating to a higher\nmaintenance dose or switching to a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2C19 or CYP2B6.

\n", + "id" : 1452093875, + "html" : "

Initiate therapy with recommended starting dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300902", - "name" : "Recommendation PA166300902", + "id" : "PA166300897", + "name" : "Recommendation PA166300897", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -80362,10 +81397,10 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2B6: Small increase in metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers.", - "CYP2C19: Normal metabolism" + "CYP2B6: Reduced metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers.", + "CYP2C19: Small increase in metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers." ], - "lookupKey" : {"CYP2B6": "Rapid Metabolizer", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2B6": "Intermediate Metabolizer", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -80373,42 +81408,42 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127639", "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 + "version" : 123 }, "text" : { - "id" : 1452093881, + "id" : 1452093876, "html" : "

Initiate therapy with recommended starting dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300937", - "name" : "Recommendation PA166300937", + "id" : "PA166300898", + "name" : "Recommendation PA166300898", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2B6: Small increase in metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers.", - "CYP2C19: n/a" + "CYP2B6: Greatly reduced metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers. Higher plasma concentrations may increase the probability of side effects.", + "CYP2C19: Small increase in metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers." ], - "lookupKey" : {"CYP2B6": "Rapid Metabolizer", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2B6": "Poor Metabolizer", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -80416,42 +81451,42 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127639", "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 + "version" : 123 }, "text" : { - "id" : 1452093916, + "id" : 1452093877, "html" : "

Initiate therapy with recommended starting dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300928", - "name" : "Recommendation PA166300928", - "alternateDrugAvailable" : true, + "id" : "PA166300899", + "name" : "Recommendation PA166300899", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ "CYP2B6: n/a", - "CYP2C19: Greatly reduced metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers. Higher plasma concentrations may increase the probability of side effects." + "CYP2C19: Small increase in metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers." ], - "lookupKey" : {"CYP2B6": "No Result", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2B6": "Indeterminate", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -80459,42 +81494,42 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127639", "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 + "version" : 123 }, "text" : { - "id" : 1452093907, - "html" : "

Consider a lower starting dose, slower titration schedule and 50% reduction of standard maintenance dose as compared to CYP2C19 normal metabolizers or select a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2C19.

\n

Other Considerations

\n

CYP2B6 metabolizer status, drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be also considered.

\n", + "id" : 1452093878, + "html" : "

Initiate therapy with recommended starting dose.

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Initiate therapy with recommended starting dose.

\n", + "id" : 1452093879, + "html" : "

Initiate therapy with recommended starting dose

\n

Other Considerations

\n

CYP2B6 metabolizer status, drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be also considered.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300897", - "name" : "Recommendation PA166300897", + "id" : "PA166300901", + "name" : "Recommendation PA166300901", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -80534,10 +81569,10 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2B6: Reduced metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers.", - "CYP2C19: Small increase in metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers." + "CYP2B6: Increase in metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers.", + "CYP2C19: Normal metabolism" ], - "lookupKey" : {"CYP2B6": "Intermediate Metabolizer", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2B6": "Ultrarapid Metabolizer", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -80545,42 +81580,42 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127639", "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 + "version" : 123 }, "text" : { - "id" : 1452093876, + "id" : 1452093880, "html" : "

Initiate therapy with recommended starting dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300946", - "name" : "Recommendation PA166300946", + "id" : "PA166300902", + "name" : "Recommendation PA166300902", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2B6: n/a", - "CYP2C19: n/a" + "CYP2B6: Small increase in metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers.", + "CYP2C19: Normal metabolism" ], - "lookupKey" : {"CYP2B6": "Indeterminate", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2B6": "Rapid Metabolizer", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -80588,42 +81623,42 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127639", "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 + "version" : 123 }, "text" : { - "id" : 1452093925, - "html" : "

No recommendation

\n", + "id" : 1452093881, + "html" : "

Initiate therapy with recommended starting dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300933", - "name" : "Recommendation PA166300933", - "alternateDrugAvailable" : true, + "id" : "PA166300903", + "name" : "Recommendation PA166300903", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2B6: Greatly reduced metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers. Higher plasma concentrations may increase the probability of side effects.", - "CYP2C19: Greatly reduced metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers. Higher plasma concentrations may increase the probability of side effects." + "CYP2B6: Normal metabolism of sertraline to less active compounds.", + "CYP2C19: Normal metabolism" ], - "lookupKey" : {"CYP2B6": "Poor Metabolizer", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2B6": "Normal Metabolizer", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -80631,26 +81666,26 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127639", "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 + "version" : 123 }, "text" : { - "id" : 1452093912, - "html" : "

Select an alternative antidepressant not primarily metabolized by CYP2C19 or CYP2B6.

\n", + "id" : 1452093882, + "html" : "

Initiate therapy with recommended starting dose.

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Initiate therapy with recommended starting dose. Consider a slower titration schedule and lower maintenance dose.

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Consider a lower starting dose, slower titration schedule and 50% reduction of standard maintenance dose as compared to CYP2C19 normal metabolizers or select a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2C19.

\n", + "id" : 1452093885, + "html" : "

Initiate therapy with recommended starting dose.

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Initiate therapy with recommended starting dose. Consider a slower titration schedule and lower maintenance dose than normal metabolizers.

\n", + "id" : 1452093886, + "html" : "

Initiate therapy with recommended starting dose. Consider a slower titration schedule and lower maintenance dose than normal metabolizers.

\n

Other Considerations

\n

CYP2B6 metabolizer status, drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be also considered.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300893", - "name" : "Recommendation PA166300893", + "id" : "PA166300908", + "name" : "Recommendation PA166300908", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2B6: n/a", - "CYP2C19: Small increase in metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers." + "CYP2B6: Increase in metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers.", + "CYP2C19: Reduced metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers." ], - "lookupKey" : {"CYP2B6": "No Result", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2B6": "Ultrarapid Metabolizer", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -80803,26 +81838,26 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127639", "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 + "version" : 123 }, "text" : { - "id" : 1452093872, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

CYP2B6 metabolizer status, drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be also considered.

\n", + "id" : 1452093887, + "html" : "

Initiate therapy with recommended starting dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300941", - "name" : "Recommendation PA166300941", + "id" : "PA166300909", + "name" : "Recommendation PA166300909", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -80835,10 +81870,10 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2B6: Increase in metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers.", - "CYP2C19: n/a" + "CYP2B6: Small increase in metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers.", + "CYP2C19: Reduced metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers." ], - "lookupKey" : {"CYP2B6": "Ultrarapid Metabolizer", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2B6": "Rapid Metabolizer", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -80846,42 +81881,42 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127639", "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 + "version" : 123 }, "text" : { - "id" : 1452093920, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

CYPC19 metabolizer status, drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be also considered.

\n", + "id" : 1452093888, + "html" : "

Initiate therapy with recommended starting dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300906", - "name" : "Recommendation PA166300906", + "id" : "PA166300910", + "name" : "Recommendation PA166300910", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2B6: n/a", - "CYP2C19: Normal metabolism" + "CYP2B6: Normal metabolism of sertraline to less active compounds.", + "CYP2C19: Reduced metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers." ], - "lookupKey" : {"CYP2B6": "Indeterminate", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2B6": "Normal Metabolizer", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -80889,27 +81924,27 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127639", "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 + "version" : 123 }, "text" : { - "id" : 1452093885, - "html" : "

Initiate therapy with recommended starting dose.

\n", + "id" : 1452093889, + "html" : "

Initiate therapy with recommended starting dose. Consider a slower titration schedule and lower maintenance dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300888", - "name" : "Recommendation PA166300888", - "alternateDrugAvailable" : true, + "id" : "PA166300911", + "name" : "Recommendation PA166300911", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -80921,10 +81956,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2B6: Small increase in metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers.", - "CYP2C19: Small increase in metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers." + "CYP2B6: Reduced metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers.", + "CYP2C19: Reduced metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers." ], - "lookupKey" : {"CYP2B6": "Rapid Metabolizer", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2B6": "Intermediate Metabolizer", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -80932,26 +81967,26 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127639", "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 + "version" : 123 }, "text" : { - "id" : 1452093867, - "html" : "

Initiate therapy with recommended starting dose. If patient does not adequately respond to recommended maintenance dosing, consider titrating to a higher\nmaintenance dose or switching to a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2C19 or CYP2B6.

\n", + "id" : 1452093890, + "html" : "

Initiate therapy with recommended starting dose. Consider a slower titration schedule and lower maintenance dose than normal metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300919", - "name" : "Recommendation PA166300919", + "id" : "PA166300912", + "name" : "Recommendation PA166300912", "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, @@ -80967,7 +82002,7 @@ "CYP2B6: Greatly reduced metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers. Higher plasma concentrations may increase the probability of side effects.", "CYP2C19: Reduced metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers." ], - "lookupKey" : {"CYP2B6": "Poor Metabolizer", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2B6": "Poor Metabolizer", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -80975,26 +82010,26 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127639", "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 + "version" : 123 }, "text" : { - "id" : 1452093898, + "id" : 1452093891, "html" : "

Consider a lower starting dose, slower titration schedule and 50% reduction of standard maintenance dose as compared to CYP2B6 normal metabolizers

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300938", - "name" : "Recommendation PA166300938", + "id" : "PA166300913", + "name" : "Recommendation PA166300913", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -81005,12 +82040,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2B6: Normal metabolism of sertraline to less active compounds.", - "CYP2C19: n/a" + "CYP2B6: n/a", + "CYP2C19: Reduced metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers." ], - "lookupKey" : {"CYP2B6": "Normal Metabolizer", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2B6": "Indeterminate", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -81018,27 +82053,27 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127639", "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 + "version" : 123 }, "text" : { - "id" : 1452093917, - "html" : "

Initiate therapy with recommended starting dose.

\n", + "id" : 1452093892, + "html" : "

Initiate therapy with recommended starting dose. Consider a slower titration schedule and lower maintenance dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300925", - "name" : "Recommendation PA166300925", - "alternateDrugAvailable" : true, + "id" : "PA166300914", + "name" : "Recommendation PA166300914", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, "parents" : [], @@ -81050,10 +82085,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2B6: Reduced metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers.", - "CYP2C19: Greatly reduced metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers. Higher plasma concentrations may increase the probability of side effects." + "CYP2B6: n/a", + "CYP2C19: Reduced metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers." ], - "lookupKey" : {"CYP2B6": "Intermediate Metabolizer", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2B6": "No Result", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -81061,26 +82096,26 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127639", "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 + "version" : 123 }, "text" : { - "id" : 1452093904, - "html" : "

Consider a lower starting dose, slower titration schedule and 50% reduction of standard maintenance dose as compared to CYP2C19 normal metabolizers or select a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2C19.

\n", + "id" : 1452093893, + "html" : "

Initiate therapy with recommended starting dose. Consider a slower titration schedule and lower maintenance dose than CYP2C19 normal metabolizers.

\n

Other Considerations

\n

CYP2B6 metabolizer status, drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be also considered.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300916", - "name" : "Recommendation PA166300916", + "id" : "PA166300915", + "name" : "Recommendation PA166300915", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -81093,10 +82128,10 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2B6: Small increase in metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers.", + "CYP2B6: Increase in metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers.", "CYP2C19: Reduced metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers." ], - "lookupKey" : {"CYP2B6": "Rapid Metabolizer", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2B6": "Ultrarapid Metabolizer", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -81104,42 +82139,42 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127639", "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 + "version" : 123 }, "text" : { - "id" : 1452093895, + "id" : 1452093894, "html" : "

Initiate therapy with recommended starting dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300898", - "name" : "Recommendation PA166300898", + "id" : "PA166300916", + "name" : "Recommendation PA166300916", "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2B6: Greatly reduced metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers. Higher plasma concentrations may increase the probability of side effects.", - "CYP2C19: Small increase in metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers." + "CYP2B6: Small increase in metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers.", + "CYP2C19: Reduced metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers." ], - "lookupKey" : {"CYP2B6": "Poor Metabolizer", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2B6": "Rapid Metabolizer", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -81147,42 +82182,42 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127639", "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 + "version" : 123 }, "text" : { - "id" : 1452093877, + "id" : 1452093895, "html" : "

Initiate therapy with recommended starting dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300903", - "name" : "Recommendation PA166300903", + "id" : "PA166300917", + "name" : "Recommendation PA166300917", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ "CYP2B6: Normal metabolism of sertraline to less active compounds.", - "CYP2C19: Normal metabolism" + "CYP2C19: Reduced metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers." ], - "lookupKey" : {"CYP2B6": "Normal Metabolizer", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2B6": "Normal Metabolizer", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -81190,26 +82225,26 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127639", "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 + "version" : 123 }, "text" : { - "id" : 1452093882, - "html" : "

Initiate therapy with recommended starting dose.

\n", + "id" : 1452093896, + "html" : "

Initiate therapy with recommended starting dose. Consider a slower titration schedule and lower maintenance dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300885", - "name" : "Recommendation PA166300885", + "id" : "PA166300942", + "name" : "Recommendation PA166300942", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -81222,10 +82257,10 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2B6: n/a", - "CYP2C19: Small increase in metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers." + "CYP2B6: Small increase in metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers.", + "CYP2C19: n/a" ], - "lookupKey" : {"CYP2B6": "Indeterminate", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2B6": "Rapid Metabolizer", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -81233,42 +82268,42 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127639", "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 + "version" : 123 }, "text" : { - "id" : 1452093864, - "html" : "

Initiate therapy with recommended starting dose.

\n", + "id" : 1452093921, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

CYPC19 metabolizer status, drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be also considered.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300934", - "name" : "Recommendation PA166300934", + "id" : "PA166300922", + "name" : "Recommendation PA166300922", "alternateDrugAvailable" : true, "classification" : { - "id" : 981501931, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2B6: n/a", + "CYP2B6: Increase in metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers.", "CYP2C19: Greatly reduced metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers. Higher plasma concentrations may increase the probability of side effects." ], - "lookupKey" : {"CYP2B6": "Indeterminate", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2B6": "Ultrarapid Metabolizer", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -81276,42 +82311,42 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127639", "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 + "version" : 123 }, "text" : { - "id" : 1452093913, + "id" : 1452093901, "html" : "

Consider a lower starting dose, slower titration schedule and 50% reduction of standard maintenance dose as compared to CYP2C19 normal metabolizers or select a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2C19.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300921", - "name" : "Recommendation PA166300921", + "id" : "PA166300923", + "name" : "Recommendation PA166300923", "alternateDrugAvailable" : true, "classification" : { - "id" : 981501931, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2B6: n/a", + "CYP2B6: Small increase in metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers.", "CYP2C19: Greatly reduced metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers. Higher plasma concentrations may increase the probability of side effects." ], - "lookupKey" : {"CYP2B6": "No Result", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2B6": "Rapid Metabolizer", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -81319,42 +82354,42 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127639", "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 + "version" : 123 }, "text" : { - "id" : 1452093900, - "html" : "

Consider a lower starting dose, slower titration schedule and 50% reduction of standard maintenance dose as compared to CYP2C19 normal metabolizers or select a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2C19.

\n

Other Considerations

\n

CYP2B6 metabolizer status, drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be also considered.

\n", + "id" : 1452093902, + "html" : "

Consider a lower starting dose, slower titration schedule and 50% reduction of standard maintenance dose as compared to CYP2C19 normal metabolizers or select a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2C19.

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Consider a lower starting dose, slower titration schedule and 50% reduction of standard maintenance dose as compared to CYP2B6 normal metabolizers

\n", + "id" : 1452093903, + "html" : "

Consider a lower starting dose, slower titration schedule and 50% reduction of standard maintenance dose as compared to CYP2C19 normal metabolizers or select a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2C19.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300894", - "name" : "Recommendation PA166300894", + "id" : "PA166300925", + "name" : "Recommendation PA166300925", "alternateDrugAvailable" : true, "classification" : { - "id" : 981565059, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2B6: Increase in metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers.", - "CYP2C19: Small increase in metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers." + "CYP2B6: Reduced metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers.", + "CYP2C19: Greatly reduced metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers. Higher plasma concentrations may increase the probability of side effects." ], - "lookupKey" : {"CYP2B6": "Ultrarapid Metabolizer", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2B6": "Intermediate Metabolizer", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -81405,26 +82440,26 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127639", "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 + "version" : 123 }, "text" : { - "id" : 1452093873, - "html" : "

Initiate therapy with recommended starting dose. If patient does not adequately respond to recommended maintenance dosing, consider titrating to a higher\nmaintenance dose or switching to a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2C19 or CYP2B6.

\n", + "id" : 1452093904, + "html" : "

Consider a lower starting dose, slower titration schedule and 50% reduction of standard maintenance dose as compared to CYP2C19 normal metabolizers or select a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2C19.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300942", - "name" : "Recommendation PA166300942", + "id" : "PA166300943", + "name" : "Recommendation PA166300943", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -81437,10 +82472,10 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2B6: Small increase in metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers.", + "CYP2B6: Normal metabolism of sertraline to less active compounds.", "CYP2C19: n/a" ], - "lookupKey" : {"CYP2B6": "Rapid Metabolizer", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2B6": "Normal Metabolizer", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -81448,42 +82483,42 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127639", "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 + "version" : 123 }, "text" : { - "id" : 1452093921, + "id" : 1452093922, "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

CYPC19 metabolizer status, drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be also considered.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300929", - "name" : "Recommendation PA166300929", + "id" : "PA166300927", + "name" : "Recommendation PA166300927", "alternateDrugAvailable" : true, "classification" : { - "id" : 981565059, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2B6: Increase in metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers.", + "CYP2B6: n/a", "CYP2C19: Greatly reduced metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers. Higher plasma concentrations may increase the probability of side effects." ], - "lookupKey" : {"CYP2B6": "Ultrarapid Metabolizer", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2B6": "Indeterminate", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -81491,27 +82526,27 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127639", "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 + "version" : 123 }, "text" : { - "id" : 1452093908, + "id" : 1452093906, "html" : "

Consider a lower starting dose, slower titration schedule and 50% reduction of standard maintenance dose as compared to CYP2C19 normal metabolizers or select a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2C19.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300907", - "name" : "Recommendation PA166300907", - "alternateDrugAvailable" : false, + "id" : "PA166300928", + "name" : "Recommendation PA166300928", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501931, "parents" : [], @@ -81524,9 +82559,9 @@ "dosingInformation" : true, "implications" : [ "CYP2B6: n/a", - "CYP2C19: Reduced metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers." + "CYP2C19: Greatly reduced metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers. Higher plasma concentrations may increase the probability of side effects." ], - "lookupKey" : {"CYP2B6": "No Result", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2B6": "No Result", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -81534,42 +82569,42 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127639", "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 + "version" : 123 }, "text" : { - "id" : 1452093886, - "html" : "

Initiate therapy with recommended starting dose. Consider a slower titration schedule and lower maintenance dose than normal metabolizers.

\n

Other Considerations

\n

CYP2B6 metabolizer status, drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be also considered.

\n", + "id" : 1452093907, + "html" : "

Consider a lower starting dose, slower titration schedule and 50% reduction of standard maintenance dose as compared to CYP2C19 normal metabolizers or select a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2C19.

\n

Other Considerations

\n

CYP2B6 metabolizer status, drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be also considered.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300889", - "name" : "Recommendation PA166300889", - "alternateDrugAvailable" : false, + "id" : "PA166300929", + "name" : "Recommendation PA166300929", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2B6: Normal metabolism of sertraline to less active compounds.", - "CYP2C19: Small increase in metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers." + "CYP2B6: Increase in metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers.", + "CYP2C19: Greatly reduced metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers. Higher plasma concentrations may increase the probability of side effects." ], - "lookupKey" : {"CYP2B6": "Normal Metabolizer", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2B6": "Ultrarapid Metabolizer", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -81577,26 +82612,26 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127639", "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 + "version" : 123 }, "text" : { - "id" : 1452093868, - "html" : "

Initiate therapy with recommended starting dose.

\n", + "id" : 1452093908, + "html" : "

Consider a lower starting dose, slower titration schedule and 50% reduction of standard maintenance dose as compared to CYP2C19 normal metabolizers or select a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2C19.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300926", - "name" : "Recommendation PA166300926", + "id" : "PA166300930", + "name" : "Recommendation PA166300930", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -81607,12 +82642,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2B6: Greatly reduced metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers. Higher plasma concentrations may increase the probability of side effects.", + "CYP2B6: Small increase in metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers.", "CYP2C19: Greatly reduced metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers. Higher plasma concentrations may increase the probability of side effects." ], - "lookupKey" : {"CYP2B6": "Poor Metabolizer", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2B6": "Rapid Metabolizer", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -81620,27 +82655,27 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127639", "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 + "version" : 123 }, "text" : { - "id" : 1452093905, - "html" : "

Select an alternative antidepressant not primarily metabolized by CYP2C19 or CYP2B6.

\n", + "id" : 1452093909, + "html" : "

Consider a lower starting dose, slower titration schedule and 50% reduction of standard maintenance dose as compared to CYP2C19 normal metabolizers or select a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2C19.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300913", - "name" : "Recommendation PA166300913", - "alternateDrugAvailable" : false, + "id" : "PA166300931", + "name" : "Recommendation PA166300931", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501931, "parents" : [], @@ -81652,10 +82687,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2B6: n/a", - "CYP2C19: Reduced metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers." + "CYP2B6: Normal metabolism of sertraline to less active compounds.", + "CYP2C19: Greatly reduced metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers. Higher plasma concentrations may increase the probability of side effects." ], - "lookupKey" : {"CYP2B6": "Indeterminate", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2B6": "Normal Metabolizer", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -81663,42 +82698,42 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127639", "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 + "version" : 123 }, "text" : { - "id" : 1452093892, - "html" : "

Initiate therapy with recommended starting dose. Consider a slower titration schedule and lower maintenance dose.

\n", + "id" : 1452093910, + "html" : "

Consider a lower starting dose, slower titration schedule and 50% reduction of standard maintenance dose as compared to CYP2C19 normal metabolizers or select a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2C19.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300895", - "name" : "Recommendation PA166300895", + "id" : "PA166300932", + "name" : "Recommendation PA166300932", "alternateDrugAvailable" : true, "classification" : { - "id" : 981565059, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2B6: Small increase in metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers.", - "CYP2C19: Small increase in metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers." + "CYP2B6: Reduced metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers.", + "CYP2C19: Greatly reduced metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers. Higher plasma concentrations may increase the probability of side effects." ], - "lookupKey" : {"CYP2B6": "Rapid Metabolizer", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2B6": "Intermediate Metabolizer", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -81706,42 +82741,42 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127639", "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 + "version" : 123 }, "text" : { - "id" : 1452093874, - "html" : "

Initiate therapy with recommended starting dose. If patient does not adequately respond to recommended maintenance dosing, consider titrating to a higher\nmaintenance dose or switching to a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2C19 or CYP2B6.

\n", + "id" : 1452093911, + "html" : "

Consider a lower starting dose, slower titration schedule and 50% reduction of standard maintenance dose as compared to CYP2C19 normal metabolizers or select a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2C19.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300900", - "name" : "Recommendation PA166300900", + "id" : "PA166300944", + "name" : "Recommendation PA166300944", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2B6: n/a", - "CYP2C19: Normal metabolism" + "CYP2B6: Reduced metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers.", + "CYP2C19: n/a" ], - "lookupKey" : {"CYP2B6": "No Result", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2B6": "Intermediate Metabolizer", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -81749,27 +82784,27 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127639", "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 + "version" : 123 }, "text" : { - "id" : 1452093879, - "html" : "

Initiate therapy with recommended starting dose

\n

Other Considerations

\n

CYP2B6 metabolizer status, drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be also considered.

\n", + "id" : 1452093923, + "html" : "

Initiate therapy with recommended starting dose. Consider a slower titration schedule and lower maintenance dose than CYP2B6 normal metabolizers.

\n

Other Considerations

\n

CYPC19 metabolizer status, drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be also considered.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300904", - "name" : "Recommendation PA166300904", - "alternateDrugAvailable" : false, + "id" : "PA166300934", + "name" : "Recommendation PA166300934", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501931, "parents" : [], @@ -81781,10 +82816,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2B6: Reduced metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers.", - "CYP2C19: Normal metabolism" + "CYP2B6: n/a", + "CYP2C19: Greatly reduced metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers. Higher plasma concentrations may increase the probability of side effects." ], - "lookupKey" : {"CYP2B6": "Intermediate Metabolizer", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2B6": "Indeterminate", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -81792,42 +82827,42 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127639", "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 + "version" : 123 }, "text" : { - "id" : 1452093883, - "html" : "

Initiate therapy with recommended starting dose. Consider a slower titration schedule and lower maintenance dose.

\n", + "id" : 1452093913, + "html" : "

Consider a lower starting dose, slower titration schedule and 50% reduction of standard maintenance dose as compared to CYP2C19 normal metabolizers or select a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2C19.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300886", - "name" : "Recommendation PA166300886", + "id" : "PA166300946", + "name" : "Recommendation PA166300946", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ "CYP2B6: n/a", - "CYP2C19: Small increase in metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers." + "CYP2C19: n/a" ], - "lookupKey" : {"CYP2B6": "No Result", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2B6": "Indeterminate", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -81835,42 +82870,42 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127639", "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 + "version" : 123 }, "text" : { - "id" : 1452093865, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

CYP2B6 metabolizer status, drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be also considered.

\n", + "id" : 1452093925, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300939", - "name" : "Recommendation PA166300939", - "alternateDrugAvailable" : false, + "id" : "PA166300940", + "name" : "Recommendation PA166300940", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501931, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2B6: Reduced metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers.", + "CYP2B6: Greatly reduced metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers. Higher plasma concentrations may increase the probability of side effects.", "CYP2C19: n/a" ], - "lookupKey" : {"CYP2B6": "Intermediate Metabolizer", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2B6": "Poor Metabolizer", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -81878,27 +82913,70 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127639", "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 + "version" : 123 }, "text" : { - "id" : 1452093918, - "html" : "

Initiate therapy with recommended starting dose. Consider a slower titration schedule and lower maintenance dose.

\n", + "id" : 1452093919, + "html" : "

Consider a lower starting dose, slower titration schedule and 25% reduction of standard maintenance dose as CYP2B6 normal metabolizers or select a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2B6.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300891", - "name" : "Recommendation PA166300891", - "alternateDrugAvailable" : false, + "id" : "PA166300945", + "name" : "Recommendation PA166300945", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981565059, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "CYP2B6: Greatly reduced metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers. Higher plasma concentrations may increase the probability of side effects.", + "CYP2C19: n/a" + ], + "lookupKey" : {"CYP2B6": "Poor Metabolizer", "CYP2C19": "No Result"}, + "otherPrescribingGuidance" : false, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA451333", + "name" : "sertraline", + "version" : 44 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166127639", + "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", + "version" : 123 + }, + "text" : { + "id" : 1452093924, + "html" : "

Consider a lower starting dose, slower titration schedule and 25% reduction of standard maintenance dose as compared to CYP2B6 normal metabolizers or select a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2B6.

\n

Other Considerations

\n

CYPC19 metabolizer status, drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be also considered.

\n", + "version" : 0 + }, + "version" : 1 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166300926", + "name" : "Recommendation PA166300926", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -81911,9 +82989,9 @@ "dosingInformation" : false, "implications" : [ "CYP2B6: Greatly reduced metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers. Higher plasma concentrations may increase the probability of side effects.", - "CYP2C19: Small increase in metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers." + "CYP2C19: Greatly reduced metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers. Higher plasma concentrations may increase the probability of side effects." ], - "lookupKey" : {"CYP2B6": "Poor Metabolizer", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2B6": "Poor Metabolizer", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -81921,27 +82999,27 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127639", "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 + "version" : 123 }, "text" : { - "id" : 1452093870, - "html" : "

Initiate therapy with recommended starting dose.

\n", + "id" : 1452093905, + "html" : "

Select an alternative antidepressant not primarily metabolized by CYP2C19 or CYP2B6.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300944", - "name" : "Recommendation PA166300944", - "alternateDrugAvailable" : false, + "id" : "PA166300933", + "name" : "Recommendation PA166300933", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -81951,12 +83029,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2B6: Reduced metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers.", - "CYP2C19: n/a" + "CYP2B6: Greatly reduced metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers. Higher plasma concentrations may increase the probability of side effects.", + "CYP2C19: Greatly reduced metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers. Higher plasma concentrations may increase the probability of side effects." ], - "lookupKey" : {"CYP2B6": "Intermediate Metabolizer", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2B6": "Poor Metabolizer", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -81964,21 +83042,21 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127639", "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 + "version" : 123 }, "text" : { - "id" : 1452093923, - "html" : "

Initiate therapy with recommended starting dose. Consider a slower titration schedule and lower maintenance dose than CYP2B6 normal metabolizers.

\n

Other Considerations

\n

CYPC19 metabolizer status, drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be also considered.

\n", + "id" : 1452093912, + "html" : "

Select an alternative antidepressant not primarily metabolized by CYP2C19 or CYP2B6.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", @@ -82007,42 +83085,42 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127639", "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 + "version" : 123 }, "text" : { "id" : 1452093914, "html" : "

No recommendation

\n

Other Considerations

\n

CYP2B6 metabolizer status, drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be also considered.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300922", - "name" : "Recommendation PA166300922", - "alternateDrugAvailable" : true, + "id" : "PA166300936", + "name" : "Recommendation PA166300936", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ "CYP2B6: Increase in metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers.", - "CYP2C19: Greatly reduced metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers. Higher plasma concentrations may increase the probability of side effects." + "CYP2C19: n/a" ], - "lookupKey" : {"CYP2B6": "Ultrarapid Metabolizer", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2B6": "Ultrarapid Metabolizer", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -82050,26 +83128,26 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127639", "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 + "version" : 123 }, "text" : { - "id" : 1452093901, - "html" : "

Consider a lower starting dose, slower titration schedule and 50% reduction of standard maintenance dose as compared to CYP2C19 normal metabolizers or select a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2C19.

\n", + "id" : 1452093915, + "html" : "

Initiate therapy with recommended starting dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300890", - "name" : "Recommendation PA166300890", + "id" : "PA166300937", + "name" : "Recommendation PA166300937", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -82082,10 +83160,10 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2B6: Reduced metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers.", - "CYP2C19: Small increase in metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers." + "CYP2B6: Small increase in metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers.", + "CYP2C19: n/a" ], - "lookupKey" : {"CYP2B6": "Intermediate Metabolizer", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2B6": "Rapid Metabolizer", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -82093,33 +83171,33 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127639", "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 + "version" : 123 }, "text" : { - "id" : 1452093869, + "id" : 1452093916, "html" : "

Initiate therapy with recommended starting dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300943", - "name" : "Recommendation PA166300943", + "id" : "PA166300938", + "name" : "Recommendation PA166300938", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, @@ -82128,50 +83206,7 @@ "CYP2B6: Normal metabolism of sertraline to less active compounds.", "CYP2C19: n/a" ], - "lookupKey" : {"CYP2B6": "Normal Metabolizer", "CYP2C19": "No Result"}, - "otherPrescribingGuidance" : false, - "population" : "general", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA451333", - "name" : "sertraline", - "version" : 14 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166127639", - "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 - }, - "text" : { - "id" : 1452093922, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

CYPC19 metabolizer status, drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be also considered.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166300930", - "name" : "Recommendation PA166300930", - "alternateDrugAvailable" : true, - "classification" : { - "id" : 981565059, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : true, - "implications" : [ - "CYP2B6: Small increase in metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers.", - "CYP2C19: Greatly reduced metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers. Higher plasma concentrations may increase the probability of side effects." - ], - "lookupKey" : {"CYP2B6": "Rapid Metabolizer", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2B6": "Normal Metabolizer", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -82179,26 +83214,26 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127639", "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 + "version" : 123 }, "text" : { - "id" : 1452093909, - "html" : "

Consider a lower starting dose, slower titration schedule and 50% reduction of standard maintenance dose as compared to CYP2C19 normal metabolizers or select a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2C19.

\n", + "id" : 1452093917, + "html" : "

Initiate therapy with recommended starting dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300917", - "name" : "Recommendation PA166300917", + "id" : "PA166300939", + "name" : "Recommendation PA166300939", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -82211,10 +83246,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2B6: Normal metabolism of sertraline to less active compounds.", - "CYP2C19: Reduced metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers." + "CYP2B6: Reduced metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers.", + "CYP2C19: n/a" ], - "lookupKey" : {"CYP2B6": "Normal Metabolizer", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2B6": "Intermediate Metabolizer", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -82222,69 +83257,26 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127639", "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 + "version" : 123 }, "text" : { - "id" : 1452093896, + "id" : 1452093918, "html" : "

Initiate therapy with recommended starting dose. Consider a slower titration schedule and lower maintenance dose.

\n", "version" : 0 }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166300899", - "name" : "Recommendation PA166300899", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 981501930, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "CYP2B6: n/a", - "CYP2C19: Small increase in metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers." - ], - "lookupKey" : {"CYP2B6": "Indeterminate", "CYP2C19": "Rapid Metabolizer"}, - "otherPrescribingGuidance" : false, - "population" : "general", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA451333", - "name" : "sertraline", - "version" : 14 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166127639", - "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 - }, - "text" : { - "id" : 1452093878, - "html" : "

Initiate therapy with recommended starting dose.

\n", - "version" : 0 - }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300908", - "name" : "Recommendation PA166300908", + "id" : "PA166300941", + "name" : "Recommendation PA166300941", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -82298,9 +83290,9 @@ "dosingInformation" : false, "implications" : [ "CYP2B6: Increase in metabolism of sertraline to less active compounds when compared to CYP2B6 normal metabolizers.", - "CYP2C19: Reduced metabolism of sertraline to less active compounds when compared to CYP2C19 normal metabolizers." + "CYP2C19: n/a" ], - "lookupKey" : {"CYP2B6": "Ultrarapid Metabolizer", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2B6": "Ultrarapid Metabolizer", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -82308,21 +83300,21 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166127639", "name" : "Annotation of CPIC Guideline for sertraline and CYP2B6, CYP2C19", - "version" : 48 + "version" : 123 }, "text" : { - "id" : 1452093887, - "html" : "

Initiate therapy with recommended starting dose.

\n", + "id" : 1452093920, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

CYPC19 metabolizer status, drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be also considered.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166127639" @@ -82686,14 +83678,14 @@ "id" : "PA165819265", "symbol" : "SLCO1B1*15", "name" : "*15", - "version" : 23 + "version" : 39 }, { "objCls" : "Haplotype", "id" : "PA165819255", "symbol" : "SLCO1B1*5", "name" : "*5", - "version" : 23 + "version" : 39 } ], "relatedChemicals" : [ @@ -82701,7 +83693,7 @@ "objCls" : "Chemical", "id" : "PA451363", "name" : "simvastatin", - "version" : 24 + "version" : 87 } ], "relatedGenes" : [ @@ -82710,44 +83702,44 @@ "id" : "PA134865839", "symbol" : "SLCO1B1", "name" : "solute carrier organic anion transporter family member 1B1", - "version" : 49 + "version" : 109 } ], "source" : "CPIC", "summaryMarkdown" : { "id" : 1447981966, "html" : "

Prescribe an alternative statin depending on the desired potency for patients with SLCO1B1 decreased function, possible decreased function or poor function phenotype. If simvastatin therapy is warranted in patients with SLCO1B1 decreased or possible decreased phenotype, limit dose to <20mg/day.

\n", - "version" : 13 + "version" : 18 }, "terms" : [], "textMarkdown" : { "id" : 1451433711, "html" : "

This annotation is based on the CPIC® guideline for SLCO1B1, ABCG2, and CYP2C9 and statin-associated musculoskeletal symptoms.

\n

February 2022 Update

\n\n\n

Adapted from Table 1 and 2 of the 2022 guideline update manuscript.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
PhenotypeGenotypeExamples of diplotypes aImplications for simvastatinDosing recommendations for simvastatin b,cClassification of recommendations d
Normal functionAn individual carrying two normal function alleles or one normal plus one increased function allele*1/*1, *1/*14Typical myopathy risk and statin exposurePrescribe desired starting dose and adjust doses based on disease-specific guidelines.Strong
Increased functionAn individual carrying two increased function alleles*14/*14Typical myopathy risk and statin exposurePrescribe desired starting dose and adjust doses based on disease-specific guidelines.Strong
Decreased functionAn individual carrying one normal or increased function allele plus one no function allele*1/*5, *1/*15Increased simvastatin acid exposure as compared to normal function; increased risk of myopathyPrescribe an alternative statin depending on the desired potency (see Figure 1 for recommendations for alternative statins). If simvastatin therapy is warranted, limit dose to <20mg/day.Strong
Possible decreased functionAn individual carrying one no function allele plus one uncertain/unknown function allele*5/*6, *15/*10, *5/*43Increased simvastatin acid exposure as compared to normal function; increased risk of myopathyPrescribe an alternative statin depending on the desired potency (see Figure 1 for recommendations for alternative statins). If simvastatin therapy is warranted, limit dose to <20mg/day.Strong
Poor functionAn individual carrying two no function alleles*5/*5, *5/*15, *15/*15Increased simvastatin acid exposure compared to normal and decreased function; highly increased myopathy riskPrescribe an alternative statin depending on the desired potency (see Figure 1 for recommendations for alternative statins).Strong
IndeterminateAn individual carrying one normal function allele plus one uncertain or unknown function allele OR allele combinations with uncertain and/or unknown function alleles*1/*7, *1/*10, *7/*10n/aNo recommendation.No recommendation.
\n

Figure 1 : SLCO1B1 recommendations with intensity and statin dose stratified by SLCO1B1 phenotype; all doses assume adult dosing.

\n

Adapted from Figure 1 of the 2022 guideline manuscript

\n

\"Fig1\"

\n\n

October 2014 Update

\n

Advance online publication 9 July 2014.

\n\n

"In 2011 and updated in 2013, the FDA added warnings to the simvastatin product label to direct providers away from initiating at the 80 mg simvastatin dose. "

\n

"At lower simvastatin doses (e.g., 40 mg daily), it is our position that SLCO1B1 genotype (if available) could be used to warn providers about modest increases in myopathy risk for patients with a C allele at rs4149056. In these circumstances, we recommend a lower dose of simvastatin or use an alternative statin (e.g. pravastatin or rosuvastatin) and we also highlight the potential utility of routine CK surveillance (Table 2). If patients with a C allele at rs4149056 do not achieve optimal LDL cholesterol-lowering efficacy with a lower dose (e.g. 20 mg) of simvastatin, we recommend the prescribing physician consider an alternate statin based on (i) potency differences (i.e., use a lower dose of a higher potency statin such as atorvastatin, rosuvastatin, or pitavastatin), (ii) drug-drug interactions (e.g., boceprevir, clarithromycin, cyclosporine, strong CYP3A4 inhibitors, etc.), and (iii) relevant co-morbidities (e.g., trauma, significant renal impairment, post-solid organ transplant, thyroid disease etc.)."

\n

"At the time of this writing, there are no data available regarding SLCO1B1 genotype effects on simvastatin response or myopathy in pediatric patient populations, although there is no reason to suspect that the polymorphisms in SLCO1B1 will affect simvastatin's metabolism differently in children compared to adults."

\n\n\n

Adapted from Table 1 and 2 of the 2014 guideline update manuscript.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
PhenotypeExamples of diplotypes aGenotype at rs4149056Implications for simvastatinDosing recommendations for simvastatin b,cClassification of recommendations d
Normal function, Homozygous wild-type (two normal function alleles)*1a/*1a, *1a/*1b, *1b/*1bTTNormal myopathy riskPrescribe desired starting dose and adjust doses of simvastatin based on disease-specific guidelines.Strong
Intermediate function, Heterozygous (one normal function allele plus one decreased function allele)*1a/*5, *1a/*15, *1a/*17, *1b/*5, *1b/*15, *1b/*17TCIntermediate myopathy riskPrescribe a lower dose or consider an alternative statin (e.g. pravastatin or rosuvastatin); consider routine CK surveillance.Strong
Low function, Homozygous variant or mutant (two decreased function alleles)*5/*5, *5/*15, *5/*17, *15/*15, *15/*17, *17/*17CCHigh myopathy riskPrescribe a lower dose or consider an alternative statin (e.g. pravastatin or rosuvastatin); consider routine CK surveillance.Strong
\n

CK, creatine kinase.

\n

a SLCO1B1 alleles are often named using star allele nomenclature, representing various SNPs alone or in combination (2014 Update Supplemental Table S1) that are associated with low SLCO1B1 protein expression or function (2014 Update Supplemental Table S2). The minor C allele at rs4149056 is contained within SLCO1B1*5 (rs4149056 alone) as well as the *15 and *17 haplotypes and is associated with lower plasma clearance of simvastatin. The magnitude of this effect is similar for *5, *15, and *17 haplotypes.

\n

b In all cases, the potential for drug-drug interaction should be evaluated prior to initiating a prescription.

\n

c FDA recommends against 80mg (unless already tolerated 12 months).

\n

d See Supplementary Materials (text section entitled "Levels of Evidence") online for additional details regarding the three-tiered system used to grade the quality of evidence.

\n

July 2012

\n

Advance online publication May 2012.

\n\n", - "version" : 3 + "version" : 15 }, "userId" : "whaleyr", - "version" : 52 + "version" : 148 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166298506", - "name" : "Recommendation PA166298506", - "alternateDrugAvailable" : false, + "id" : "PA166298504", + "name" : "Recommendation PA166298504", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "SLCO1B1: n/a" + "SLCO1B1: Increased simvastatin acid exposure as compared to normal function; increased risk of myopathy" ], - "lookupKey" : {"SLCO1B1": "Indeterminate"}, + "lookupKey" : {"SLCO1B1": "Decreased Function"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -82755,27 +83747,27 @@ "objCls" : "Chemical", "id" : "PA451363", "name" : "simvastatin", - "version" : 24 + "version" : 87 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105005", "name" : "Annotation of CPIC Guideline for simvastatin and SLCO1B1", - "version" : 52 + "version" : 148 }, "text" : { - "id" : 1452061108, - "html" : "

No recommendation

\n", + "id" : 1452061106, + "html" : "

Prescribe an alternative statin depending on the desired potency (see Figure 1 of PMID: 35152405 for recommendations for alternative statins). If simvastatin therapy is warranted, limit dose to <20mg/day.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298501", - "name" : "Recommendation PA166298501", - "alternateDrugAvailable" : false, + "id" : "PA166298505", + "name" : "Recommendation PA166298505", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, "parents" : [], @@ -82787,9 +83779,9 @@ }, "dosingInformation" : false, "implications" : [ - "SLCO1B1: Typical myopathy risk and statin exposure" + "SLCO1B1: Increased simvastatin acid exposure compared to normal and decreased function; highly increased myopathy risk" ], - "lookupKey" : {"SLCO1B1": "Increased Function"}, + "lookupKey" : {"SLCO1B1": "Poor Function"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -82797,27 +83789,27 @@ "objCls" : "Chemical", "id" : "PA451363", "name" : "simvastatin", - "version" : 24 + "version" : 87 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105005", "name" : "Annotation of CPIC Guideline for simvastatin and SLCO1B1", - "version" : 52 + "version" : 148 }, "text" : { - "id" : 1452061103, - "html" : "

Prescribe desired starting dose and adjust doses based on disease-specific guidelines.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and ancestry should be evaluated prior to initiating a statin.

\n", + "id" : 1452061107, + "html" : "

Prescribe an alternative statin depending on the desired potency (see Figure 1 of PMID: 35152405 for recommendations for alternative statins).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298505", - "name" : "Recommendation PA166298505", - "alternateDrugAvailable" : true, + "id" : "PA166298501", + "name" : "Recommendation PA166298501", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, "parents" : [], @@ -82829,9 +83821,9 @@ }, "dosingInformation" : false, "implications" : [ - "SLCO1B1: Increased simvastatin acid exposure compared to normal and decreased function; highly increased myopathy risk" + "SLCO1B1: Typical myopathy risk and statin exposure" ], - "lookupKey" : {"SLCO1B1": "Poor Function"}, + "lookupKey" : {"SLCO1B1": "Increased Function"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -82839,21 +83831,21 @@ "objCls" : "Chemical", "id" : "PA451363", "name" : "simvastatin", - "version" : 24 + "version" : 87 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105005", "name" : "Annotation of CPIC Guideline for simvastatin and SLCO1B1", - "version" : 52 + "version" : 148 }, "text" : { - "id" : 1452061107, - "html" : "

Prescribe an alternative statin depending on the desired potency (see Figure 1 of PMID: 35152405 for recommendations for alternative statins).

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452061103, + "html" : "

Prescribe desired starting dose and adjust doses based on disease-specific guidelines.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and ancestry should be evaluated prior to initiating a statin.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -82881,21 +83873,21 @@ "objCls" : "Chemical", "id" : "PA451363", "name" : "simvastatin", - "version" : 24 + "version" : 87 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105005", "name" : "Annotation of CPIC Guideline for simvastatin and SLCO1B1", - "version" : 52 + "version" : 148 }, "text" : { "id" : 1452061104, "html" : "

Prescribe desired starting dose and adjust doses based on disease-specific guidelines.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function and ancestry should be evaluated prior to initiating a statin.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -82923,41 +83915,41 @@ "objCls" : "Chemical", "id" : "PA451363", "name" : "simvastatin", - "version" : 24 + "version" : 87 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105005", "name" : "Annotation of CPIC Guideline for simvastatin and SLCO1B1", - "version" : 52 + "version" : 148 }, "text" : { "id" : 1452061105, "html" : "

Prescribe an alternative statin depending on the desired potency (see Figure 1 of PMID: 35152405 for recommendations for alternative statins). If simvastatin therapy is warranted, limit dose to <20mg/day.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298504", - "name" : "Recommendation PA166298504", - "alternateDrugAvailable" : true, + "id" : "PA166298506", + "name" : "Recommendation PA166298506", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "SLCO1B1: Increased simvastatin acid exposure as compared to normal function; increased risk of myopathy" + "SLCO1B1: n/a" ], - "lookupKey" : {"SLCO1B1": "Decreased Function"}, + "lookupKey" : {"SLCO1B1": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -82965,21 +83957,21 @@ "objCls" : "Chemical", "id" : "PA451363", "name" : "simvastatin", - "version" : 24 + "version" : 87 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105005", "name" : "Annotation of CPIC Guideline for simvastatin and SLCO1B1", - "version" : 52 + "version" : 148 }, "text" : { - "id" : 1452061106, - "html" : "

Prescribe an alternative statin depending on the desired potency (see Figure 1 of PMID: 35152405 for recommendations for alternative statins). If simvastatin therapy is warranted, limit dose to <20mg/day.

\n

Other Considerations

\n

The potential for drug-drug interactions and dose limits based on renal and hepatic function should be evaluated prior to initiating a statin. The effects of drug-drug interactions may be more pronounced resulting in a higher risk of myopathy.

\n", + "id" : 1452061108, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166105005" @@ -83132,7 +84124,7 @@ "objCls" : "Chemical", "id" : "PA451578", "name" : "tacrolimus", - "version" : 25 + "version" : 81 } ], "relatedGenes" : [ @@ -83141,44 +84133,44 @@ "id" : "PA131", "symbol" : "CYP3A5", "name" : "cytochrome P450 family 3 subfamily A member 5", - "version" : 7962 + "version" : 8072 } ], "source" : "CPIC", "summaryMarkdown" : { "id" : 1447982329, "html" : "

The CPIC dosing guideline for tacrolimus recommends increasing the starting dose by 1.5 to 2 times the recommended starting dose in patients who are CYP3A5 intermediate or extensive metabolizers, though total starting dose should not exceed 0.3 mg/kg/day. Therapeutic drug monitoring should also be used to guide dose adjustments.

\n", - "version" : 0 + "version" : 1 }, "terms" : [], "textMarkdown" : { "id" : 1451433665, "html" : "

This annotation is based on the CPIC® guideline for tacrolimus and CYP3A5.

\n

July 2015

\n

Advanced online publication March 2015

\n\n

Table 1: Dosing recommendations for tacrolimus based on CYP3A5 phenotype:

\n

Adapted from Tables 1 and 2 of the 2015 guideline manuscript.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Likely phenotype aGenotypesExamples of diplotypes bImplications for tacrolimus pharmacologic measuresTherapeutic Recommendations cClassification of recommendations e
Extensive metabolizer (CYP3A5 expresser)An individual carrying two functional alleles*1/*1Lower dose-adjusted trough concentrations of tacrolimus and decreased chance of achieving target tacrolimus concentrationsIncrease starting dose 1.5 to 2 times recommended starting dose d. Total starting dose should not exceed 0.3mg/kg/day. Use therapeutic drug monitoring to guide dose adjustmentsStrong
Intermediate metabolizer (CYP3A5 expresser)An individual carrying one functional allele and one non-functional allele*1/*3, *1/*6, *1/*7Lower dose-adjusted trough concentrations of tacrolimus and decreased chance of achieving target tacrolimus concentrationsIncrease starting dose 1.5 to 2 times recommended starting dose d. Total starting dose should not exceed 0.3mg/kg/day. Use therapeutic drug monitoring to guide dose adjustmentsStrong
Poor metabolizer (CYP3A5 non-expresser)An individual carrying two non-functional alleles*3/*3, *6/*6, *7/*7, *3/*6, *3/*7, *6/*7Higher (“normal”) dose-adjusted trough concentrations of tacrolimus and increased chance of achieving target tacrolimus concentrationsInitiate therapy with standard recommended dose. Use therapeutic drug monitoring to guide dose adjustmentsStrong
\n

a Typically with other CYP enzymes, an extensive metabolizer would be classified as a “normal” metabolizer, and therefore, the drug dose would not change based on the patient’s genotype. However, in the case of CYP3A5 and tacrolimus, a CYP3A5 expresser (i.e. CYP3A5 extensive metabolizer or intermediate metabolizer) would require a higher recommended starting dose and the CYP3A5 non-expresser (i.e. poor metabolizer) would require the standard recommended starting dose.

\n

b Additional rare variants such as CYP3A5*2, *8, and *9 may be found which are of unknown functional significance. However, if a copy of *1 is present, expected phenotype would be intermediate metabolizer.

\n

c This recommendation includes the use of tacrolimus in kidney, heart, lung and hematopoietic stem cell transplant patients, and liver transplant patients where the donor and recipient genotypes are identical.

\n

d Further dose adjustments or selection of alternative therapy may be necessary due to other clinical factors (e.g., medication interactions, or hepatic function)

\n

e Rating scheme is described in 2015 Supplement.

\n", - "version" : 1 + "version" : 2 }, "userId" : "whaleyr", - "version" : 39 + "version" : 190 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166298514", - "name" : "Recommendation PA166298514", + "id" : "PA166298511", + "name" : "Recommendation PA166298511", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP3A5: n/a" + "CYP3A5: Lower dose-adjusted trough concentrations of tacrolimus and decreased chance of achieving target tacrolimus concentrations." ], - "lookupKey" : {"CYP3A5": "Indeterminate"}, + "lookupKey" : {"CYP3A5": "Possible Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -83186,26 +84178,26 @@ "objCls" : "Chemical", "id" : "PA451578", "name" : "tacrolimus", - "version" : 25 + "version" : 81 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166124619", "name" : "Annotation of CPIC Guideline for tacrolimus and CYP3A5", - "version" : 39 + "version" : 190 }, "text" : { - "id" : 1452061116, - "html" : "

No recommendation

\n", + "id" : 1452061113, + "html" : "

Increase starting dose 1.5 to 2 times recommended starting dose. Total starting dose should not exceed 0.3 mg/kg/day. Use therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

This recommendation includes the use of tacrolimus in kidney, heart, lung and hematopoietic stem cell transplant patients, and liver transplant patients where the donor and recipient genotypes are identical. Further dose adjustments or selection of alternative therapy may be necessary due to other clinical factors (e.g., medication interactions, or hepatic function).Typically with other CYP enzymes, a normal metabolizer would be classified as having normal metabolism, and therefore, the drug dose would not change based on the patient’s genotype. However, in the case of CYP3A5 and tacrolimus, a CYP3A5 expresser (i.e., CYP3A5 normal metabolizer or intermediate metabolizer) would require a higher recommended starting dose and the CYP3A5 non-expresser (i.e., poor metabolizer) would require the standard recommended starting dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298510", - "name" : "Recommendation PA166298510", + "id" : "PA166298512", + "name" : "Recommendation PA166298512", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -83220,7 +84212,7 @@ "implications" : [ "CYP3A5: Lower dose-adjusted trough concentrations of tacrolimus and decreased chance of achieving target tacrolimus concentrations." ], - "lookupKey" : {"CYP3A5": "Normal Metabolizer"}, + "lookupKey" : {"CYP3A5": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -83228,26 +84220,26 @@ "objCls" : "Chemical", "id" : "PA451578", "name" : "tacrolimus", - "version" : 25 + "version" : 81 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166124619", "name" : "Annotation of CPIC Guideline for tacrolimus and CYP3A5", - "version" : 39 + "version" : 190 }, "text" : { - "id" : 1452061112, - "html" : "

Increase starting dose 1.5 to 2 times recommended starting dose. Total starting dose should not exceed 0.3 mg/kg/day. Use therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

This recommendation includes the use of tacrolimus in kidney, heart, lung and hematopoietic stem cell transplant patients, and liver transplant patients where the donor and recipient genotypes are identical. Further dose adjustments or selection of alternative therapy may be necessary due to other clinical factors (e.g., medication interactions, or hepatic function). Typically with other CYP enzymes, a normal metabolizer would be classified as having normal metabolism, and therefore, the drug dose would not change based on the patient’s genotype. However, in the case of CYP3A5 and tacrolimus, a CYP3A5 expresser (i.e., CYP3A5 normal metabolizer or intermediate metabolizer) would require a higher recommended starting dose, and the CYP3A5 non-expresser (i.e., poor metabolizer) would require the standard recommended starting dose.

\n", + "id" : 1452061114, + "html" : "

Increase starting dose 1.5 to 2 times recommended starting dose. Total starting dose should not exceed 0.3 mg/kg/day. Use therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

This recommendation includes the use of tacrolimus in kidney, heart, lung and hematopoietic stem cell transplant patients, and liver transplant patients where the donor and recipient genotypes are identical. Further dose adjustments or selection of alternative therapy may be necessary due to other clinical factors (e.g., medication interactions, or hepatic function).Typically with other CYP enzymes, a normal metabolizer would be classified as having normal metabolism, and therefore, the drug dose would not change based on the patient’s genotype. However, in the case of CYP3A5 and tacrolimus, a CYP3A5 expresser (i.e., CYP3A5 normal metabolizer or intermediate metabolizer) would require a higher recommended starting dose and the CYP3A5 non-expresser (i.e., poor metabolizer) would require the standard recommended starting dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298511", - "name" : "Recommendation PA166298511", + "id" : "PA166298513", + "name" : "Recommendation PA166298513", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -83258,11 +84250,11 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP3A5: Lower dose-adjusted trough concentrations of tacrolimus and decreased chance of achieving target tacrolimus concentrations." + "CYP3A5: Higher (\"normal\") dose-adjusted trough concentrations of tacrolimus and increased chance of achieving target tacrolimus concentrations." ], - "lookupKey" : {"CYP3A5": "Possible Intermediate Metabolizer"}, + "lookupKey" : {"CYP3A5": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -83270,41 +84262,41 @@ "objCls" : "Chemical", "id" : "PA451578", "name" : "tacrolimus", - "version" : 25 + "version" : 81 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166124619", "name" : "Annotation of CPIC Guideline for tacrolimus and CYP3A5", - "version" : 39 + "version" : 190 }, "text" : { - "id" : 1452061113, - "html" : "

Increase starting dose 1.5 to 2 times recommended starting dose. Total starting dose should not exceed 0.3 mg/kg/day. Use therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

This recommendation includes the use of tacrolimus in kidney, heart, lung and hematopoietic stem cell transplant patients, and liver transplant patients where the donor and recipient genotypes are identical. Further dose adjustments or selection of alternative therapy may be necessary due to other clinical factors (e.g., medication interactions, or hepatic function).Typically with other CYP enzymes, a normal metabolizer would be classified as having normal metabolism, and therefore, the drug dose would not change based on the patient’s genotype. However, in the case of CYP3A5 and tacrolimus, a CYP3A5 expresser (i.e., CYP3A5 normal metabolizer or intermediate metabolizer) would require a higher recommended starting dose and the CYP3A5 non-expresser (i.e., poor metabolizer) would require the standard recommended starting dose.

\n", + "id" : 1452061115, + "html" : "

Initiate therapy with standard recommended dose. Use therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

This recommendation includes the use of tacrolimus in kidney, heart, lung and hematopoietic stem cell transplant patients, and liver transplant patients where the donor and recipient genotypes are identical. Typically with other CYP enzymes, a normal metabolizer would be classified as having normal metabolism, and therefore, the drug dose would not change based on the patient’s genotype. However, in the case of CYP3A5 and tacrolimus, a CYP3A5 expresser (i.e., CYP3A5 normal metabolizer or intermediate metabolizer) would require a higher recommended starting dose and the CYP3A5 non-expresser (i.e., poor metabolizer) would require the standard recommended starting dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 4 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298512", - "name" : "Recommendation PA166298512", + "id" : "PA166298514", + "name" : "Recommendation PA166298514", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP3A5: Lower dose-adjusted trough concentrations of tacrolimus and decreased chance of achieving target tacrolimus concentrations." + "CYP3A5: n/a" ], - "lookupKey" : {"CYP3A5": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP3A5": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -83312,26 +84304,26 @@ "objCls" : "Chemical", "id" : "PA451578", "name" : "tacrolimus", - "version" : 25 + "version" : 81 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166124619", "name" : "Annotation of CPIC Guideline for tacrolimus and CYP3A5", - "version" : 39 + "version" : 190 }, "text" : { - "id" : 1452061114, - "html" : "

Increase starting dose 1.5 to 2 times recommended starting dose. Total starting dose should not exceed 0.3 mg/kg/day. Use therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

This recommendation includes the use of tacrolimus in kidney, heart, lung and hematopoietic stem cell transplant patients, and liver transplant patients where the donor and recipient genotypes are identical. Further dose adjustments or selection of alternative therapy may be necessary due to other clinical factors (e.g., medication interactions, or hepatic function).Typically with other CYP enzymes, a normal metabolizer would be classified as having normal metabolism, and therefore, the drug dose would not change based on the patient’s genotype. However, in the case of CYP3A5 and tacrolimus, a CYP3A5 expresser (i.e., CYP3A5 normal metabolizer or intermediate metabolizer) would require a higher recommended starting dose and the CYP3A5 non-expresser (i.e., poor metabolizer) would require the standard recommended starting dose.

\n", + "id" : 1452061116, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298513", - "name" : "Recommendation PA166298513", + "id" : "PA166298510", + "name" : "Recommendation PA166298510", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -83342,11 +84334,11 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP3A5: Higher (\"normal\") dose-adjusted trough concentrations of tacrolimus and increased chance of achieving target tacrolimus concentrations." + "CYP3A5: Lower dose-adjusted trough concentrations of tacrolimus and decreased chance of achieving target tacrolimus concentrations." ], - "lookupKey" : {"CYP3A5": "Poor Metabolizer"}, + "lookupKey" : {"CYP3A5": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -83354,21 +84346,21 @@ "objCls" : "Chemical", "id" : "PA451578", "name" : "tacrolimus", - "version" : 25 + "version" : 81 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166124619", "name" : "Annotation of CPIC Guideline for tacrolimus and CYP3A5", - "version" : 39 + "version" : 190 }, "text" : { - "id" : 1452061115, - "html" : "

Initiate therapy with standard recommended dose. Use therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

This recommendation includes the use of tacrolimus in kidney, heart, lung and hematopoietic stem cell transplant patients, and liver transplant patients where the donor and recipient genotypes are identical. Typically with other CYP enzymes, a normal metabolizer would be classified as having normal metabolism, and therefore, the drug dose would not change based on the patient’s genotype. However, in the case of CYP3A5 and tacrolimus, a CYP3A5 expresser (i.e., CYP3A5 normal metabolizer or intermediate metabolizer) would require a higher recommended starting dose and the CYP3A5 non-expresser (i.e., poor metabolizer) would require the standard recommended starting dose.

\n", + "id" : 1452061112, + "html" : "

Increase starting dose 1.5 to 2 times recommended starting dose. Total starting dose should not exceed 0.3 mg/kg/day. Use therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

This recommendation includes the use of tacrolimus in kidney, heart, lung and hematopoietic stem cell transplant patients, and liver transplant patients where the donor and recipient genotypes are identical. Further dose adjustments or selection of alternative therapy may be necessary due to other clinical factors (e.g., medication interactions, or hepatic function). Typically with other CYP enzymes, a normal metabolizer would be classified as having normal metabolism, and therefore, the drug dose would not change based on the patient’s genotype. However, in the case of CYP3A5 and tacrolimus, a CYP3A5 expresser (i.e., CYP3A5 normal metabolizer or intermediate metabolizer) would require a higher recommended starting dose, and the CYP3A5 non-expresser (i.e., poor metabolizer) would require the standard recommended starting dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166124619" @@ -83535,7 +84527,7 @@ "objCls" : "Chemical", "id" : "PA451581", "name" : "tamoxifen", - "version" : 23 + "version" : 82 } ], "relatedGenes" : [ @@ -83544,7 +84536,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "CPIC", @@ -83557,16 +84549,16 @@ "textMarkdown" : { "id" : 1451433667, "html" : "

This annotation is based on the CPIC® guideline for tamoxifen and CYP2D6.

\n

October 2019 Update

\n

CYP2D6 genotype to phenotype translation changes: Up until August 2019, there were a few inconsistencies in the translation of CYP2D6 genotype to phenotype translation across guidelines (i.e. CPIC and DPWG) and between clinical genetic testing laboratories. CPIC recently conducted a modified-Delphi project to obtain consensus for a uniform system for translating CYP2D6 genotype to phenotype among a panel of international CYP2D6 experts more information. Modifications to CPIC’s prior system include downgrading the value assigned to the CYP2D6*10 allele for activity score calculation from 0.5 to 0.25 and changing the phenotype assignment for an activity score of 1 from normal metabolizer to intermediate metabolizer (table of all previous and new phenotype groupings).

\n

As a result, the following changes have been made in the CYP2D6 allele functionality table, CYP2D6 genotype to phenotype table, Tamoxifen pre- and post-test alerts and flow chart (access tables below):

\n\n

May 2018

\n

Accepted article preview online January 2018; Advance online publication January 2018

\n\n\n

Adapted from Tables 1 and 2 of the 2017 guideline manuscript.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
PhenotypeaActivity ScoreGenotypeExamples of genotypesbImplicationsTherapeutic recommendationscClassification of recommendationsd
CYP2D6 Ultrarapid Metabolizer>2An individual carrying duplications of functional alleles*1/*1xN, *1/*2xN, *2/*2xNeTherapeutic endoxifen concentrationsAvoid moderate and strong CYP2D6 inhibitors. Initiate therapy with recommended standard of care dosing (tamoxifen 20 mg/day).Strong
CYP2D6 Normal metabolizer1.5 and 2An individual carrying two normal function alleles or one normal function and one decreased function allele*1/*1, *1/*2, *1/*9, *1/*41, *2/*2Therapeutic endoxifen concentrationsAvoid moderate and strong CYP2D6 inhibitors. Initiate therapy with recommended standard of care dosing (tamoxifen 20 mg/day).Strong
CYP2D6 Normal metabolizer or Intermediate metabolizer (controversy remains)f1 (no *10 allele present)cAn individual carrying two decreased function alleles or one normal function and one no function allele. An activity score (AS) of 1.0 is associated with decreased tamoxifen metabolism to endoxifen compared to those with an AS of 1.5 or 2.*1/*4, *1/*5, *41/*41Lower endoxifen concentrations compared to normal metabolizers; higher risk of breast cancer recurrence, event-free and recurrence-free survival compared to normal metabolizers.Consider hormonal therapy such as an aromatase inhibitor for postmenopausal women or aromatase inhibitor along with ovarian function suppression in premenopausal women, given that these approaches are superior to tamoxifen regardless of CYP2D6 genotype [Articles:26211827, 24881463]. If aromatase inhibitor use is contraindicated, consideration should be given to use a higher but FDA approved tamoxifen dose (40 mg/day) [Article:27226358]. Avoid CYP2D6 strong to weak inhibitors.Optionalc
CYP2D6 Normal metabolizer or Intermediate metabolizer (controversy remains)f1 (*10 allele present)cAn individual carrying two decreased function alleles with the *10 allele present. An activity score (AS) of 1.0 is associated with decreased tamoxifen metabolism to endoxifen compared to those with an AS of 1.5 or 2.*10/*10, *10/*41Lower endoxifen concentrations compared to normal metabolizers; higher risk of breast cancer recurrence, event-free and recurrence-free survival compared to normal metabolizers.Consider hormonal therapy such as an aromatase inhibitor for postmenopausal women or aromatase inhibitor along with ovarian function suppression in premenopausal women, given that these approaches are superior to tamoxifen regardless of CYP2D6 genotype [Articles:26211827, 24881463]. If aromatase inhibitor use is contraindicated, consideration should be given to use a higher but FDA approved tamoxifen dose (40 mg/day) [Article:27226358]. Avoid CYP2D6 strong to weak inhibitors.Moderatec
CYP2D6 Intermediate metabolizer0.5An individual carrying one decreased function and one no function allele*4/*10,*4/*41, *5/*9Lower endoxifen concentrations compared to normal metabolizers; higher risk of breast cancer recurrence, event-free and recurrence-free survival compared to normal metabolizers.Consider hormonal therapy such as an aromatase inhibitor for postmenopausal women or aromatase inhibitor along with ovarian function suppression in premenopausal women, given that these approaches are superior to tamoxifen regardless of CYP2D6 genotype [Articles:26211827, 24881463]. If aromatase inhibitor use is contraindicated, consideration should be given to use a higher but FDA approved tamoxifen dose (40 mg/day) [Article:27226358]. Avoid CYP2D6 strong to weak inhibitors.Moderate
CYP2D6 Poor metabolizer0An individual carrying only no functional alleles*3/*4,*4/*4, *5/*5, *5/*6Lower endoxifen concentrations compared to normal metabolizers; higher risk of breast cancer recurrence, event-free and recurrence-free survival compared to normal metabolizers.Recommend alternative hormonal therapy such as an aromatase inhibitor for postmenopausal women or aromatase inhibitor along with ovarian function suppression in premenopausal women given that these approaches are superior to tamoxifen regardless of CYP2D6 genotype [Articles:26211827, 24881463] and based on knowledge that CYP2D6 poor metabolizers switched from tamoxifen to anastrozole do not have an increased risk of recurrence [Article:23213055]. Note, higher dose tamoxifen (40 mg/day) increases but does not normalize endoxifen concentrations and can be considered if there are contraindications to aromatase inhibitor therapy [Articles:27226358, 21768473].Strong
\n

a See the CYP2D6 frequency table for race-specific allele and phenotype frequencies.
\nb For a complete list of CYP2D6 diplotypes and resulting phenotypes, see the CYP2D6 genotype to phenotype table . Note that genotypes with an activity score of 1 are classified as NMs in the online CYP2D6 genotype to phenotype table.
\nc CPIC has generally classified patients with an activity score of 1 as a “normal metabolizer”. However, in the case of tamoxifen, prescribing recommendations for those with an AS of 1.0 are allele dependent, based on the presence of the *10 allele. Those patients with an AS of 1.0 on the basis a *10 allele are provided a “moderate,” recommendation. In contrast, prescribing recommendations for those with an activity score of 1 based on the presence of CYP2D6 alleles other than *10 are graded as “optional” because the recommendations are primarily extrapolated from evidence generated from *10 individuals (i.e. limited data for clinical outcomes and pharmacokinetics for this group).
\nd Rating scheme described in Supplement.
\ne Where xN represents the number of CYP2D6 gene copies. For individuals with CYP2D6 duplications or multiplications, see supplemental data for additional information on how to translate diplotypes into phenotypes.
\nf Patients with an activity score of 1.0 may be classified as intermediate metabolizers by some reference laboratories. A group of CYP2D6 experts are currently working to standardize the CYP2D6 genotype to phenotype translation system. CPIC will update the CPIC website accordingly CYP2D6 genotype to phenotype table.

\n", - "version" : 1 + "version" : 2 }, "userId" : "katrin", - "version" : 12 + "version" : 53 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166298391", - "name" : "Recommendation PA166298391", + "id" : "PA166298482", + "name" : "Recommendation PA166298482", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -83581,7 +84573,7 @@ "implications" : [ "CYP2D6: Therapeutic endoxifen concentrations" ], - "lookupKey" : {"CYP2D6": "3.0"}, + "lookupKey" : {"CYP2D6": "≥5.0"}, "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ @@ -83589,26 +84581,26 @@ "objCls" : "Chemical", "id" : "PA451581", "name" : "tamoxifen", - "version" : 23 + "version" : 82 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166176068", "name" : "Annotation of CPIC Guideline for tamoxifen and CYP2D6", - "version" : 12 + "version" : 53 }, "text" : { - "id" : 1452060993, + "id" : 1452061084, "html" : "

Avoid moderate and strong CYP2D6 inhibitors. Initiate therapy with recommended standard of care dosing (tamoxifen 20 mg/day).

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298237", - "name" : "Recommendation PA166298237", + "id" : "PA166298508", + "name" : "Recommendation PA166298508", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -83623,7 +84615,7 @@ "implications" : [ "CYP2D6: Therapeutic endoxifen concentrations" ], - "lookupKey" : {"CYP2D6": "4.0"}, + "lookupKey" : {"CYP2D6": "≥4.0"}, "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ @@ -83631,231 +84623,243 @@ "objCls" : "Chemical", "id" : "PA451581", "name" : "tamoxifen", - "version" : 23 + "version" : 82 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166176068", "name" : "Annotation of CPIC Guideline for tamoxifen and CYP2D6", - "version" : 12 + "version" : 53 }, "text" : { - "id" : 1452060839, + "id" : 1452061110, "html" : "

Avoid moderate and strong CYP2D6 inhibitors. Initiate therapy with recommended standard of care dosing (tamoxifen 20 mg/day).

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298527", - "name" : "Recommendation PA166298527", - "alternateDrugAvailable" : true, + "id" : "PA166298507", + "name" : "Recommendation PA166298507", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2D6: Lower endoxifen concentrations compared to normal metabolizers; higher risk of breast cancer recurrence, event-free and recurrence-free survival compared to normal metabolizers." + "CYP2D6: Therapeutic endoxifen concentrations" ], - "lookupKey" : {"CYP2D6": "0.75"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"CYP2D6": "≥3.75"}, + "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451581", "name" : "tamoxifen", - "version" : 23 + "version" : 82 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166176068", "name" : "Annotation of CPIC Guideline for tamoxifen and CYP2D6", - "version" : 12 + "version" : 53 }, "text" : { - "id" : 1452061129, - "html" : "

Consider hormonal therapy such as an aromatase inhibitor for postmenopausal women or aromatase inhibitor along with ovarian function suppression in premenopausal women, given that these approaches are superior to tamoxifen regardless of CYP2D6 genotype (PMID 26211827). If aromatase inhibitor use is contraindicated, consideration should be given to use a higher but FDA approved tamoxifen dose (40 mg/day)(PMID 27226358). Avoid CYP2D6 strong to weak inhibitors.

\n", + "id" : 1452061109, + "html" : "

Avoid moderate and strong CYP2D6 inhibitors. Initiate therapy with recommended standard of care dosing (tamoxifen 20 mg/day).

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298523", - "name" : "Recommendation PA166298523", - "alternateDrugAvailable" : false, + "id" : "PA166298526", + "name" : "Recommendation PA166298526", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2D6: Therapeutic endoxifen concentrations" + "CYP2D6: Lower endoxifen concentrations compared to normal metabolizers; higher risk of breast cancer recurrence, event-free and recurrence-free survival compared to normal metabolizers." ], - "lookupKey" : {"CYP2D6": "1.75"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"CYP2D6": "1.0"}, + "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451581", "name" : "tamoxifen", - "version" : 23 + "version" : 82 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166176068", "name" : "Annotation of CPIC Guideline for tamoxifen and CYP2D6", - "version" : 12 + "version" : 53 }, "text" : { - "id" : 1452061125, - "html" : "

Avoid moderate and strong CYP2D6 inhibitors. Initiate therapy with recommended standard of care dosing (tamoxifen 20 mg/day).

\n", + "id" : 1452061128, + "html" : "

Consider hormonal therapy such as an aromatase inhibitor for postmenopausal women or aromatase inhibitor along with ovarian function suppression in premenopausal women, given that these approaches are superior to tamoxifen regardless of CYP2D6 genotype (PMID 26211827). If aromatase inhibitor use is contraindicated, consideration should be given to use a higher but FDA approved tamoxifen dose (40 mg/day)(PMID 27226358). Avoid CYP2D6 strong to weak inhibitors.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301328", - "name" : "Recommendation Annotation PA166301328", - "alternateDrugAvailable" : false, - "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations"}, + "id" : "PA166298527", + "name" : "Recommendation PA166298527", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981501931, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "CYP2D6: Lower endoxifen concentrations compared to normal metabolizers; higher risk of breast cancer recurrence, event-free and recurrence-free survival compared to normal metabolizers." + ], + "lookupKey" : {"CYP2D6": "0.75"}, "otherPrescribingGuidance" : false, + "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451581", "name" : "tamoxifen", - "version" : 23 + "version" : 82 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166176068", "name" : "Annotation of CPIC Guideline for tamoxifen and CYP2D6", - "version" : 12 + "version" : 53 }, "text" : { - "id" : 1452095647, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "id" : 1452061129, + "html" : "

Consider hormonal therapy such as an aromatase inhibitor for postmenopausal women or aromatase inhibitor along with ovarian function suppression in premenopausal women, given that these approaches are superior to tamoxifen regardless of CYP2D6 genotype (PMID 26211827). If aromatase inhibitor use is contraindicated, consideration should be given to use a higher but FDA approved tamoxifen dose (40 mg/day)(PMID 27226358). Avoid CYP2D6 strong to weak inhibitors.

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Avoid moderate and strong CYP2D6 inhibitors. Initiate therapy with recommended standard of care dosing (tamoxifen 20 mg/day).

\n", + "id" : 1452061130, + "html" : "

Consider hormonal therapy such as an aromatase inhibitor for postmenopausal women or aromatase inhibitor along with ovarian function suppression in premenopausal women, given that these approaches are superior to tamoxifen regardless of CYP2D6 genotype (PMID 26211827). If aromatase inhibitor use is contraindicated, consideration should be given to use a higher but FDA approved tamoxifen dose (40 mg/day)(PMID 27226358). Avoid CYP2D6 strong to weak inhibitors.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298507", - "name" : "Recommendation PA166298507", - "alternateDrugAvailable" : false, + "id" : "PA166298529", + "name" : "Recommendation PA166298529", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2D6: Therapeutic endoxifen concentrations" + "CYP2D6: Lower endoxifen concentrations compared to normal metabolizers; higher risk of breast cancer recurrence, event-free and recurrence-free survival compared to normal metabolizers." ], - "lookupKey" : {"CYP2D6": "≥3.75"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"CYP2D6": "0.25"}, + "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451581", "name" : "tamoxifen", - "version" : 23 + "version" : 82 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166176068", "name" : "Annotation of CPIC Guideline for tamoxifen and CYP2D6", - "version" : 12 + "version" : 53 }, "text" : { - "id" : 1452061109, - "html" : "

Avoid moderate and strong CYP2D6 inhibitors. Initiate therapy with recommended standard of care dosing (tamoxifen 20 mg/day).

\n", + "id" : 1452061131, + "html" : "

Consider hormonal therapy such as an aromatase inhibitor for postmenopausal women or aromatase inhibitor along with ovarian function suppression in premenopausal women, given that these approaches are superior to tamoxifen regardless of CYP2D6 genotype (PMID 26211827). If aromatase inhibitor use is contraindicated, consideration should be given to use a higher but FDA approved tamoxifen dose (40 mg/day)(PMID 27226358). Avoid CYP2D6 strong to weak inhibitors.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298528", - "name" : "Recommendation PA166298528", + "id" : "PA166298530", + "name" : "Recommendation PA166298530", "alternateDrugAvailable" : true, "classification" : { - "id" : 981501931, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, @@ -83863,7 +84867,7 @@ "implications" : [ "CYP2D6: Lower endoxifen concentrations compared to normal metabolizers; higher risk of breast cancer recurrence, event-free and recurrence-free survival compared to normal metabolizers." ], - "lookupKey" : {"CYP2D6": "0.5"}, + "lookupKey" : {"CYP2D6": "0.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -83871,26 +84875,26 @@ "objCls" : "Chemical", "id" : "PA451581", "name" : "tamoxifen", - "version" : 23 + "version" : 82 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166176068", "name" : "Annotation of CPIC Guideline for tamoxifen and CYP2D6", - "version" : 12 + "version" : 53 }, "text" : { - "id" : 1452061130, - "html" : "

Consider hormonal therapy such as an aromatase inhibitor for postmenopausal women or aromatase inhibitor along with ovarian function suppression in premenopausal women, given that these approaches are superior to tamoxifen regardless of CYP2D6 genotype (PMID 26211827). If aromatase inhibitor use is contraindicated, consideration should be given to use a higher but FDA approved tamoxifen dose (40 mg/day)(PMID 27226358). Avoid CYP2D6 strong to weak inhibitors.

\n", + "id" : 1452061132, + "html" : "

Recommend alternative hormonal therapy such as an aromatase inhibitor for postmenopausal women or aromatase inhibitor along with ovarian function suppression in premenopausal women given that these approaches are superior to tamoxifen regardless of CYP2D6 genotype (PMID 26211827) and based on knowledge that CYP2D6 poor metabolizers switched from tamoxifen to anastrozole do not have an increased risk of recurrence (PMID 23213055). Note, higher dose tamoxifen (40 mg/day) increases but does not normalize endoxifen concentrations and can be considered if there are contraindications to aromatase inhibitor therapy (PMID 27226358, 21768473).

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298524", - "name" : "Recommendation PA166298524", + "id" : "PA166298520", + "name" : "Recommendation PA166298520", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -83905,7 +84909,7 @@ "implications" : [ "CYP2D6: Therapeutic endoxifen concentrations" ], - "lookupKey" : {"CYP2D6": "1.5"}, + "lookupKey" : {"CYP2D6": "≥6.0"}, "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ @@ -83913,26 +84917,26 @@ "objCls" : "Chemical", "id" : "PA451581", "name" : "tamoxifen", - "version" : 23 + "version" : 82 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166176068", "name" : "Annotation of CPIC Guideline for tamoxifen and CYP2D6", - "version" : 12 + "version" : 53 }, "text" : { - "id" : 1452061126, + "id" : 1452061122, "html" : "

Avoid moderate and strong CYP2D6 inhibitors. Initiate therapy with recommended standard of care dosing (tamoxifen 20 mg/day).

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298380", - "name" : "Recommendation PA166298380", + "id" : "PA166298521", + "name" : "Recommendation PA166298521", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -83947,7 +84951,7 @@ "implications" : [ "CYP2D6: Therapeutic endoxifen concentrations" ], - "lookupKey" : {"CYP2D6": "2.75"}, + "lookupKey" : {"CYP2D6": "2.25"}, "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ @@ -83955,27 +84959,27 @@ "objCls" : "Chemical", "id" : "PA451581", "name" : "tamoxifen", - "version" : 23 + "version" : 82 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166176068", "name" : "Annotation of CPIC Guideline for tamoxifen and CYP2D6", - "version" : 12 + "version" : 53 }, "text" : { - "id" : 1452060982, + "id" : 1452061123, "html" : "

Avoid moderate and strong CYP2D6 inhibitors. Initiate therapy with recommended standard of care dosing (tamoxifen 20 mg/day).

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298530", - "name" : "Recommendation PA166298530", - "alternateDrugAvailable" : true, + "id" : "PA166298522", + "name" : "Recommendation PA166298522", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, "parents" : [], @@ -83985,38 +84989,38 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2D6: Lower endoxifen concentrations compared to normal metabolizers; higher risk of breast cancer recurrence, event-free and recurrence-free survival compared to normal metabolizers." + "CYP2D6: Therapeutic endoxifen concentrations" ], - "lookupKey" : {"CYP2D6": "0.0"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"CYP2D6": "2.0"}, + "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451581", "name" : "tamoxifen", - "version" : 23 + "version" : 82 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166176068", "name" : "Annotation of CPIC Guideline for tamoxifen and CYP2D6", - "version" : 12 + "version" : 53 }, "text" : { - "id" : 1452061132, - "html" : "

Recommend alternative hormonal therapy such as an aromatase inhibitor for postmenopausal women or aromatase inhibitor along with ovarian function suppression in premenopausal women given that these approaches are superior to tamoxifen regardless of CYP2D6 genotype (PMID 26211827) and based on knowledge that CYP2D6 poor metabolizers switched from tamoxifen to anastrozole do not have an increased risk of recurrence (PMID 23213055). Note, higher dose tamoxifen (40 mg/day) increases but does not normalize endoxifen concentrations and can be considered if there are contraindications to aromatase inhibitor therapy (PMID 27226358, 21768473).

\n", + "id" : 1452061124, + "html" : "

Avoid moderate and strong CYP2D6 inhibitors. Initiate therapy with recommended standard of care dosing (tamoxifen 20 mg/day).

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297837", - "name" : "Recommendation PA166297837", + "id" : "PA166298523", + "name" : "Recommendation PA166298523", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -84031,7 +85035,7 @@ "implications" : [ "CYP2D6: Therapeutic endoxifen concentrations" ], - "lookupKey" : {"CYP2D6": "≥3.25"}, + "lookupKey" : {"CYP2D6": "1.75"}, "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ @@ -84039,26 +85043,26 @@ "objCls" : "Chemical", "id" : "PA451581", "name" : "tamoxifen", - "version" : 23 + "version" : 82 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166176068", "name" : "Annotation of CPIC Guideline for tamoxifen and CYP2D6", - "version" : 12 + "version" : 53 }, "text" : { - "id" : 1452060439, + "id" : 1452061125, "html" : "

Avoid moderate and strong CYP2D6 inhibitors. Initiate therapy with recommended standard of care dosing (tamoxifen 20 mg/day).

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298464", - "name" : "Recommendation PA166298464", + "id" : "PA166298524", + "name" : "Recommendation PA166298524", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -84073,7 +85077,7 @@ "implications" : [ "CYP2D6: Therapeutic endoxifen concentrations" ], - "lookupKey" : {"CYP2D6": "2.5"}, + "lookupKey" : {"CYP2D6": "1.5"}, "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ @@ -84081,26 +85085,26 @@ "objCls" : "Chemical", "id" : "PA451581", "name" : "tamoxifen", - "version" : 23 + "version" : 82 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166176068", "name" : "Annotation of CPIC Guideline for tamoxifen and CYP2D6", - "version" : 12 + "version" : 53 }, "text" : { - "id" : 1452061066, + "id" : 1452061126, "html" : "

Avoid moderate and strong CYP2D6 inhibitors. Initiate therapy with recommended standard of care dosing (tamoxifen 20 mg/day).

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298508", - "name" : "Recommendation PA166298508", + "id" : "PA166298525", + "name" : "Recommendation PA166298525", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -84115,7 +85119,7 @@ "implications" : [ "CYP2D6: Therapeutic endoxifen concentrations" ], - "lookupKey" : {"CYP2D6": "≥4.0"}, + "lookupKey" : {"CYP2D6": "1.25"}, "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ @@ -84123,21 +85127,21 @@ "objCls" : "Chemical", "id" : "PA451581", "name" : "tamoxifen", - "version" : 23 + "version" : 82 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166176068", "name" : "Annotation of CPIC Guideline for tamoxifen and CYP2D6", - "version" : 12 + "version" : 53 }, "text" : { - "id" : 1452061110, + "id" : 1452061127, "html" : "

Avoid moderate and strong CYP2D6 inhibitors. Initiate therapy with recommended standard of care dosing (tamoxifen 20 mg/day).

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -84165,110 +85169,98 @@ "objCls" : "Chemical", "id" : "PA451581", "name" : "tamoxifen", - "version" : 23 + "version" : 82 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166176068", "name" : "Annotation of CPIC Guideline for tamoxifen and CYP2D6", - "version" : 12 + "version" : 53 }, "text" : { "id" : 1452061133, "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166297353", - "name" : "Recommendation PA166297353", + "id" : "PA166301328", + "name" : "Recommendation Annotation PA166301328", "alternateDrugAvailable" : false, - "classification" : { - "id" : 981501930, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", - "valid" : true, - "version" : 0 - }, "dosingInformation" : false, - "implications" : [ - "CYP2D6: Therapeutic endoxifen concentrations" - ], - "lookupKey" : {"CYP2D6": "≥3.5"}, - "otherPrescribingGuidance" : true, - "population" : "general", + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations"}, + "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451581", "name" : "tamoxifen", - "version" : 23 + "version" : 82 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166176068", "name" : "Annotation of CPIC Guideline for tamoxifen and CYP2D6", - "version" : 12 + "version" : 53 }, "text" : { - "id" : 1452059955, - "html" : "

Avoid moderate and strong CYP2D6 inhibitors. Initiate therapy with recommended standard of care dosing (tamoxifen 20 mg/day).

\n", + "id" : 1452095647, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298529", - "name" : "Recommendation PA166298529", - "alternateDrugAvailable" : true, + "id" : "PA166298464", + "name" : "Recommendation PA166298464", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2D6: Lower endoxifen concentrations compared to normal metabolizers; higher risk of breast cancer recurrence, event-free and recurrence-free survival compared to normal metabolizers." + "CYP2D6: Therapeutic endoxifen concentrations" ], - "lookupKey" : {"CYP2D6": "0.25"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"CYP2D6": "2.5"}, + "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451581", "name" : "tamoxifen", - "version" : 23 + "version" : 82 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166176068", "name" : "Annotation of CPIC Guideline for tamoxifen and CYP2D6", - "version" : 12 + "version" : 53 }, "text" : { - "id" : 1452061131, - "html" : "

Consider hormonal therapy such as an aromatase inhibitor for postmenopausal women or aromatase inhibitor along with ovarian function suppression in premenopausal women, given that these approaches are superior to tamoxifen regardless of CYP2D6 genotype (PMID 26211827). If aromatase inhibitor use is contraindicated, consideration should be given to use a higher but FDA approved tamoxifen dose (40 mg/day)(PMID 27226358). Avoid CYP2D6 strong to weak inhibitors.

\n", + "id" : 1452061066, + "html" : "

Avoid moderate and strong CYP2D6 inhibitors. Initiate therapy with recommended standard of care dosing (tamoxifen 20 mg/day).

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298521", - "name" : "Recommendation PA166298521", + "id" : "PA166297837", + "name" : "Recommendation PA166297837", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -84283,7 +85275,7 @@ "implications" : [ "CYP2D6: Therapeutic endoxifen concentrations" ], - "lookupKey" : {"CYP2D6": "2.25"}, + "lookupKey" : {"CYP2D6": "≥3.25"}, "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ @@ -84291,21 +85283,21 @@ "objCls" : "Chemical", "id" : "PA451581", "name" : "tamoxifen", - "version" : 23 + "version" : 82 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166176068", "name" : "Annotation of CPIC Guideline for tamoxifen and CYP2D6", - "version" : 12 + "version" : 53 }, "text" : { - "id" : 1452061123, + "id" : 1452060439, "html" : "

Avoid moderate and strong CYP2D6 inhibitors. Initiate therapy with recommended standard of care dosing (tamoxifen 20 mg/day).

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -84333,26 +85325,26 @@ "objCls" : "Chemical", "id" : "PA451581", "name" : "tamoxifen", - "version" : 23 + "version" : 82 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166176068", "name" : "Annotation of CPIC Guideline for tamoxifen and CYP2D6", - "version" : 12 + "version" : 53 }, "text" : { "id" : 1452060757, "html" : "

Avoid moderate and strong CYP2D6 inhibitors. Initiate therapy with recommended standard of care dosing (tamoxifen 20 mg/day).

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298525", - "name" : "Recommendation PA166298525", + "id" : "PA166298391", + "name" : "Recommendation PA166298391", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -84367,7 +85359,7 @@ "implications" : [ "CYP2D6: Therapeutic endoxifen concentrations" ], - "lookupKey" : {"CYP2D6": "1.25"}, + "lookupKey" : {"CYP2D6": "3.0"}, "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ @@ -84375,68 +85367,68 @@ "objCls" : "Chemical", "id" : "PA451581", "name" : "tamoxifen", - "version" : 23 + "version" : 82 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166176068", "name" : "Annotation of CPIC Guideline for tamoxifen and CYP2D6", - "version" : 12 + "version" : 53 }, "text" : { - "id" : 1452061127, + "id" : 1452060993, "html" : "

Avoid moderate and strong CYP2D6 inhibitors. Initiate therapy with recommended standard of care dosing (tamoxifen 20 mg/day).

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298526", - "name" : "Recommendation PA166298526", - "alternateDrugAvailable" : true, + "id" : "PA166297353", + "name" : "Recommendation PA166297353", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2D6: Lower endoxifen concentrations compared to normal metabolizers; higher risk of breast cancer recurrence, event-free and recurrence-free survival compared to normal metabolizers." + "CYP2D6: Therapeutic endoxifen concentrations" ], - "lookupKey" : {"CYP2D6": "1.0"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"CYP2D6": "≥3.5"}, + "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451581", "name" : "tamoxifen", - "version" : 23 + "version" : 82 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166176068", "name" : "Annotation of CPIC Guideline for tamoxifen and CYP2D6", - "version" : 12 + "version" : 53 }, "text" : { - "id" : 1452061128, - "html" : "

Consider hormonal therapy such as an aromatase inhibitor for postmenopausal women or aromatase inhibitor along with ovarian function suppression in premenopausal women, given that these approaches are superior to tamoxifen regardless of CYP2D6 genotype (PMID 26211827). If aromatase inhibitor use is contraindicated, consideration should be given to use a higher but FDA approved tamoxifen dose (40 mg/day)(PMID 27226358). Avoid CYP2D6 strong to weak inhibitors.

\n", + "id" : 1452059955, + "html" : "

Avoid moderate and strong CYP2D6 inhibitors. Initiate therapy with recommended standard of care dosing (tamoxifen 20 mg/day).

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298522", - "name" : "Recommendation PA166298522", + "id" : "PA166298237", + "name" : "Recommendation PA166298237", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -84451,7 +85443,7 @@ "implications" : [ "CYP2D6: Therapeutic endoxifen concentrations" ], - "lookupKey" : {"CYP2D6": "2.0"}, + "lookupKey" : {"CYP2D6": "4.0"}, "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ @@ -84459,26 +85451,26 @@ "objCls" : "Chemical", "id" : "PA451581", "name" : "tamoxifen", - "version" : 23 + "version" : 82 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166176068", "name" : "Annotation of CPIC Guideline for tamoxifen and CYP2D6", - "version" : 12 + "version" : 53 }, "text" : { - "id" : 1452061124, + "id" : 1452060839, "html" : "

Avoid moderate and strong CYP2D6 inhibitors. Initiate therapy with recommended standard of care dosing (tamoxifen 20 mg/day).

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298482", - "name" : "Recommendation PA166298482", + "id" : "PA166298380", + "name" : "Recommendation PA166298380", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -84493,7 +85485,7 @@ "implications" : [ "CYP2D6: Therapeutic endoxifen concentrations" ], - "lookupKey" : {"CYP2D6": "≥5.0"}, + "lookupKey" : {"CYP2D6": "2.75"}, "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ @@ -84501,21 +85493,21 @@ "objCls" : "Chemical", "id" : "PA451581", "name" : "tamoxifen", - "version" : 23 + "version" : 82 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166176068", "name" : "Annotation of CPIC Guideline for tamoxifen and CYP2D6", - "version" : 12 + "version" : 53 }, "text" : { - "id" : 1452061084, + "id" : 1452060982, "html" : "

Avoid moderate and strong CYP2D6 inhibitors. Initiate therapy with recommended standard of care dosing (tamoxifen 20 mg/day).

\n", "version" : 0 }, - "version" : 0 + "version" : 2 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166176068" @@ -84849,7 +85841,7 @@ "objCls" : "Chemical", "id" : "PA131890625", "name" : "tenoxicam", - "version" : 6 + "version" : 21 } ], "relatedGenes" : [ @@ -84858,7 +85850,7 @@ "id" : "PA126", "symbol" : "CYP2C9", "name" : "cytochrome P450 family 2 subfamily C member 9", - "version" : 7877 + "version" : 7952 } ], "source" : "CPIC", @@ -84874,28 +85866,28 @@ "version" : 1 }, "userId" : "lgong", - "version" : 9 + "version" : 92 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166298532", - "name" : "Recommendation PA166298532", - "alternateDrugAvailable" : false, + "id" : "PA166298536", + "name" : "Recommendation PA166298536", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2C9: Normal metabolism" + "CYP2C9: Significantly reduced metabolism and prolonged half-life; higher plasma concentrations may increase probability and/or severity of toxicities" ], - "lookupKey" : {"CYP2C9": "2.0"}, + "lookupKey" : {"CYP2C9": "0.5"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -84903,26 +85895,26 @@ "objCls" : "Chemical", "id" : "PA131890625", "name" : "tenoxicam", - "version" : 6 + "version" : 21 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166192341", "name" : "Annotation of CPIC Guideline for tenoxicam and CYP2C9", - "version" : 9 + "version" : 92 }, "text" : { - "id" : 1452061134, - "html" : "

Initiate therapy with recommended starting dose. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals.

\n", + "id" : 1452061138, + "html" : "

Choose an alternative therapy not metabolized by CYP2C9 or not significantly impacted by CYP2C9 genetic variants in vivo or choose an NSAID metabolized by CYP2C9 but with a shorter half-life (see CPIC THERAPEUTIC RECOMMENDATIONS FOR CELECOXIB, FLURBIPROFEN, LORNOXICAM, AND IBUPROFEN BASED ON CYP2C9 PHENOTYPE).

\n

Other Considerations

\n

Alternative therapies not primarily metabolized by CYP2C9 include aspirin, ketorolac, naproxen and sulindac. Selection of therapy will depend on individual patient treatment goals and risks for toxicity.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298536", - "name" : "Recommendation PA166298536", + "id" : "PA166298537", + "name" : "Recommendation PA166298537", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -84937,7 +85929,7 @@ "implications" : [ "CYP2C9: Significantly reduced metabolism and prolonged half-life; higher plasma concentrations may increase probability and/or severity of toxicities" ], - "lookupKey" : {"CYP2C9": "0.5"}, + "lookupKey" : {"CYP2C9": "0.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -84945,17 +85937,17 @@ "objCls" : "Chemical", "id" : "PA131890625", "name" : "tenoxicam", - "version" : 6 + "version" : 21 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166192341", "name" : "Annotation of CPIC Guideline for tenoxicam and CYP2C9", - "version" : 9 + "version" : 92 }, "text" : { - "id" : 1452061138, + "id" : 1452061139, "html" : "

Choose an alternative therapy not metabolized by CYP2C9 or not significantly impacted by CYP2C9 genetic variants in vivo or choose an NSAID metabolized by CYP2C9 but with a shorter half-life (see CPIC THERAPEUTIC RECOMMENDATIONS FOR CELECOXIB, FLURBIPROFEN, LORNOXICAM, AND IBUPROFEN BASED ON CYP2C9 PHENOTYPE).

\n

Other Considerations

\n

Alternative therapies not primarily metabolized by CYP2C9 include aspirin, ketorolac, naproxen and sulindac. Selection of therapy will depend on individual patient treatment goals and risks for toxicity.

\n", "version" : 0 }, @@ -84963,23 +85955,23 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298533", - "name" : "Recommendation PA166298533", + "id" : "PA166298532", + "name" : "Recommendation PA166298532", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2C9: Mildly reduced metabolism" + "CYP2C9: Normal metabolism" ], - "lookupKey" : {"CYP2C9": "1.5"}, + "lookupKey" : {"CYP2C9": "2.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -84987,41 +85979,41 @@ "objCls" : "Chemical", "id" : "PA131890625", "name" : "tenoxicam", - "version" : 6 + "version" : 21 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166192341", "name" : "Annotation of CPIC Guideline for tenoxicam and CYP2C9", - "version" : 9 + "version" : 92 }, "text" : { - "id" : 1452061135, - "html" : "

Initiate therapy with recommended starting dose. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals.

\n

Other Considerations

\n

IMs might have a higher than normal risk of adverse events especially in individuals with other factors affecting clearance of these drugs such as hepatic impairment or advanced age.

\n", + "id" : 1452061134, + "html" : "

Initiate therapy with recommended starting dose. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298537", - "name" : "Recommendation PA166298537", - "alternateDrugAvailable" : true, + "id" : "PA166298533", + "name" : "Recommendation PA166298533", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2C9: Significantly reduced metabolism and prolonged half-life; higher plasma concentrations may increase probability and/or severity of toxicities" + "CYP2C9: Mildly reduced metabolism" ], - "lookupKey" : {"CYP2C9": "0.0"}, + "lookupKey" : {"CYP2C9": "1.5"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -85029,41 +86021,41 @@ "objCls" : "Chemical", "id" : "PA131890625", "name" : "tenoxicam", - "version" : 6 + "version" : 21 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166192341", "name" : "Annotation of CPIC Guideline for tenoxicam and CYP2C9", - "version" : 9 + "version" : 92 }, "text" : { - "id" : 1452061139, - "html" : "

Choose an alternative therapy not metabolized by CYP2C9 or not significantly impacted by CYP2C9 genetic variants in vivo or choose an NSAID metabolized by CYP2C9 but with a shorter half-life (see CPIC THERAPEUTIC RECOMMENDATIONS FOR CELECOXIB, FLURBIPROFEN, LORNOXICAM, AND IBUPROFEN BASED ON CYP2C9 PHENOTYPE).

\n

Other Considerations

\n

Alternative therapies not primarily metabolized by CYP2C9 include aspirin, ketorolac, naproxen and sulindac. Selection of therapy will depend on individual patient treatment goals and risks for toxicity.

\n", + "id" : 1452061135, + "html" : "

Initiate therapy with recommended starting dose. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals.

\n

Other Considerations

\n

IMs might have a higher than normal risk of adverse events especially in individuals with other factors affecting clearance of these drugs such as hepatic impairment or advanced age.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298538", - "name" : "Recommendation PA166298538", - "alternateDrugAvailable" : false, + "id" : "PA166298535", + "name" : "Recommendation PA166298535", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2C9: n/a" + "CYP2C9: Moderately reduced metabolism; higher plasma concentrations may increase probability of toxicities" ], - "lookupKey" : {"CYP2C9": "n/a"}, + "lookupKey" : {"CYP2C9": "1.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -85071,41 +86063,41 @@ "objCls" : "Chemical", "id" : "PA131890625", "name" : "tenoxicam", - "version" : 6 + "version" : 21 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166192341", "name" : "Annotation of CPIC Guideline for tenoxicam and CYP2C9", - "version" : 9 + "version" : 92 }, "text" : { - "id" : 1452061140, - "html" : "

No recommendation

\n", + "id" : 1452061137, + "html" : "

Choose an alternative therapy not metabolized by CYP2C9 or not significantly impacted by CYP2C9 genetic variants in vivo or choose an NSAID metabolized by CYP2C9 but with a shorter half-life (see CPIC THERAPEUTIC RECOMMENDATIONS FOR CELECOXIB, FLURBIPROFEN, LORNOXICAM, AND IBUPROFEN BASED ON CYP2C9 PHENOTYPE).

\n

Other Considerations

\n

Alternative therapies not primarily metabolized by CYP2C9 include aspirin, ketorolac, naproxen and sulindac. Selection of therapy will depend on individual patient treatment goals and risks for toxicity.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298535", - "name" : "Recommendation PA166298535", - "alternateDrugAvailable" : true, + "id" : "PA166298538", + "name" : "Recommendation PA166298538", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2C9: Moderately reduced metabolism; higher plasma concentrations may increase probability of toxicities" + "CYP2C9: n/a" ], - "lookupKey" : {"CYP2C9": "1.0"}, + "lookupKey" : {"CYP2C9": "n/a"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -85113,21 +86105,21 @@ "objCls" : "Chemical", "id" : "PA131890625", "name" : "tenoxicam", - "version" : 6 + "version" : 21 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166192341", "name" : "Annotation of CPIC Guideline for tenoxicam and CYP2C9", - "version" : 9 + "version" : 92 }, "text" : { - "id" : 1452061137, - "html" : "

Choose an alternative therapy not metabolized by CYP2C9 or not significantly impacted by CYP2C9 genetic variants in vivo or choose an NSAID metabolized by CYP2C9 but with a shorter half-life (see CPIC THERAPEUTIC RECOMMENDATIONS FOR CELECOXIB, FLURBIPROFEN, LORNOXICAM, AND IBUPROFEN BASED ON CYP2C9 PHENOTYPE).

\n

Other Considerations

\n

Alternative therapies not primarily metabolized by CYP2C9 include aspirin, ketorolac, naproxen and sulindac. Selection of therapy will depend on individual patient treatment goals and risks for toxicity.

\n", + "id" : 1452061140, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166192341" @@ -85418,7 +86410,7 @@ "date" : "2024-03-21T00:00:00-07:00", "description" : "Updated recommendations for the following phenotypes: TPMT Intermediate Metabolizer/NUDT15 Intermediate Metabolizer, TPMT Intermediate Metabolizer/Possible NUDT15 Intermediate Metabolizer, Possible TPMT Intermediate Metabolizer/NUDT15 Intermediate Metabolizer, Possible TPMT Intermediate Metabolizer/Possible NUDT15 Intermediate Metabolizer", "type" : "Update", - "version" : 0 + "version" : 2 } ], "literature" : [ @@ -85435,7 +86427,7 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "relatedGenes" : [ @@ -85444,14 +86436,14 @@ "id" : "PA134963132", "symbol" : "NUDT15", "name" : "nudix hydrolase 15", - "version" : 11 + "version" : 39 }, { "objCls" : "Gene", "id" : "PA356", "symbol" : "TPMT", "name" : "thiopurine S-methyltransferase", - "version" : 7545 + "version" : 7628 } ], "source" : "CPIC", @@ -85464,17 +86456,17 @@ "textMarkdown" : { "id" : 1451433636, "html" : "

This annotation is based on the CPIC® guideline for thiopurines and TPMT and NUDT15.

\n

February 2024 Update

\n

CPIC have updated the recommendations for patients who are intermediate metabolizers of both TPMT and NUDT15. Patients who are intermediate metabolizers or possible intermediate metabolizers for both genes are recommended to begin with a starting dose of 20-50% of the normal dosage. The recommendations in the genotype picker tool and on this annotation page have been updated accordingly.

\n

October 2018 Update

\n

Advance online publication November 2018.

\n\n\n

Adapted from Tables 1 and 2 of the 2018 guideline update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
TPMT phenotypeGenotypesExamples of diplotypesImplicationsDosing recommendationsClassification of recommendations
Normal MetabolizerAn individual carrying two normal function alleles*1/*1Lower concentrations of TGN metabolites, but note that TGN after thioguanine are 5-10X higher than TGN after mercaptopurine or azathioprine. Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression.Start with normal starting dosea (e.g. 40-60 mg/m2/day) and adjust doses of thioguanine and of other myelosuppressive therapy without any special emphasis on thioguanine. Allow 2 weeks to reach steady-state after each dose adjustment.Strong
Intermediate MetabolizerAn individual carrying one normal function allele and one no function allele*1/*2, *1/*3A, *1/*3B, *1/*3C, *1/*4Moderate to high concentrations of TGN metabolites; but note that TGN after thioguanine are 5-10X higher than TGN after mercaptopurine or azathioprine. Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression.Start with reduced doses (50% to 80% of normal dose) if normal starting dosea is > or = 40-60 mg/m2/day (e.g. 20-48 mg/m2/day) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing thioguanine over other agents.Moderate
Possible Intermediate MetabolizerAn individual carrying one uncertain/unknown function allele and one no function allele*2/*8, *3A/*7Moderate to high concentrations of TGN metabolites; but note that TGN after thioguanine are 5-10X higher than TGN after mercaptopurine or azathioprine. Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression.Start with reduced doses (50% to 80% of normal dose) if normal starting dosea is > or = 40-60 mg/m2/day (e.g. 20-48 mg/m2/day) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing thioguanine over other agents.Moderate
Poor MetabolizerAn individual carrying two no function alleles*3A/*3A, *2/*3A, *3A/*3C, *3C/*4, *2/*3C, *3A/*4Extremely high concentrations of TGN metabolites; fatal toxicity possible without dose decrease. Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression.Start with drastically reduced doses (reduce daily dosea by 10-fold and dose thrice weekly instead of daily) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing thioguanine over other agents. For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy.Strong
IndeterminateAn individual carrying two uncertain/unknown function alleles OR one normal function allele and one uncertain/unknown function allele*6/*8, *1/*8NoneNoneNone
aNormal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.
\n\n

Adapted from Tables 1 and 2 of the 2018 guideline update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
NUDT15 phenotypeGenotypesExamples of diplotypesImplicationsDosing recommendationsClassification of recommendations
Normal MetabolizerAn individual carrying two normal function alleles*1/*1Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppressionStart with normal starting dosea (40-60 mg/day). Adjust doses of thioguanine and of other myelosuppressive therapy without any special emphasis on thioguanine. Allow 2 weeks to reach steady-state after each dose adjustment.Strong
Intermediate MetabolizerAn individual carrying one normal function allele and one no function allele*1/*2, *1/*3Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression.Start with reduced doses (50% to 80% of normal dose) if normal starting dosea is > or = 40-60 mg/m2/day) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing thioguanine over other agents.Moderate
Possible Intermediate MetabolizerAn individual carrying one uncertain function allele and one no function allele*2/*5, *3/*6Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression.Start with reduced doses (50% to 80% of normal dose) if normal starting dosea is > or = 40-60 mg/m2/day) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing thioguanine over other agents.Moderate
Poor MetabolizerAn individual carrying two no function alleles*2/*2, *2/*3, *3/*3Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppressionReduce doses to 25% of normal dosea and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment. In setting of myelosuppression, emphasis should be on reducing thioguanine over other agents. For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy.Strong
IndeterminateAn individual carrying two uncertain function alleles OR one normal function allele and one uncertain function allele*1/*4, *1/*5, *4/*5, *5/*6NoneNoneNone
aNormal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.
\n\n

Adapted from Figure 2 and Table 2 of the 2018 guideline update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
PhenotypeTPMT Normal MetabolizerTPMT Intermediate MetabolizerTPMT Possible Intermediate MetabolizerTPMT Poor MetabolizerIndeterminate
NUDT 15 Normal MetabolizerUse standard doseStart with reduced doses (50% to 80% of normal dose) if normal starting dosea is > or = 40-60 mg/m2/day (e.g. 20-48 mg/m2/day) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing thioguanine over other agents.See TPMT Intermediate Metabolizer.Start with drastically reduced doses (reduce daily dosea by 10-fold and dose thrice weekly instead of daily) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing thioguanine over other agents. For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy.None
NUDT15 Intermediate MetabolizerStart with reduced doses (50% to 80% of normal dose) if normal starting dosea is > or = 40-60 mg/m2/day) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing thioguanine over other agents.Start with reduced doses (20% to 50% of normal dose) if normal starting dose is ≥ 40-60 mg/m2/day (e.g., 8-30 mg/m2/day) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. At least 2-4 weeks will be required to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing thioguanine over other agents (PMID 20354201, 11037857).See TPMT Intermediate Metabolizer/NUDT15 Intermediate Metabolizer.Start with drastically reduced doses (reduce daily dosea by 10-fold and dose thrice weekly instead of daily) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing thioguanine over other agents. For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy.None
NUDT15 Possible Intermediate MetabolizerSee NUDT15 Intermediate Metabolizer.See TPMT Intermediate Metabolizer/NUDT15 Intermediate Metabolizer.See TPMT Intermediate Metabolizer/NUDT15 Intermediate Metabolizer.See NUDT15 Intermediate Metabolizer.None
NUDT15 Poor MetabolizerReduce doses to 25% of normal dosea and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment. In setting of myelosuppression, emphasis should be on reducing thioguanine over other agents. For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy.Reduce doses to 25% of normal dosea and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment. In setting of myelosuppression, emphasis should be on reducing thioguanine over other agents. For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy.See TPMT Intermediate Metabolizer.Start with drastically reduced doses (reduce daily dosea by 10-fold and dose thrice weekly instead of daily) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing thioguanine over other agents. For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy.None
NUDT15 IndeterminateNoneNoneNoneNoneNone
aNormal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.
\n

May 2016 Update on PharmGKB

\n

Several studies have reported that individuals who carry low-function alleles for NUDT15 are unable to tolerate usual doses of thiopurines. [Articles:25108385, 25624441, 26033531, 26076924, 26405151, 26503813, 26590936, 26735160, 26878724] These alleles are more common among those of Asian ancestry and Hispanic ethnicity than others. [Articles:25624441, 26878724] The dose tolerated by those with two low-function alleles is only ~ 10% that tolerated by those with no low-function NUDT15 or TPMT alleles. [Articles:25624441, 26878724] CPIC is planning a guideline to address NUDT15 variants and possible dosing recommendations for thiopurines.

\n

April 2013 Update

\n

Advance online publication January 2013.

\n\n

March 2011

\n

Advance online publication January 2011.

\n\n", - "version" : 3 + "version" : 5 }, "userId" : "rachel", - "version" : 46 + "version" : 248 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166298563", - "name" : "Recommendation PA166298563", - "alternateDrugAvailable" : false, + "id" : "PA166298542", + "name" : "Recommendation PA166298542", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, "parents" : [], @@ -85484,55 +86476,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, - "implications" : [ - "NUDT15: n/a", - "TPMT: Lower concentrations of TGN metabolites, but note that TGN after thioguanine are 5-10X higher than TGN after mercaptopurine or azathioprine. Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression." - ], - "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "Indeterminate"}, - "otherPrescribingGuidance" : true, - "population" : "general", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA451663", - "name" : "thioguanine", - "version" : 14 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166104965", - "name" : "Annotation of CPIC Guideline for thioguanine and NUDT15, TPMT", - "version" : 46 - }, - "text" : { - "id" : 1452061165, - "html" : "

Based on TPMT status, start with normal starting dose (e.g., 40-60 mg/m2/day) and adjust doses of thioguanine and of other myelosuppressive therapy without any special emphasis on thioguanine. Allow 2 weeks to reach steady-state after each dose adjustment (PMID 203542+J1301, 11037857). NUDT15 status could not be determined based on genotyping. If thiopurines are required and NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166298550", - "name" : "Recommendation PA166298550", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 981501931, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", - "valid" : true, - "version" : 0 - }, "dosingInformation" : true, "implications" : [ - "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "NUDT15: Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", "TPMT: n/a" ], - "lookupKey" : {"TPMT": "No Result", "NUDT15": "Possible Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -85540,42 +86489,42 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104965", "name" : "Annotation of CPIC Guideline for thioguanine and NUDT15, TPMT", - "version" : 46 + "version" : 248 }, "text" : { - "id" : 1452061152, - "html" : "

Based on NUDT15, start with reduced doses (50% to 80% of normal dose) if normal starting dose is ≥ 40-60 mg/m2/day (e.g., 20-48 mg/m2/day) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing thioguanine over other agents (PMID 20354201, 11037857). TPMT genotype is not available. Consider evaluating erythrocyte TPMT activity to assess TPMT phenotype. If thiopurines are required and either TPMT or NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers. Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", + "id" : 1452061144, + "html" : "

Based on NUDT15, reduce starting doses to 25% of normal dose and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment. In setting of myelosuppression, emphasis should be on reducing thioguanine over other agents. For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy (PMID 20354201). TPMT phenotype could not be assigned based on genotyping performed. Consider evaluating TPMT erythrocyte activity to assess TPMT phenotype. If thiopurines are required and TPMT status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers. Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298567", - "name" : "Recommendation PA166298567", - "alternateDrugAvailable" : false, + "id" : "PA166298549", + "name" : "Recommendation PA166298549", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501931, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", - "TPMT: Lower concentrations of TGN metabolites, but note that TGN after thioguanine are 5-10X higher than TGN after mercaptopurine or azathioprine. Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression." + "NUDT15: Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "TPMT: n/a" ], - "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "Possible Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "No Result", "NUDT15": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -85583,18 +86532,18 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104965", "name" : "Annotation of CPIC Guideline for thioguanine and NUDT15, TPMT", - "version" : 46 + "version" : 248 }, "text" : { - "id" : 1452061169, - "html" : "

Start with reduced doses (50% to 80% of normal dose) if normal starting dose is ≥ 40-60 mg/m2/day (e.g., 20-48 mg/m2/day) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing thioguanine over other agents (PMID 20354201, 11037857).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "id" : 1452061151, + "html" : "

Based on NUDT15, reduce starting doses to 25% of normal dose and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment. In setting of myelosuppression, emphasis should be on reducing thioguanine over other agents. For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy (PMID 20354201). TPMT genotype is not available. Consider evaluating TPMT erythrocyte activity to assess TPMT phenotype. If thiopurines are required and TPMT status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers. Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", "version" : 0 }, "version" : 0 @@ -85626,14 +86575,14 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104965", "name" : "Annotation of CPIC Guideline for thioguanine and NUDT15, TPMT", - "version" : 46 + "version" : 248 }, "text" : { "id" : 1452061156, @@ -85644,9 +86593,9 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298541", - "name" : "Recommendation PA166298541", - "alternateDrugAvailable" : false, + "id" : "PA166298560", + "name" : "Recommendation PA166298560", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, "parents" : [], @@ -85656,39 +86605,39 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "NUDT15: Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression", - "TPMT: n/a" + "NUDT15: Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "TPMT: Moderate to high concentrations of TGN metabolites; but note that TGN after thioguanine are 5-10X higher than TGN after mercaptopurine or azathioprine. Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression" ], - "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "Normal Metabolizer"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Poor Metabolizer"}, + "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104965", "name" : "Annotation of CPIC Guideline for thioguanine and NUDT15, TPMT", - "version" : 46 + "version" : 248 }, "text" : { - "id" : 1452061143, - "html" : "

Based on NUDT15, start with normal starting dose (e.g., 40-60 mg/m2/day) and adjust doses of thioguanine and of other myelosuppressive therapy without any special emphasis on thioguanine. Allow 2 weeks to reach steady-state after each dose adjustment (PMID 20354201, 11037857). However, TPMT phenotype could not be assigned based on genotyping performed. Consider evaluating TPMT erythrocyte activity to assess TPMT phenotype. If thiopurines are required and TPMT status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers. Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", + "id" : 1452061162, + "html" : "

Reduce starting doses to 25% of normal dose and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment. In setting of myelosuppression, emphasis should be on reducing thioguanine over other agents. For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy (PMID 20354201).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298549", - "name" : "Recommendation PA166298549", + "id" : "PA166298566", + "name" : "Recommendation PA166298566", "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, @@ -85702,9 +86651,9 @@ "dosingInformation" : true, "implications" : [ "NUDT15: Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", - "TPMT: n/a" + "TPMT: Lower concentrations of TGN metabolites, but note that TGN after thioguanine are 5-10X higher than TGN after mercaptopurine or azathioprine. Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression." ], - "lookupKey" : {"TPMT": "No Result", "NUDT15": "Poor Metabolizer"}, + "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -85712,42 +86661,42 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104965", "name" : "Annotation of CPIC Guideline for thioguanine and NUDT15, TPMT", - "version" : 46 + "version" : 248 }, "text" : { - "id" : 1452061151, - "html" : "

Based on NUDT15, reduce starting doses to 25% of normal dose and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment. In setting of myelosuppression, emphasis should be on reducing thioguanine over other agents. For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy (PMID 20354201). TPMT genotype is not available. Consider evaluating TPMT erythrocyte activity to assess TPMT phenotype. If thiopurines are required and TPMT status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers. Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", + "id" : 1452061168, + "html" : "

Reduce starting doses to 25% of normal dose and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment. In setting of myelosuppression, emphasis should be on reducing thioguanine over other agents. For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy (PMID 20354201).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298558", - "name" : "Recommendation PA166298558", - "alternateDrugAvailable" : false, + "id" : "PA166298570", + "name" : "Recommendation PA166298570", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501931, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", - "TPMT: Moderate to high concentrations of TGN metabolites; but note that TGN after thioguanine are 5-10X higher than TGN after mercaptopurine or azathioprine. Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression" + "NUDT15: n/a", + "TPMT: Extremely high concentrations of TGN metabolites; fatal toxicity possible without dose decrease. Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." ], - "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -85755,27 +86704,27 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104965", "name" : "Annotation of CPIC Guideline for thioguanine and NUDT15, TPMT", - "version" : 46 + "version" : 248 }, "text" : { - "id" : 1452061160, - "html" : "

Start with reduced doses (20% to 50% of normal dose) if normal starting dose is ≥ 40-60 mg/m2/day (e.g., 8-30 mg/m2/day) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. At least 2-4 weeks will be required to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing thioguanine over other agents (PMID 20354201, 11037857).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", - "version" : 1 + "id" : 1452061172, + "html" : "

Based on TPMT status, start with drastically reduced doses (PMID 11037857) (reduce daily dose by 10-fold and dose thrice weekly instead of daily) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing thioguanine over other agents. For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy (PMID 20354201). NUDT15 status could not be determined based on genotyping. If thiopurines are required and NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "version" : 0 }, - "version" : 1 + "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298545", - "name" : "Recommendation PA166298545", - "alternateDrugAvailable" : false, + "id" : "PA166298571", + "name" : "Recommendation PA166298571", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, "parents" : [], @@ -85785,39 +86734,39 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "NUDT15: n/a", - "TPMT: n/a" + "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "TPMT: Extremely high concentrations of TGN metabolites; fatal toxicity possible without dose decrease. Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." ], - "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "No Result"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Intermediate Metabolizer"}, + "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104965", "name" : "Annotation of CPIC Guideline for thioguanine and NUDT15, TPMT", - "version" : 46 + "version" : 248 }, "text" : { - "id" : 1452061147, - "html" : "

TPMT phenotype could not be assigned based on genotyping performed and NUDT15 genotype is not available. Consider evaluating TPMT erythrocyte activity to assess TPMT phenotype. If thiopurines are required and either TPMT or NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", + "id" : 1452061173, + "html" : "

Start with drastically reduced doses (PMID 11037857) (reduce daily dose by 10-fold and dose thrice weekly instead of daily) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing thioguanine over other agents. For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy (PMID 20354201).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298571", - "name" : "Recommendation PA166298571", + "id" : "PA166298572", + "name" : "Recommendation PA166298572", "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, @@ -85830,10 +86779,10 @@ }, "dosingInformation" : true, "implications" : [ - "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "NUDT15: Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression", "TPMT: Extremely high concentrations of TGN metabolites; fatal toxicity possible without dose decrease. Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." ], - "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -85841,17 +86790,17 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104965", "name" : "Annotation of CPIC Guideline for thioguanine and NUDT15, TPMT", - "version" : 46 + "version" : 248 }, "text" : { - "id" : 1452061173, + "id" : 1452061174, "html" : "

Start with drastically reduced doses (PMID 11037857) (reduce daily dose by 10-fold and dose thrice weekly instead of daily) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing thioguanine over other agents. For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy (PMID 20354201).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", "version" : 0 }, @@ -85859,24 +86808,24 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298564", - "name" : "Recommendation PA166298564", - "alternateDrugAvailable" : false, + "id" : "PA166298573", + "name" : "Recommendation PA166298573", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501931, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", - "TPMT: Lower concentrations of TGN metabolites, but note that TGN after thioguanine are 5-10X higher than TGN after mercaptopurine or azathioprine. Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression." + "NUDT15: Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "TPMT: Extremely high concentrations of TGN metabolites; fatal toxicity possible without dose decrease. Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." ], - "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -85884,42 +86833,42 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104965", "name" : "Annotation of CPIC Guideline for thioguanine and NUDT15, TPMT", - "version" : 46 + "version" : 248 }, "text" : { - "id" : 1452061166, - "html" : "

Start with reduced doses (50% to 80% of normal dose) if normal starting dose is ≥ 40-60 mg/m2/day (e.g., 20-48 mg/m2/day) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing thioguanine over other agents (PMID 20354201, 11037857).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "id" : 1452061175, + "html" : "

Start with drastically reduced doses (PMID 11037857) (reduce daily dose by 10-fold and dose thrice weekly instead of daily) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing thioguanine over other agents. For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy (PMID 20354201).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298551", - "name" : "Recommendation PA166298551", - "alternateDrugAvailable" : false, + "id" : "PA166298574", + "name" : "Recommendation PA166298574", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501931, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "NUDT15: n/a", - "TPMT: Moderate to high concentrations of TGN metabolites; but note that TGN after thioguanine are 5-10X higher than TGN after mercaptopurine or azathioprine. Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression" + "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "TPMT: Extremely high concentrations of TGN metabolites; fatal toxicity possible without dose decrease. Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." ], - "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Indeterminate"}, + "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Possible Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -85927,26 +86876,26 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104965", "name" : "Annotation of CPIC Guideline for thioguanine and NUDT15, TPMT", - "version" : 46 + "version" : 248 }, "text" : { - "id" : 1452061153, - "html" : "

Based on TPMT status, start with reduced doses (50% to 80% of normal dose) if normal starting dose is ≥ 40-60 mg/m2/day (e.g., 20-48 mg/m2/day) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing thioguanine over other agents (PMID 20354201, 11037857). NUDT15 phenotype could not be assigned based on genotyping. If thiopurines are required and either TPMT or NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "id" : 1452061176, + "html" : "

Start with drastically reduced doses (PMID 11037857) (reduce daily dose by 10-fold and dose thrice weekly instead of daily) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing thioguanine over other agents. For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy (PMID 20354201).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298573", - "name" : "Recommendation PA166298573", + "id" : "PA166298575", + "name" : "Recommendation PA166298575", "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, @@ -85959,10 +86908,10 @@ }, "dosingInformation" : true, "implications" : [ - "NUDT15: Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "NUDT15: n/a", "TPMT: Extremely high concentrations of TGN metabolites; fatal toxicity possible without dose decrease. Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." ], - "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Poor Metabolizer"}, + "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -85970,26 +86919,26 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104965", "name" : "Annotation of CPIC Guideline for thioguanine and NUDT15, TPMT", - "version" : 46 + "version" : 248 }, "text" : { - "id" : 1452061175, - "html" : "

Start with drastically reduced doses (PMID 11037857) (reduce daily dose by 10-fold and dose thrice weekly instead of daily) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing thioguanine over other agents. For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy (PMID 20354201).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "id" : 1452061177, + "html" : "

Based on TPMT status, start with drastically reduced doses (PMID 11037857) (reduce daily dose by 10-fold and dose thrice weekly instead of daily) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing thioguanine over other agents. For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy (PMID 20354201). NUDT15 genotype is not available. If thiopurines are required and NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298568", - "name" : "Recommendation PA166298568", + "id" : "PA166298541", + "name" : "Recommendation PA166298541", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -86002,10 +86951,10 @@ }, "dosingInformation" : false, "implications" : [ - "NUDT15: n/a", - "TPMT: Lower concentrations of TGN metabolites, but note that TGN after thioguanine are 5-10X higher than TGN after mercaptopurine or azathioprine. Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression." + "NUDT15: Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "TPMT: n/a" ], - "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "No Result"}, + "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "Normal Metabolizer"}, "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ @@ -86013,26 +86962,26 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104965", "name" : "Annotation of CPIC Guideline for thioguanine and NUDT15, TPMT", - "version" : 46 + "version" : 248 }, "text" : { - "id" : 1452061170, - "html" : "

Based on TPMT status, start with normal starting dose (e.g., 40-60 mg/m2/day) and adjust doses of thioguanine and of other myelosuppressive therapy without any special emphasis on thioguanine. Allow 2 weeks to reach steady-state after each dose adjustment (PMID 203542+J1301, 11037857). NUDT15 genotype is not available. If thiopurines are required and NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "id" : 1452061143, + "html" : "

Based on NUDT15, start with normal starting dose (e.g., 40-60 mg/m2/day) and adjust doses of thioguanine and of other myelosuppressive therapy without any special emphasis on thioguanine. Allow 2 weeks to reach steady-state after each dose adjustment (PMID 20354201, 11037857). However, TPMT phenotype could not be assigned based on genotyping performed. Consider evaluating TPMT erythrocyte activity to assess TPMT phenotype. If thiopurines are required and TPMT status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers. Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298555", - "name" : "Recommendation PA166298555", + "id" : "PA166298544", + "name" : "Recommendation PA166298544", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -86046,9 +86995,9 @@ "dosingInformation" : true, "implications" : [ "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", - "TPMT: Moderate to high concentrations of TGN metabolites; but note that TGN after thioguanine are 5-10X higher than TGN after mercaptopurine or azathioprine. Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression" + "TPMT: n/a" ], - "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Possible Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "Possible Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -86056,27 +87005,27 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104965", "name" : "Annotation of CPIC Guideline for thioguanine and NUDT15, TPMT", - "version" : 46 + "version" : 248 }, "text" : { - "id" : 1452061157, - "html" : "

Start with reduced doses (20% to 50% of normal dose) if normal starting dose is ≥ 40-60 mg/m2/day (e.g., 8-30 mg/m2/day) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. At least 2-4 weeks will be required to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing thioguanine over other agents (PMID 20354201, 11037857).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", - "version" : 1 + "id" : 1452061146, + "html" : "

Based on NUDT15, start with reduced doses (50% to 80% of normal dose) if normal starting dose is ≥ 40-60 mg/m2/day (e.g., 20-48 mg/m2/day) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing thioguanine over other agents (PMID 20354201, 11037857). TPMT phenotype could not be assigned based on genotyping performed. Consider evaluating erythrocyte TPMT activity to assess TPMT phenotype. If thiopurines are required and either TPMT or NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers. Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", + "version" : 0 }, "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298542", - "name" : "Recommendation PA166298542", - "alternateDrugAvailable" : true, + "id" : "PA166298545", + "name" : "Recommendation PA166298545", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, "parents" : [], @@ -86086,126 +87035,126 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "NUDT15: Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "NUDT15: n/a", "TPMT: n/a" ], - "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "Poor Metabolizer"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "No Result"}, + "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104965", "name" : "Annotation of CPIC Guideline for thioguanine and NUDT15, TPMT", - "version" : 46 + "version" : 248 }, "text" : { - "id" : 1452061144, - "html" : "

Based on NUDT15, reduce starting doses to 25% of normal dose and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment. In setting of myelosuppression, emphasis should be on reducing thioguanine over other agents. For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy (PMID 20354201). TPMT phenotype could not be assigned based on genotyping performed. Consider evaluating TPMT erythrocyte activity to assess TPMT phenotype. If thiopurines are required and TPMT status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers. Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", + "id" : 1452061147, + "html" : "

TPMT phenotype could not be assigned based on genotyping performed and NUDT15 genotype is not available. Consider evaluating TPMT erythrocyte activity to assess TPMT phenotype. If thiopurines are required and either TPMT or NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298559", - "name" : "Recommendation PA166298559", + "id" : "PA166298546", + "name" : "Recommendation PA166298546", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "NUDT15: Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression", - "TPMT: Moderate to high concentrations of TGN metabolites; but note that TGN after thioguanine are 5-10X higher than TGN after mercaptopurine or azathioprine. Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression" + "NUDT15: n/a", + "TPMT: n/a" ], - "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Normal Metabolizer"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"TPMT": "No Result", "NUDT15": "Indeterminate"}, + "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104965", "name" : "Annotation of CPIC Guideline for thioguanine and NUDT15, TPMT", - "version" : 46 + "version" : 248 }, "text" : { - "id" : 1452061161, - "html" : "

Start with reduced doses (50% to 80% of normal dose) if normal starting dose is ≥ 40-60 mg/m2/day (e.g., 20-48 mg/m2/day) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing thioguanine over other agents (PMID 20354201, 11037857).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "id" : 1452061148, + "html" : "

NUDT15 phenotype could not be assigned based on genotyping performed and there is no TPMT genotype available. Consider evaluating TPMT erythrocyte activity to assess TPMT phenotype. If thiopurines are required and either TPMT or NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298546", - "name" : "Recommendation PA166298546", + "id" : "PA166298547", + "name" : "Recommendation PA166298547", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "NUDT15: n/a", + "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", "TPMT: n/a" ], - "lookupKey" : {"TPMT": "No Result", "NUDT15": "Indeterminate"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"TPMT": "No Result", "NUDT15": "Intermediate Metabolizer"}, + "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104965", "name" : "Annotation of CPIC Guideline for thioguanine and NUDT15, TPMT", - "version" : 46 + "version" : 248 }, "text" : { - "id" : 1452061148, - "html" : "

NUDT15 phenotype could not be assigned based on genotyping performed and there is no TPMT genotype available. Consider evaluating TPMT erythrocyte activity to assess TPMT phenotype. If thiopurines are required and either TPMT or NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", + "id" : 1452061149, + "html" : "

Based on NUDT15, start with reduced doses (50% to 80% of normal dose) if normal starting dose is ≥ 40-60 mg/m2/day (e.g., 20-48 mg/m2/day) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing thioguanine over other agents (PMID 20354201, 11037857). TPMT genotype is not available. Consider evaluating erythrocyte TPMT activity to assess TPMT phenotype. If thiopurines are required and TPMT status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers. Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298572", - "name" : "Recommendation PA166298572", - "alternateDrugAvailable" : true, + "id" : "PA166298548", + "name" : "Recommendation PA166298548", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, "parents" : [], @@ -86215,39 +87164,39 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ "NUDT15: Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression", - "TPMT: Extremely high concentrations of TGN metabolites; fatal toxicity possible without dose decrease. Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." + "TPMT: n/a" ], - "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Normal Metabolizer"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"TPMT": "No Result", "NUDT15": "Normal Metabolizer"}, + "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104965", "name" : "Annotation of CPIC Guideline for thioguanine and NUDT15, TPMT", - "version" : 46 + "version" : 248 }, "text" : { - "id" : 1452061174, - "html" : "

Start with drastically reduced doses (PMID 11037857) (reduce daily dose by 10-fold and dose thrice weekly instead of daily) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing thioguanine over other agents. For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy (PMID 20354201).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "id" : 1452061150, + "html" : "

Based on NUDT15, start with normal starting dose (e.g., 40-60 mg/m2/day) and adjust doses of thioguanine and of other myelosuppressive therapy without any special emphasis on thioguanine. Allow 2 weeks to reach steady-state after each dose adjustment (PMID 20354201, 11037857). However, TPMT genotype is not available. Consider evaluating TPMT erythrocyte activity to assess TPMT phenotype. If thiopurines are required and TPMT status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers. Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298552", - "name" : "Recommendation PA166298552", + "id" : "PA166298550", + "name" : "Recommendation PA166298550", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -86261,9 +87210,9 @@ "dosingInformation" : true, "implications" : [ "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", - "TPMT: Moderate to high concentrations of TGN metabolites; but note that TGN after thioguanine are 5-10X higher than TGN after mercaptopurine or azathioprine. Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression" + "TPMT: n/a" ], - "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "No Result", "NUDT15": "Possible Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -86271,42 +87220,42 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104965", "name" : "Annotation of CPIC Guideline for thioguanine and NUDT15, TPMT", - "version" : 46 + "version" : 248 }, "text" : { - "id" : 1452061154, - "html" : "

Start with reduced doses (20% to 50% of normal dose) if normal starting dose is ≥ 40-60 mg/m2/day (e.g., 8-30 mg/m2/day) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. At least 2-4 weeks will be required to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing thioguanine over other agents (PMID 20354201, 11037857).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", - "version" : 1 + "id" : 1452061152, + "html" : "

Based on NUDT15, start with reduced doses (50% to 80% of normal dose) if normal starting dose is ≥ 40-60 mg/m2/day (e.g., 20-48 mg/m2/day) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing thioguanine over other agents (PMID 20354201, 11037857). TPMT genotype is not available. Consider evaluating erythrocyte TPMT activity to assess TPMT phenotype. If thiopurines are required and either TPMT or NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers. Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", + "version" : 0 }, "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298574", - "name" : "Recommendation PA166298574", - "alternateDrugAvailable" : true, + "id" : "PA166298551", + "name" : "Recommendation PA166298551", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", - "TPMT: Extremely high concentrations of TGN metabolites; fatal toxicity possible without dose decrease. Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." + "NUDT15: n/a", + "TPMT: Moderate to high concentrations of TGN metabolites; but note that TGN after thioguanine are 5-10X higher than TGN after mercaptopurine or azathioprine. Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression" ], - "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Possible Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -86314,26 +87263,26 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104965", "name" : "Annotation of CPIC Guideline for thioguanine and NUDT15, TPMT", - "version" : 46 + "version" : 248 }, "text" : { - "id" : 1452061176, - "html" : "

Start with drastically reduced doses (PMID 11037857) (reduce daily dose by 10-fold and dose thrice weekly instead of daily) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing thioguanine over other agents. For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy (PMID 20354201).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "id" : 1452061153, + "html" : "

Based on TPMT status, start with reduced doses (50% to 80% of normal dose) if normal starting dose is ≥ 40-60 mg/m2/day (e.g., 20-48 mg/m2/day) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing thioguanine over other agents (PMID 20354201, 11037857). NUDT15 phenotype could not be assigned based on genotyping. If thiopurines are required and either TPMT or NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298561", - "name" : "Recommendation PA166298561", + "id" : "PA166298553", + "name" : "Recommendation PA166298553", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -86346,10 +87295,10 @@ }, "dosingInformation" : true, "implications" : [ - "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "NUDT15: Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression", "TPMT: Moderate to high concentrations of TGN metabolites; but note that TGN after thioguanine are 5-10X higher than TGN after mercaptopurine or azathioprine. Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression" ], - "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Possible Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -86357,19 +87306,19 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104965", "name" : "Annotation of CPIC Guideline for thioguanine and NUDT15, TPMT", - "version" : 46 + "version" : 248 }, "text" : { - "id" : 1452061163, - "html" : "

Start with reduced doses (20% to 50% of normal dose) if normal starting dose is ≥ 40-60 mg/m2/day (e.g., 8-30 mg/m2/day) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. At least 2-4 weeks will be required to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing thioguanine over other agents (PMID 20354201, 11037857).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", - "version" : 1 + "id" : 1452061155, + "html" : "

Start with reduced doses (50% to 80% of normal dose) if normal starting dose is ≥ 40-60 mg/m2/day (e.g., 20-48 mg/m2/day) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing thioguanine over other agents (PMID 20354201, 11037857).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "version" : 0 }, "version" : 1 }, @@ -86400,42 +87349,42 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104965", "name" : "Annotation of CPIC Guideline for thioguanine and NUDT15, TPMT", - "version" : 46 + "version" : 248 }, "text" : { "id" : 1452061158, "html" : "

Based on TPMT status, start with reduced doses (50% to 80% of normal dose) if normal starting dose is ≥ 40-60 mg/m2/day (e.g., 20-48 mg/m2/day) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing thioguanine over other agents (PMID 20354201, 11037857). NUDT15 genotype is not available. If thiopurines are required and either TPMT or NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298565", - "name" : "Recommendation PA166298565", + "id" : "PA166298557", + "name" : "Recommendation PA166298557", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "NUDT15: Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression", - "TPMT: Lower concentrations of TGN metabolites, but note that TGN after thioguanine are 5-10X higher than TGN after mercaptopurine or azathioprine. Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression." + "NUDT15: n/a", + "TPMT: Moderate to high concentrations of TGN metabolites; but note that TGN after thioguanine are 5-10X higher than TGN after mercaptopurine or azathioprine. Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression" ], - "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "Normal Metabolizer"}, + "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -86443,26 +87392,26 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104965", "name" : "Annotation of CPIC Guideline for thioguanine and NUDT15, TPMT", - "version" : 46 + "version" : 248 }, "text" : { - "id" : 1452061167, - "html" : "

Start with normal starting dose (e.g., 40-60 mg/m2/day) and adjust doses of thioguanine and of other myelosuppressive therapy without any special emphasis on thioguanine. Allow 2 weeks to reach steady-state after each dose adjustment (PMID 20354201, 11037857).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "id" : 1452061159, + "html" : "

Based on TPMT status, start with reduced doses (50% to 80% of normal dose) if normal starting dose is ≥ 40-60 mg/m2/day (e.g., 20-48 mg/m2/day) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing thioguanine over other agents (PMID 20354201, 11037857). NUDT15 phenotype could not be assigned based on genotyping. If thiopurines are required and NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298547", - "name" : "Recommendation PA166298547", + "id" : "PA166298559", + "name" : "Recommendation PA166298559", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -86475,10 +87424,10 @@ }, "dosingInformation" : true, "implications" : [ - "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", - "TPMT: n/a" + "NUDT15: Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "TPMT: Moderate to high concentrations of TGN metabolites; but note that TGN after thioguanine are 5-10X higher than TGN after mercaptopurine or azathioprine. Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression" ], - "lookupKey" : {"TPMT": "No Result", "NUDT15": "Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -86486,42 +87435,42 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104965", "name" : "Annotation of CPIC Guideline for thioguanine and NUDT15, TPMT", - "version" : 46 + "version" : 248 }, "text" : { - "id" : 1452061149, - "html" : "

Based on NUDT15, start with reduced doses (50% to 80% of normal dose) if normal starting dose is ≥ 40-60 mg/m2/day (e.g., 20-48 mg/m2/day) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing thioguanine over other agents (PMID 20354201, 11037857). TPMT genotype is not available. Consider evaluating erythrocyte TPMT activity to assess TPMT phenotype. If thiopurines are required and TPMT status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers. Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", + "id" : 1452061161, + "html" : "

Start with reduced doses (50% to 80% of normal dose) if normal starting dose is ≥ 40-60 mg/m2/day (e.g., 20-48 mg/m2/day) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing thioguanine over other agents (PMID 20354201, 11037857).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298560", - "name" : "Recommendation PA166298560", - "alternateDrugAvailable" : true, + "id" : "PA166298562", + "name" : "Recommendation PA166298562", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "NUDT15: Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "NUDT15: n/a", "TPMT: Moderate to high concentrations of TGN metabolites; but note that TGN after thioguanine are 5-10X higher than TGN after mercaptopurine or azathioprine. Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression" ], - "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Poor Metabolizer"}, + "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -86529,85 +87478,85 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104965", "name" : "Annotation of CPIC Guideline for thioguanine and NUDT15, TPMT", - "version" : 46 + "version" : 248 }, "text" : { - "id" : 1452061162, - "html" : "

Reduce starting doses to 25% of normal dose and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment. In setting of myelosuppression, emphasis should be on reducing thioguanine over other agents. For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy (PMID 20354201).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "id" : 1452061164, + "html" : "

Based on TPMT status, start with reduced doses (50% to 80% of normal dose) if normal starting dose is ≥ 40-60 mg/m2/day (e.g., 20-48 mg/m2/day) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing thioguanine over other agents (PMID 20354201, 11037857). NUDT15 genotype is not available. If thiopurines are required and NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298540", - "name" : "Recommendation PA166298540", + "id" : "PA166298563", + "name" : "Recommendation PA166298563", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", - "TPMT: n/a" + "NUDT15: n/a", + "TPMT: Lower concentrations of TGN metabolites, but note that TGN after thioguanine are 5-10X higher than TGN after mercaptopurine or azathioprine. Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression." ], - "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "Intermediate Metabolizer"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "Indeterminate"}, + "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104965", "name" : "Annotation of CPIC Guideline for thioguanine and NUDT15, TPMT", - "version" : 46 + "version" : 248 }, "text" : { - "id" : 1452061142, - "html" : "

Based on NUDT15, start with reduced doses (50% to 80% of normal dose) if normal starting dose is ≥ 40-60 mg/m2/day (e.g., 20-48 mg/m2/day) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing thioguanine over other agents (PMID 20354201, 11037857). TPMT phenotype could not be assigned based on genotyping performed. Consider evaluating erythrocyte TPMT activity to assess TPMT phenotype. If thiopurines are required and TPMT status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers. Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", + "id" : 1452061165, + "html" : "

Based on TPMT status, start with normal starting dose (e.g., 40-60 mg/m2/day) and adjust doses of thioguanine and of other myelosuppressive therapy without any special emphasis on thioguanine. Allow 2 weeks to reach steady-state after each dose adjustment (PMID 203542+J1301, 11037857). NUDT15 status could not be determined based on genotyping. If thiopurines are required and NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298575", - "name" : "Recommendation PA166298575", - "alternateDrugAvailable" : true, + "id" : "PA166298564", + "name" : "Recommendation PA166298564", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "NUDT15: n/a", - "TPMT: Extremely high concentrations of TGN metabolites; fatal toxicity possible without dose decrease. Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." + "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "TPMT: Lower concentrations of TGN metabolites, but note that TGN after thioguanine are 5-10X higher than TGN after mercaptopurine or azathioprine. Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression." ], - "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "No Result"}, + "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -86615,42 +87564,42 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104965", "name" : "Annotation of CPIC Guideline for thioguanine and NUDT15, TPMT", - "version" : 46 + "version" : 248 }, "text" : { - "id" : 1452061177, - "html" : "

Based on TPMT status, start with drastically reduced doses (PMID 11037857) (reduce daily dose by 10-fold and dose thrice weekly instead of daily) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing thioguanine over other agents. For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy (PMID 20354201). NUDT15 genotype is not available. If thiopurines are required and NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "id" : 1452061166, + "html" : "

Start with reduced doses (50% to 80% of normal dose) if normal starting dose is ≥ 40-60 mg/m2/day (e.g., 20-48 mg/m2/day) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing thioguanine over other agents (PMID 20354201, 11037857).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298562", - "name" : "Recommendation PA166298562", + "id" : "PA166298565", + "name" : "Recommendation PA166298565", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "NUDT15: n/a", - "TPMT: Moderate to high concentrations of TGN metabolites; but note that TGN after thioguanine are 5-10X higher than TGN after mercaptopurine or azathioprine. Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression" + "NUDT15: Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "TPMT: Lower concentrations of TGN metabolites, but note that TGN after thioguanine are 5-10X higher than TGN after mercaptopurine or azathioprine. Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression." ], - "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "No Result"}, + "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -86658,26 +87607,26 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104965", "name" : "Annotation of CPIC Guideline for thioguanine and NUDT15, TPMT", - "version" : 46 + "version" : 248 }, "text" : { - "id" : 1452061164, - "html" : "

Based on TPMT status, start with reduced doses (50% to 80% of normal dose) if normal starting dose is ≥ 40-60 mg/m2/day (e.g., 20-48 mg/m2/day) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing thioguanine over other agents (PMID 20354201, 11037857). NUDT15 genotype is not available. If thiopurines are required and NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "id" : 1452061167, + "html" : "

Start with normal starting dose (e.g., 40-60 mg/m2/day) and adjust doses of thioguanine and of other myelosuppressive therapy without any special emphasis on thioguanine. Allow 2 weeks to reach steady-state after each dose adjustment (PMID 20354201, 11037857).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298544", - "name" : "Recommendation PA166298544", + "id" : "PA166298567", + "name" : "Recommendation PA166298567", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -86691,9 +87640,9 @@ "dosingInformation" : true, "implications" : [ "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", - "TPMT: n/a" + "TPMT: Lower concentrations of TGN metabolites, but note that TGN after thioguanine are 5-10X higher than TGN after mercaptopurine or azathioprine. Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression." ], - "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "Possible Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "Possible Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -86701,27 +87650,27 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104965", "name" : "Annotation of CPIC Guideline for thioguanine and NUDT15, TPMT", - "version" : 46 + "version" : 248 }, "text" : { - "id" : 1452061146, - "html" : "

Based on NUDT15, start with reduced doses (50% to 80% of normal dose) if normal starting dose is ≥ 40-60 mg/m2/day (e.g., 20-48 mg/m2/day) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing thioguanine over other agents (PMID 20354201, 11037857). TPMT phenotype could not be assigned based on genotyping performed. Consider evaluating erythrocyte TPMT activity to assess TPMT phenotype. If thiopurines are required and either TPMT or NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers. Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", + "id" : 1452061169, + "html" : "

Start with reduced doses (50% to 80% of normal dose) if normal starting dose is ≥ 40-60 mg/m2/day (e.g., 20-48 mg/m2/day) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing thioguanine over other agents (PMID 20354201, 11037857).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298566", - "name" : "Recommendation PA166298566", - "alternateDrugAvailable" : true, + "id" : "PA166298568", + "name" : "Recommendation PA166298568", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, "parents" : [], @@ -86731,39 +87680,39 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "NUDT15: Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "NUDT15: n/a", "TPMT: Lower concentrations of TGN metabolites, but note that TGN after thioguanine are 5-10X higher than TGN after mercaptopurine or azathioprine. Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression." ], - "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "Poor Metabolizer"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "No Result"}, + "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104965", "name" : "Annotation of CPIC Guideline for thioguanine and NUDT15, TPMT", - "version" : 46 + "version" : 248 }, "text" : { - "id" : 1452061168, - "html" : "

Reduce starting doses to 25% of normal dose and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment. In setting of myelosuppression, emphasis should be on reducing thioguanine over other agents. For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy (PMID 20354201).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "id" : 1452061170, + "html" : "

Based on TPMT status, start with normal starting dose (e.g., 40-60 mg/m2/day) and adjust doses of thioguanine and of other myelosuppressive therapy without any special emphasis on thioguanine. Allow 2 weeks to reach steady-state after each dose adjustment (PMID 203542+J1301, 11037857). NUDT15 genotype is not available. If thiopurines are required and NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298553", - "name" : "Recommendation PA166298553", + "id" : "PA166298552", + "name" : "Recommendation PA166298552", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -86776,10 +87725,10 @@ }, "dosingInformation" : true, "implications" : [ - "NUDT15: Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", "TPMT: Moderate to high concentrations of TGN metabolites; but note that TGN after thioguanine are 5-10X higher than TGN after mercaptopurine or azathioprine. Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression" ], - "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Normal Metabolizer"}, + "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -86787,112 +87736,112 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104965", "name" : "Annotation of CPIC Guideline for thioguanine and NUDT15, TPMT", - "version" : 46 + "version" : 248 }, "text" : { - "id" : 1452061155, - "html" : "

Start with reduced doses (50% to 80% of normal dose) if normal starting dose is ≥ 40-60 mg/m2/day (e.g., 20-48 mg/m2/day) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing thioguanine over other agents (PMID 20354201, 11037857).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", - "version" : 0 + "id" : 1452061154, + "html" : "

Start with reduced doses (20% to 50% of normal dose) if normal starting dose is ≥ 40-60 mg/m2/day (e.g., 8-30 mg/m2/day) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. At least 2-4 weeks will be required to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing thioguanine over other agents (PMID 20354201, 11037857).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298548", - "name" : "Recommendation PA166298548", + "id" : "PA166298558", + "name" : "Recommendation PA166298558", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "NUDT15: Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression", - "TPMT: n/a" + "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "TPMT: Moderate to high concentrations of TGN metabolites; but note that TGN after thioguanine are 5-10X higher than TGN after mercaptopurine or azathioprine. Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression" ], - "lookupKey" : {"TPMT": "No Result", "NUDT15": "Normal Metabolizer"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Intermediate Metabolizer"}, + "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104965", "name" : "Annotation of CPIC Guideline for thioguanine and NUDT15, TPMT", - "version" : 46 + "version" : 248 }, "text" : { - "id" : 1452061150, - "html" : "

Based on NUDT15, start with normal starting dose (e.g., 40-60 mg/m2/day) and adjust doses of thioguanine and of other myelosuppressive therapy without any special emphasis on thioguanine. Allow 2 weeks to reach steady-state after each dose adjustment (PMID 20354201, 11037857). However, TPMT genotype is not available. Consider evaluating TPMT erythrocyte activity to assess TPMT phenotype. If thiopurines are required and TPMT status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers. Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", - "version" : 0 + "id" : 1452061160, + "html" : "

Start with reduced doses (20% to 50% of normal dose) if normal starting dose is ≥ 40-60 mg/m2/day (e.g., 8-30 mg/m2/day) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. At least 2-4 weeks will be required to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing thioguanine over other agents (PMID 20354201, 11037857).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298539", - "name" : "Recommendation PA166298539", + "id" : "PA166298561", + "name" : "Recommendation PA166298561", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "NUDT15: n/a", - "TPMT: n/a" + "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "TPMT: Moderate to high concentrations of TGN metabolites; but note that TGN after thioguanine are 5-10X higher than TGN after mercaptopurine or azathioprine. Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression" ], - "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "Indeterminate"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Possible Intermediate Metabolizer"}, + "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104965", "name" : "Annotation of CPIC Guideline for thioguanine and NUDT15, TPMT", - "version" : 46 + "version" : 248 }, "text" : { - "id" : 1452061141, - "html" : "

Neither TPMT or NUDT15 phenotype could be assigned based on genotyping performed. Consider evaluating TPMT erythrocyte activity to assess TPMT phenotype. If thiopurines are required and either TPMT or NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", - "version" : 0 + "id" : 1452061163, + "html" : "

Start with reduced doses (20% to 50% of normal dose) if normal starting dose is ≥ 40-60 mg/m2/day (e.g., 8-30 mg/m2/day) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. At least 2-4 weeks will be required to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing thioguanine over other agents (PMID 20354201, 11037857).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298557", - "name" : "Recommendation PA166298557", + "id" : "PA166298540", + "name" : "Recommendation PA166298540", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -86905,10 +87854,10 @@ }, "dosingInformation" : true, "implications" : [ - "NUDT15: n/a", - "TPMT: Moderate to high concentrations of TGN metabolites; but note that TGN after thioguanine are 5-10X higher than TGN after mercaptopurine or azathioprine. Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression" + "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "TPMT: n/a" ], - "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Indeterminate"}, + "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -86916,27 +87865,27 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104965", "name" : "Annotation of CPIC Guideline for thioguanine and NUDT15, TPMT", - "version" : 46 + "version" : 248 }, "text" : { - "id" : 1452061159, - "html" : "

Based on TPMT status, start with reduced doses (50% to 80% of normal dose) if normal starting dose is ≥ 40-60 mg/m2/day (e.g., 20-48 mg/m2/day) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing thioguanine over other agents (PMID 20354201, 11037857). NUDT15 phenotype could not be assigned based on genotyping. If thiopurines are required and NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "id" : 1452061142, + "html" : "

Based on NUDT15, start with reduced doses (50% to 80% of normal dose) if normal starting dose is ≥ 40-60 mg/m2/day (e.g., 20-48 mg/m2/day) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing thioguanine over other agents (PMID 20354201, 11037857). TPMT phenotype could not be assigned based on genotyping performed. Consider evaluating erythrocyte TPMT activity to assess TPMT phenotype. If thiopurines are required and TPMT status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers. Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298570", - "name" : "Recommendation PA166298570", - "alternateDrugAvailable" : true, + "id" : "PA166298539", + "name" : "Recommendation PA166298539", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, "parents" : [], @@ -86946,34 +87895,77 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ "NUDT15: n/a", - "TPMT: Extremely high concentrations of TGN metabolites; fatal toxicity possible without dose decrease. Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression." + "TPMT: n/a" ], - "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Indeterminate"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "Indeterminate"}, + "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104965", "name" : "Annotation of CPIC Guideline for thioguanine and NUDT15, TPMT", - "version" : 46 + "version" : 248 }, "text" : { - "id" : 1452061172, - "html" : "

Based on TPMT status, start with drastically reduced doses (PMID 11037857) (reduce daily dose by 10-fold and dose thrice weekly instead of daily) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing thioguanine over other agents. For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy (PMID 20354201). NUDT15 status could not be determined based on genotyping. If thiopurines are required and NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "id" : 1452061141, + "html" : "

Neither TPMT or NUDT15 phenotype could be assigned based on genotyping performed. Consider evaluating TPMT erythrocyte activity to assess TPMT phenotype. If thiopurines are required and either TPMT or NUDT15 status is unknown, monitor closely for toxicity.

\n

Other Considerations

\n

Erythrocyte TPMT activity test results can be falsely low at diagnosis of leukemia and is unreliable in the case of recent red blood cell transfusions.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166298555", + "name" : "Recommendation PA166298555", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501931, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "NUDT15: Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression", + "TPMT: Moderate to high concentrations of TGN metabolites; but note that TGN after thioguanine are 5-10X higher than TGN after mercaptopurine or azathioprine. Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression" + ], + "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Possible Intermediate Metabolizer"}, + "otherPrescribingGuidance" : false, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA451663", + "name" : "thioguanine", + "version" : 41 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104965", + "name" : "Annotation of CPIC Guideline for thioguanine and NUDT15, TPMT", + "version" : 248 + }, + "text" : { + "id" : 1452061157, + "html" : "

Start with reduced doses (20% to 50% of normal dose) if normal starting dose is ≥ 40-60 mg/m2/day (e.g., 8-30 mg/m2/day) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. At least 2-4 weeks will be required to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing thioguanine over other agents (PMID 20354201, 11037857).

\n

Other Considerations

\n

Normal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.

\n", + "version" : 1 + }, + "version" : 3 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166104965" @@ -87136,7 +88128,7 @@ "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "relatedGenes" : [ @@ -87145,14 +88137,14 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "CPIC", "summaryMarkdown" : { "id" : 1451309820, "html" : "

Alternate non-codeine analgesics are recommended for CYP2D6 ultrarapid and poor metabolizers. A label recommended age- or weight-specific dose of tramadol is warranted for CYP2D6 normal and intermediate metabolizers.

\n", - "version" : 0 + "version" : 1 }, "terms" : [], "textMarkdown" : { @@ -87161,28 +88153,28 @@ "version" : 2 }, "userId" : "rachel", - "version" : 8 + "version" : 66 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166298598", - "name" : "Recommendation PA166298598", - "alternateDrugAvailable" : true, + "id" : "PA166298577", + "name" : "Recommendation PA166298577", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Increased formation of O-desmethyltramadol (active metabolite) leading to higher risk of toxicity" + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "≥6.0"}, + "lookupKey" : {"CYP2D6": "n/a"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -87190,105 +88182,105 @@ "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166228101", "name" : "Annotation of CPIC Guideline for tramadol and CYP2D6", - "version" : 8 + "version" : 66 }, "text" : { - "id" : 1452061200, - "html" : "

Avoid tramadol use because of potential for toxicity. If opioid use is warranted, consider a non-codeine opioid.

\n", + "id" : 1452061179, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298585", - "name" : "Recommendation PA166298585", + "id" : "PA166298578", + "name" : "Recommendation PA166298578", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Expected O-desmethyltramadol (active metabolite) formation" + "CYP2D6: Reduced O-desmethyltramadol (active metabolite) formation" ], - "lookupKey" : {"CYP2D6": "2.0"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"CYP2D6": "0.25"}, + "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166228101", "name" : "Annotation of CPIC Guideline for tramadol and CYP2D6", - "version" : 8 + "version" : 66 }, "text" : { - "id" : 1452061187, - "html" : "

Use tramadol label recommended age- or weight-specific dosing.

\n", + "id" : 1452061180, + "html" : "

Use tramadol label recommended age- or weight-specific dosing. If no response and opioid use is warranted, consider non-codeine opioid.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298589", - "name" : "Recommendation PA166298589", - "alternateDrugAvailable" : true, + "id" : "PA166298579", + "name" : "Recommendation PA166298579", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Increased formation of O-desmethyltramadol (active metabolite) leading to higher risk of toxicity" + "CYP2D6: Reduced O-desmethyltramadol (active metabolite) formation" ], - "lookupKey" : {"CYP2D6": "3.0"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"CYP2D6": "0.5"}, + "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166228101", "name" : "Annotation of CPIC Guideline for tramadol and CYP2D6", - "version" : 8 + "version" : 66 }, "text" : { - "id" : 1452061191, - "html" : "

Avoid tramadol use because of potential for toxicity. If opioid use is warranted, consider a non-codeine opioid.

\n", + "id" : 1452061181, + "html" : "

Use tramadol label recommended age- or weight-specific dosing. If no response and opioid use is warranted, consider non-codeine opioid.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -87316,27 +88308,27 @@ "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166228101", "name" : "Annotation of CPIC Guideline for tramadol and CYP2D6", - "version" : 8 + "version" : 66 }, "text" : { "id" : 1452061182, "html" : "

Use tramadol label recommended age- or weight-specific dosing. If no response and opioid use is warranted, consider non-codeine opioid.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298584", - "name" : "Recommendation PA166298584", - "alternateDrugAvailable" : false, + "id" : "PA166298587", + "name" : "Recommendation PA166298587", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, "parents" : [], @@ -87348,9 +88340,9 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Expected O-desmethyltramadol (active metabolite) formation" + "CYP2D6: Greatly reduced O-desmethyltramadol (active metabolite) formation leading to diminished analgesia." ], - "lookupKey" : {"CYP2D6": "1.75"}, + "lookupKey" : {"CYP2D6": "0.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -87358,56 +88350,26 @@ "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166228101", - "name" : "Annotation of CPIC Guideline for tramadol and CYP2D6", - "version" : 8 - }, - "text" : { - "id" : 1452061186, - "html" : "

Use tramadol label recommended age- or weight-specific dosing.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166301329", - "name" : "Recommendation Annotation PA166301329", - "alternateDrugAvailable" : false, - "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA451735", - "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166228101", "name" : "Annotation of CPIC Guideline for tramadol and CYP2D6", - "version" : 8 + "version" : 66 }, "text" : { - "id" : 1452095648, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "id" : 1452061189, + "html" : "

Avoid tramadol use because of possibility of diminished analgesia. If opioid use is warranted, consider a non-codeine opioid.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298593", - "name" : "Recommendation PA166298593", + "id" : "PA166298588", + "name" : "Recommendation PA166298588", "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, @@ -87422,7 +88384,7 @@ "implications" : [ "CYP2D6: Increased formation of O-desmethyltramadol (active metabolite) leading to higher risk of toxicity" ], - "lookupKey" : {"CYP2D6": "≥3.25"}, + "lookupKey" : {"CYP2D6": "2.5"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -87430,17 +88392,17 @@ "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166228101", "name" : "Annotation of CPIC Guideline for tramadol and CYP2D6", - "version" : 8 + "version" : 66 }, "text" : { - "id" : 1452061195, + "id" : 1452061190, "html" : "

Avoid tramadol use because of potential for toxicity. If opioid use is warranted, consider a non-codeine opioid.

\n", "version" : 0 }, @@ -87448,9 +88410,9 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298586", - "name" : "Recommendation PA166298586", - "alternateDrugAvailable" : false, + "id" : "PA166298589", + "name" : "Recommendation PA166298589", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, "parents" : [], @@ -87462,9 +88424,9 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Expected O-desmethyltramadol (active metabolite) formation" + "CYP2D6: Increased formation of O-desmethyltramadol (active metabolite) leading to higher risk of toxicity" ], - "lookupKey" : {"CYP2D6": "2.25"}, + "lookupKey" : {"CYP2D6": "3.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -87472,41 +88434,41 @@ "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166228101", "name" : "Annotation of CPIC Guideline for tramadol and CYP2D6", - "version" : 8 + "version" : 66 }, "text" : { - "id" : 1452061188, - "html" : "

Use tramadol label recommended age- or weight-specific dosing.

\n", + "id" : 1452061191, + "html" : "

Avoid tramadol use because of potential for toxicity. If opioid use is warranted, consider a non-codeine opioid.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298577", - "name" : "Recommendation PA166298577", - "alternateDrugAvailable" : false, + "id" : "PA166298591", + "name" : "Recommendation PA166298591", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: n/a" + "CYP2D6: Increased formation of O-desmethyltramadol (active metabolite) leading to higher risk of toxicity" ], - "lookupKey" : {"CYP2D6": "n/a"}, + "lookupKey" : {"CYP2D6": "4.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -87514,26 +88476,26 @@ "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166228101", "name" : "Annotation of CPIC Guideline for tramadol and CYP2D6", - "version" : 8 + "version" : 66 }, "text" : { - "id" : 1452061179, - "html" : "

No recommendation

\n", + "id" : 1452061193, + "html" : "

Avoid tramadol use because of potential for toxicity. If opioid use is warranted, consider a non-codeine opioid.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298590", - "name" : "Recommendation PA166298590", + "id" : "PA166298592", + "name" : "Recommendation PA166298592", "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, @@ -87548,7 +88510,7 @@ "implications" : [ "CYP2D6: Increased formation of O-desmethyltramadol (active metabolite) leading to higher risk of toxicity" ], - "lookupKey" : {"CYP2D6": "2.75"}, + "lookupKey" : {"CYP2D6": "≥3.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -87556,17 +88518,17 @@ "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166228101", "name" : "Annotation of CPIC Guideline for tramadol and CYP2D6", - "version" : 8 + "version" : 66 }, "text" : { - "id" : 1452061192, + "id" : 1452061194, "html" : "

Avoid tramadol use because of potential for toxicity. If opioid use is warranted, consider a non-codeine opioid.

\n", "version" : 0 }, @@ -87574,8 +88536,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298594", - "name" : "Recommendation PA166298594", + "id" : "PA166298593", + "name" : "Recommendation PA166298593", "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, @@ -87590,7 +88552,7 @@ "implications" : [ "CYP2D6: Increased formation of O-desmethyltramadol (active metabolite) leading to higher risk of toxicity" ], - "lookupKey" : {"CYP2D6": "≥3.5"}, + "lookupKey" : {"CYP2D6": "≥3.25"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -87598,17 +88560,17 @@ "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166228101", "name" : "Annotation of CPIC Guideline for tramadol and CYP2D6", - "version" : 8 + "version" : 66 }, "text" : { - "id" : 1452061196, + "id" : 1452061195, "html" : "

Avoid tramadol use because of potential for toxicity. If opioid use is warranted, consider a non-codeine opioid.

\n", "version" : 0 }, @@ -87616,50 +88578,50 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298581", - "name" : "Recommendation PA166298581", - "alternateDrugAvailable" : false, + "id" : "PA166298594", + "name" : "Recommendation PA166298594", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Reduced O-desmethyltramadol (active metabolite) formation" + "CYP2D6: Increased formation of O-desmethyltramadol (active metabolite) leading to higher risk of toxicity" ], - "lookupKey" : {"CYP2D6": "1.0"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"CYP2D6": "≥3.5"}, + "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166228101", "name" : "Annotation of CPIC Guideline for tramadol and CYP2D6", - "version" : 8 + "version" : 66 }, "text" : { - "id" : 1452061183, - "html" : "

Use tramadol label recommended age- or weight-specific dosing. If no response and opioid use is warranted, consider non-codeine opioid.

\n", + "id" : 1452061196, + "html" : "

Avoid tramadol use because of potential for toxicity. If opioid use is warranted, consider a non-codeine opioid.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298591", - "name" : "Recommendation PA166298591", + "id" : "PA166298595", + "name" : "Recommendation PA166298595", "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, @@ -87674,7 +88636,7 @@ "implications" : [ "CYP2D6: Increased formation of O-desmethyltramadol (active metabolite) leading to higher risk of toxicity" ], - "lookupKey" : {"CYP2D6": "4.0"}, + "lookupKey" : {"CYP2D6": "≥4.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -87682,17 +88644,17 @@ "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166228101", "name" : "Annotation of CPIC Guideline for tramadol and CYP2D6", - "version" : 8 + "version" : 66 }, "text" : { - "id" : 1452061193, + "id" : 1452061197, "html" : "

Avoid tramadol use because of potential for toxicity. If opioid use is warranted, consider a non-codeine opioid.

\n", "version" : 0 }, @@ -87700,8 +88662,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298587", - "name" : "Recommendation PA166298587", + "id" : "PA166298597", + "name" : "Recommendation PA166298597", "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, @@ -87714,9 +88676,9 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Greatly reduced O-desmethyltramadol (active metabolite) formation leading to diminished analgesia." + "CYP2D6: Increased formation of O-desmethyltramadol (active metabolite) leading to higher risk of toxicity" ], - "lookupKey" : {"CYP2D6": "0.0"}, + "lookupKey" : {"CYP2D6": "≥5.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -87724,69 +88686,69 @@ "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166228101", "name" : "Annotation of CPIC Guideline for tramadol and CYP2D6", - "version" : 8 + "version" : 66 }, "text" : { - "id" : 1452061189, - "html" : "

Avoid tramadol use because of possibility of diminished analgesia. If opioid use is warranted, consider a non-codeine opioid.

\n", + "id" : 1452061199, + "html" : "

Avoid tramadol use because of potential for toxicity. If opioid use is warranted, consider a non-codeine opioid.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298578", - "name" : "Recommendation PA166298578", - "alternateDrugAvailable" : false, + "id" : "PA166298598", + "name" : "Recommendation PA166298598", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Reduced O-desmethyltramadol (active metabolite) formation" + "CYP2D6: Increased formation of O-desmethyltramadol (active metabolite) leading to higher risk of toxicity" ], - "lookupKey" : {"CYP2D6": "0.25"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"CYP2D6": "≥6.0"}, + "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166228101", "name" : "Annotation of CPIC Guideline for tramadol and CYP2D6", - "version" : 8 + "version" : 66 }, "text" : { - "id" : 1452061180, - "html" : "

Use tramadol label recommended age- or weight-specific dosing. If no response and opioid use is warranted, consider non-codeine opioid.

\n", + "id" : 1452061200, + "html" : "

Avoid tramadol use because of potential for toxicity. If opioid use is warranted, consider a non-codeine opioid.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298595", - "name" : "Recommendation PA166298595", - "alternateDrugAvailable" : true, + "id" : "PA166298583", + "name" : "Recommendation PA166298583", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, "parents" : [], @@ -87798,9 +88760,9 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Increased formation of O-desmethyltramadol (active metabolite) leading to higher risk of toxicity" + "CYP2D6: Expected O-desmethyltramadol (active metabolite) formation" ], - "lookupKey" : {"CYP2D6": "≥4.0"}, + "lookupKey" : {"CYP2D6": "1.5"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -87808,21 +88770,21 @@ "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166228101", "name" : "Annotation of CPIC Guideline for tramadol and CYP2D6", - "version" : 8 + "version" : 66 }, "text" : { - "id" : 1452061197, - "html" : "

Avoid tramadol use because of potential for toxicity. If opioid use is warranted, consider a non-codeine opioid.

\n", + "id" : 1452061185, + "html" : "

Use tramadol label recommended age- or weight-specific dosing.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -87850,27 +88812,27 @@ "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166228101", "name" : "Annotation of CPIC Guideline for tramadol and CYP2D6", - "version" : 8 + "version" : 66 }, "text" : { "id" : 1452061184, "html" : "

Use tramadol label recommended age- or weight-specific dosing.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298588", - "name" : "Recommendation PA166298588", - "alternateDrugAvailable" : true, + "id" : "PA166298584", + "name" : "Recommendation PA166298584", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, "parents" : [], @@ -87882,9 +88844,9 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Increased formation of O-desmethyltramadol (active metabolite) leading to higher risk of toxicity" + "CYP2D6: Expected O-desmethyltramadol (active metabolite) formation" ], - "lookupKey" : {"CYP2D6": "2.5"}, + "lookupKey" : {"CYP2D6": "1.75"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -87892,27 +88854,27 @@ "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166228101", "name" : "Annotation of CPIC Guideline for tramadol and CYP2D6", - "version" : 8 + "version" : 66 }, "text" : { - "id" : 1452061190, - "html" : "

Avoid tramadol use because of potential for toxicity. If opioid use is warranted, consider a non-codeine opioid.

\n", + "id" : 1452061186, + "html" : "

Use tramadol label recommended age- or weight-specific dosing.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298597", - "name" : "Recommendation PA166298597", - "alternateDrugAvailable" : true, + "id" : "PA166298585", + "name" : "Recommendation PA166298585", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, "parents" : [], @@ -87924,9 +88886,9 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Increased formation of O-desmethyltramadol (active metabolite) leading to higher risk of toxicity" + "CYP2D6: Expected O-desmethyltramadol (active metabolite) formation" ], - "lookupKey" : {"CYP2D6": "≥5.0"}, + "lookupKey" : {"CYP2D6": "2.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -87934,68 +88896,68 @@ "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166228101", "name" : "Annotation of CPIC Guideline for tramadol and CYP2D6", - "version" : 8 + "version" : 66 }, "text" : { - "id" : 1452061199, - "html" : "

Avoid tramadol use because of potential for toxicity. If opioid use is warranted, consider a non-codeine opioid.

\n", + "id" : 1452061187, + "html" : "

Use tramadol label recommended age- or weight-specific dosing.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298579", - "name" : "Recommendation PA166298579", + "id" : "PA166298586", + "name" : "Recommendation PA166298586", "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Reduced O-desmethyltramadol (active metabolite) formation" + "CYP2D6: Expected O-desmethyltramadol (active metabolite) formation" ], - "lookupKey" : {"CYP2D6": "0.5"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"CYP2D6": "2.25"}, + "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166228101", "name" : "Annotation of CPIC Guideline for tramadol and CYP2D6", - "version" : 8 + "version" : 66 }, "text" : { - "id" : 1452061181, - "html" : "

Use tramadol label recommended age- or weight-specific dosing. If no response and opioid use is warranted, consider non-codeine opioid.

\n", + "id" : 1452061188, + "html" : "

Use tramadol label recommended age- or weight-specific dosing.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298592", - "name" : "Recommendation PA166298592", + "id" : "PA166298590", + "name" : "Recommendation PA166298590", "alternateDrugAvailable" : true, "classification" : { "id" : 981501930, @@ -88010,7 +88972,7 @@ "implications" : [ "CYP2D6: Increased formation of O-desmethyltramadol (active metabolite) leading to higher risk of toxicity" ], - "lookupKey" : {"CYP2D6": "≥3.0"}, + "lookupKey" : {"CYP2D6": "2.75"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -88018,21 +88980,21 @@ "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166228101", "name" : "Annotation of CPIC Guideline for tramadol and CYP2D6", - "version" : 8 + "version" : 66 }, "text" : { - "id" : 1452061194, + "id" : 1452061192, "html" : "

Avoid tramadol use because of potential for toxicity. If opioid use is warranted, consider a non-codeine opioid.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -88060,60 +89022,90 @@ "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166228101", "name" : "Annotation of CPIC Guideline for tramadol and CYP2D6", - "version" : 8 + "version" : 66 }, "text" : { "id" : 1452061198, "html" : "

Avoid tramadol use because of potential for toxicity. If opioid use is warranted, consider a non-codeine opioid.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298583", - "name" : "Recommendation PA166298583", + "id" : "PA166298581", + "name" : "Recommendation PA166298581", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Expected O-desmethyltramadol (active metabolite) formation" + "CYP2D6: Reduced O-desmethyltramadol (active metabolite) formation" ], - "lookupKey" : {"CYP2D6": "1.5"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"CYP2D6": "1.0"}, + "otherPrescribingGuidance" : true, "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166228101", "name" : "Annotation of CPIC Guideline for tramadol and CYP2D6", - "version" : 8 + "version" : 66 }, "text" : { - "id" : 1452061185, - "html" : "

Use tramadol label recommended age- or weight-specific dosing.

\n", + "id" : 1452061183, + "html" : "

Use tramadol label recommended age- or weight-specific dosing. If no response and opioid use is warranted, consider non-codeine opioid.

\n", + "version" : 0 + }, + "version" : 1 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166301329", + "name" : "Recommendation Annotation PA166301329", + "alternateDrugAvailable" : false, + "dosingInformation" : false, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA451735", + "name" : "tramadol", + "version" : 40 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166228101", + "name" : "Annotation of CPIC Guideline for tramadol and CYP2D6", + "version" : 66 + }, + "text" : { + "id" : 1452095648, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", "version" : 0 }, "version" : 0 @@ -88357,7 +89349,7 @@ "pediatricMarkdown" : { "id" : 1451266644, "html" : "

Guideline excerpt: "There are scarce studies focusing solely on CYP2D6 or CYP2C19 genotype and association with pharmacokinetic parameters or treatment outcomes of TCAs in pediatric patients. CYP2D6 activity is fully mature by early childhood, but CYP2C19 activity may be increased in children relative to adults. Although further genomic ontogeny studies are needed, there is a lack of evidence suggesting that this guideline cannot be extrapolated to pediatric patients."

\n", - "version" : 0 + "version" : 1 }, "recommendation" : true, "relatedAlleles" : [], @@ -88366,7 +89358,7 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "relatedGenes" : [ @@ -88375,21 +89367,21 @@ "id" : "PA124", "symbol" : "CYP2C19", "name" : "cytochrome P450 family 2 subfamily C member 19", - "version" : 7210 + "version" : 7266 }, { "objCls" : "Gene", "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "CPIC", "summaryMarkdown" : { "id" : 1447981940, "html" : "

Tricyclic antidepressants have comparable pharmacokinetic properties, it may be reasonable to apply the CPIC Dosing Guideline for amitriptyline and CYP2C19, CYP2D6 to other tricyclics including trimipramine. The CPIC Dosing Guideline update for amitriptyline recommends an alternative drug for CYP2D6 ultrarapid or poor metabolizers and CYP2C19 ultrarapid, rapid or poor metabolizers. If amitriptyline is warranted, consider a 50% dose reduction in CYP2D6 or CYP2C19 poor metabolizers. For CYP2D6 intermediate metabolizers, a 25% dose reduction should be considered.

\n", - "version" : 1 + "version" : 2 }, "terms" : [], "textMarkdown" : { @@ -88398,13 +89390,13 @@ "version" : 1 }, "userId" : "whaleyr", - "version" : 51 + "version" : 96 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166298739", - "name" : "Recommendation PA166298739", + "id" : "PA166298607", + "name" : "Recommendation PA166298607", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -88417,10 +89409,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -88428,26 +89420,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061341, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452061209, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298770", - "name" : "Recommendation PA166298770", + "id" : "PA166298608", + "name" : "Recommendation PA166298608", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -88461,9 +89453,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -88471,26 +89463,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061372, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061210, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298673", - "name" : "Recommendation PA166298673", + "id" : "PA166298609", + "name" : "Recommendation PA166298609", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -88504,9 +89496,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -88514,26 +89506,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061275, - "html" : "

Avoid trimipramine use. If trimipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452061211, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298629", - "name" : "Recommendation PA166298629", + "id" : "PA166298611", + "name" : "Recommendation PA166298611", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -88549,7 +89541,7 @@ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -88557,17 +89549,17 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061231, + "id" : 1452061213, "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, @@ -88575,38 +89567,51 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301448", - "name" : "Recommendation Annotation PA166301448", - "alternateDrugAvailable" : false, - "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Rapid Metabolizer"}, + "id" : "PA166298612", + "name" : "Recommendation PA166298612", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981565059, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + ], + "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, + "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452095787, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "id" : 1452061214, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298726", - "name" : "Recommendation PA166298726", + "id" : "PA166298613", + "name" : "Recommendation PA166298613", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -88620,9 +89625,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -88630,26 +89635,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061328, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452061215, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298660", - "name" : "Recommendation PA166298660", + "id" : "PA166298614", + "name" : "Recommendation PA166298614", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -88663,9 +89668,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -88673,42 +89678,42 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061262, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452061216, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298616", - "name" : "Recommendation PA166298616", - "alternateDrugAvailable" : false, + "id" : "PA166298615", + "name" : "Recommendation PA166298615", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -88716,26 +89721,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061218, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452061217, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298713", - "name" : "Recommendation PA166298713", + "id" : "PA166298617", + "name" : "Recommendation PA166298617", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -88748,10 +89753,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -88759,26 +89764,112 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061315, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061219, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298695", - "name" : "Recommendation PA166298695", + "id" : "PA166298618", + "name" : "Recommendation PA166298618", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981565059, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + ], + "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Ultrarapid Metabolizer"}, + "otherPrescribingGuidance" : false, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA451791", + "name" : "trimipramine", + "version" : 29 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166105001", + "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", + "version" : 96 + }, + "text" : { + "id" : 1452061220, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166298619", + "name" : "Recommendation PA166298619", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981565059, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + ], + "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Ultrarapid Metabolizer"}, + "otherPrescribingGuidance" : false, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA451791", + "name" : "trimipramine", + "version" : 29 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166105001", + "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", + "version" : 96 + }, + "text" : { + "id" : 1452061221, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166298620", + "name" : "Recommendation PA166298620", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -88791,10 +89882,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -88802,26 +89893,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061297, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061222, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298700", - "name" : "Recommendation PA166298700", + "id" : "PA166298629", + "name" : "Recommendation PA166298629", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -88834,10 +89925,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -88845,26 +89936,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061302, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061231, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298792", - "name" : "Recommendation PA166298792", + "id" : "PA166298630", + "name" : "Recommendation PA166298630", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -88877,10 +89968,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: n/a" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -88888,27 +89979,27 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061394, - "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. If a tertiary amine is warranted, utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452061232, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298603", - "name" : "Recommendation PA166298603", - "alternateDrugAvailable" : false, + "id" : "PA166298631", + "name" : "Recommendation PA166298631", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -88920,10 +90011,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -88931,27 +90022,27 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061205, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452061233, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298748", - "name" : "Recommendation PA166298748", - "alternateDrugAvailable" : false, + "id" : "PA166298632", + "name" : "Recommendation PA166298632", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -88961,12 +90052,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: n/a" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -88974,26 +90065,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061350, - "html" : "

No recommendation

\n", + "id" : 1452061234, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298682", - "name" : "Recommendation PA166298682", + "id" : "PA166298645", + "name" : "Recommendation PA166298645", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -89007,9 +90098,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -89017,26 +90108,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061284, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061247, + "html" : "

Avoid trimipramine use. If trimipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298774", - "name" : "Recommendation PA166298774", + "id" : "PA166298646", + "name" : "Recommendation PA166298646", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -89050,9 +90141,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -89060,42 +90151,42 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061376, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061248, + "html" : "

Avoid trimipramine use. If trimipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298677", - "name" : "Recommendation PA166298677", + "id" : "PA166298641", + "name" : "Recommendation PA166298641", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -89103,57 +90194,70 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061279, + "id" : 1452061243, "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301444", - "name" : "Recommendation Annotation PA166301444", + "id" : "PA166298616", + "name" : "Recommendation PA166298616", "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501930, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", + "valid" : true, + "version" : 0 + }, "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Likely Poor Metabolizer"}, + "implications" : [ + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Normal metabolism of TCAs" + ], + "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, + "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452095783, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "id" : 1452061218, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298761", - "name" : "Recommendation PA166298761", - "alternateDrugAvailable" : true, + "id" : "PA166298640", + "name" : "Recommendation PA166298640", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -89163,12 +90267,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -89176,26 +90280,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061363, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061242, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298664", - "name" : "Recommendation PA166298664", + "id" : "PA166298610", + "name" : "Recommendation PA166298610", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -89208,10 +90312,10 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Normal metabolism of tertiary amines", "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -89219,27 +90323,27 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061266, - "html" : "

No recommendation

\n", + "id" : 1452061212, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298717", - "name" : "Recommendation PA166298717", - "alternateDrugAvailable" : true, + "id" : "PA166298639", + "name" : "Recommendation PA166298639", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -89249,12 +90353,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -89262,42 +90366,42 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061319, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061241, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298796", - "name" : "Recommendation PA166298796", - "alternateDrugAvailable" : true, + "id" : "PA166298643", + "name" : "Recommendation PA166298643", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: n/a" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -89305,27 +90409,27 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061398, - "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. For tertiary amines, consider a 50% reduction of the recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452061245, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298699", - "name" : "Recommendation PA166298699", - "alternateDrugAvailable" : true, + "id" : "PA166298638", + "name" : "Recommendation PA166298638", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -89335,12 +90439,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -89348,42 +90452,42 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061301, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061240, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298651", - "name" : "Recommendation PA166298651", - "alternateDrugAvailable" : true, + "id" : "PA166298642", + "name" : "Recommendation PA166298642", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Normal metabolism of tertiary amines", "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -89391,27 +90495,27 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061253, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452061244, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298607", - "name" : "Recommendation PA166298607", - "alternateDrugAvailable" : true, + "id" : "PA166298637", + "name" : "Recommendation PA166298637", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -89421,12 +90525,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -89434,27 +90538,27 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061209, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061239, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298704", - "name" : "Recommendation PA166298704", - "alternateDrugAvailable" : true, + "id" : "PA166298606", + "name" : "Recommendation PA166298606", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -89467,9 +90571,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -89477,27 +90581,27 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061306, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", + "id" : 1452061208, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298686", - "name" : "Recommendation PA166298686", - "alternateDrugAvailable" : true, + "id" : "PA166298636", + "name" : "Recommendation PA166298636", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -89509,10 +90613,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: n/a", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -89520,27 +90624,27 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061288, - "html" : "

Avoid trimipramine use. If a trimipramine is warranted, consider a 50% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061238, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298783", - "name" : "Recommendation PA166298783", - "alternateDrugAvailable" : true, + "id" : "PA166298628", + "name" : "Recommendation PA166298628", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -89552,10 +90656,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -89563,27 +90667,27 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061385, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452061230, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298801", - "name" : "Recommendation PA166298801", - "alternateDrugAvailable" : true, + "id" : "PA166298602", + "name" : "Recommendation PA166298602", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -89595,10 +90699,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: n/a" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -89606,27 +90710,27 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061403, - "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. If a tertiary amine is warranted, utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452061204, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298646", - "name" : "Recommendation PA166298646", - "alternateDrugAvailable" : true, + "id" : "PA166298624", + "name" : "Recommendation PA166298624", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -89638,10 +90742,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: n/a", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -89649,27 +90753,27 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061248, - "html" : "

Avoid trimipramine use. If trimipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452061226, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298730", - "name" : "Recommendation PA166298730", - "alternateDrugAvailable" : true, + "id" : "PA166298605", + "name" : "Recommendation PA166298605", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -89681,10 +90785,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -89692,26 +90796,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061332, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452061207, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298633", - "name" : "Recommendation PA166298633", + "id" : "PA166298635", + "name" : "Recommendation PA166298635", "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, @@ -89727,7 +90831,7 @@ "CYP2C19: n/a", "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -89735,27 +90839,27 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061235, + "id" : 1452061237, "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298778", - "name" : "Recommendation PA166298778", - "alternateDrugAvailable" : true, + "id" : "PA166298627", + "name" : "Recommendation PA166298627", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -89767,10 +90871,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -89778,27 +90882,27 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061380, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452061229, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298765", - "name" : "Recommendation PA166298765", - "alternateDrugAvailable" : true, + "id" : "PA166298601", + "name" : "Recommendation PA166298601", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -89811,9 +90915,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -89821,27 +90925,27 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061367, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061203, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298620", - "name" : "Recommendation PA166298620", - "alternateDrugAvailable" : true, + "id" : "PA166298623", + "name" : "Recommendation PA166298623", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -89853,10 +90957,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: n/a", "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -89864,26 +90968,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061222, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061225, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298668", - "name" : "Recommendation PA166298668", + "id" : "PA166298604", + "name" : "Recommendation PA166298604", "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, @@ -89894,12 +90998,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -89907,27 +91011,27 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061270, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452061206, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298752", - "name" : "Recommendation PA166298752", - "alternateDrugAvailable" : true, + "id" : "PA166298634", + "name" : "Recommendation PA166298634", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -89940,9 +91044,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -89950,27 +91054,27 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061354, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452061236, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298655", - "name" : "Recommendation PA166298655", - "alternateDrugAvailable" : true, + "id" : "PA166298626", + "name" : "Recommendation PA166298626", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -89982,10 +91086,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -89993,27 +91097,27 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061257, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452061228, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298708", - "name" : "Recommendation PA166298708", - "alternateDrugAvailable" : true, + "id" : "PA166298600", + "name" : "Recommendation PA166298600", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -90025,10 +91129,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -90036,27 +91140,27 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061310, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", + "id" : 1452061202, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298787", - "name" : "Recommendation PA166298787", - "alternateDrugAvailable" : true, + "id" : "PA166298622", + "name" : "Recommendation PA166298622", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -90069,9 +91173,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -90079,42 +91183,42 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061389, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452061224, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298642", - "name" : "Recommendation PA166298642", + "id" : "PA166298603", + "name" : "Recommendation PA166298603", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Normal metabolism of TCAs" + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -90122,26 +91226,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061244, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452061205, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298602", - "name" : "Recommendation PA166298602", + "id" : "PA166298633", + "name" : "Recommendation PA166298633", "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, @@ -90154,10 +91258,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: n/a", "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -90165,27 +91269,27 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061204, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061235, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298747", - "name" : "Recommendation PA166298747", - "alternateDrugAvailable" : true, + "id" : "PA166298625", + "name" : "Recommendation PA166298625", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -90197,10 +91301,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -90208,27 +91312,27 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061349, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452061227, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298681", - "name" : "Recommendation PA166298681", - "alternateDrugAvailable" : true, + "id" : "PA166298621", + "name" : "Recommendation PA166298621", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -90240,10 +91344,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: n/a", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -90251,27 +91355,27 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061283, - "html" : "

Avoid trimipramine use. If a trimipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452061223, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298637", - "name" : "Recommendation PA166298637", - "alternateDrugAvailable" : false, + "id" : "PA166298647", + "name" : "Recommendation PA166298647", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -90281,12 +91385,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -90294,26 +91398,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061239, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452061249, + "html" : "

Avoid trimipramine use. If trimipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298734", - "name" : "Recommendation PA166298734", + "id" : "PA166298648", + "name" : "Recommendation PA166298648", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -90326,10 +91430,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -90337,26 +91441,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061336, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452061250, + "html" : "

Avoid trimipramine use. If trimipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298721", - "name" : "Recommendation PA166298721", + "id" : "PA166298649", + "name" : "Recommendation PA166298649", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -90370,9 +91474,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -90380,27 +91484,27 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061323, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061251, + "html" : "

Avoid trimipramine use. If trimipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298624", - "name" : "Recommendation PA166298624", - "alternateDrugAvailable" : false, + "id" : "PA166298650", + "name" : "Recommendation PA166298650", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -90412,10 +91516,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -90423,26 +91527,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061226, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452061252, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298769", - "name" : "Recommendation PA166298769", + "id" : "PA166298651", + "name" : "Recommendation PA166298651", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -90455,10 +91559,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -90466,26 +91570,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061371, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061253, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298611", - "name" : "Recommendation PA166298611", + "id" : "PA166298652", + "name" : "Recommendation PA166298652", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -90498,10 +91602,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -90509,26 +91613,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061213, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061254, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298659", - "name" : "Recommendation PA166298659", + "id" : "PA166298653", + "name" : "Recommendation PA166298653", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -90544,7 +91648,7 @@ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -90552,17 +91656,17 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061261, + "id" : 1452061255, "html" : "

Consider alternative drug not metabolized by CYP2C19; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, @@ -90570,8 +91674,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298756", - "name" : "Recommendation PA166298756", + "id" : "PA166298654", + "name" : "Recommendation PA166298654", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -90584,10 +91688,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -90595,26 +91699,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061358, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061256, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298743", - "name" : "Recommendation PA166298743", + "id" : "PA166298655", + "name" : "Recommendation PA166298655", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -90628,9 +91732,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -90638,26 +91742,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061345, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452061257, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298690", - "name" : "Recommendation PA166298690", + "id" : "PA166298656", + "name" : "Recommendation PA166298656", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -90670,10 +91774,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -90681,26 +91785,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061292, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061258, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298727", - "name" : "Recommendation PA166298727", + "id" : "PA166298658", + "name" : "Recommendation PA166298658", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -90714,9 +91818,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -90724,42 +91828,42 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061329, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452061260, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298661", - "name" : "Recommendation PA166298661", - "alternateDrugAvailable" : false, + "id" : "PA166298659", + "name" : "Recommendation PA166298659", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -90767,26 +91871,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061263, - "html" : "

No recommendation

\n", + "id" : 1452061261, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298617", - "name" : "Recommendation PA166298617", + "id" : "PA166298660", + "name" : "Recommendation PA166298660", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -90800,9 +91904,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -90810,26 +91914,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061219, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061262, + "html" : "

Consider alternative drug not metabolized by CYP2C19; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298714", - "name" : "Recommendation PA166298714", + "id" : "PA166298670", + "name" : "Recommendation PA166298670", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -90843,9 +91947,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -90853,26 +91957,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061316, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061272, + "html" : "

Avoid trimipramine use. If trimipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298696", - "name" : "Recommendation PA166298696", + "id" : "PA166298671", + "name" : "Recommendation PA166298671", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -90885,10 +91989,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -90896,26 +92000,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061298, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061273, + "html" : "

Avoid trimipramine use. If trimipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298793", - "name" : "Recommendation PA166298793", + "id" : "PA166298672", + "name" : "Recommendation PA166298672", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -90928,10 +92032,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: n/a" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -90939,27 +92043,27 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061395, - "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. If a tertiary amine is warranted, utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452061274, + "html" : "

Avoid trimipramine use. If trimipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298599", - "name" : "Recommendation PA166298599", - "alternateDrugAvailable" : false, + "id" : "PA166298673", + "name" : "Recommendation PA166298673", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -90971,10 +92075,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -90982,57 +92086,70 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061201, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061275, + "html" : "

Avoid trimipramine use. If trimipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301447", - "name" : "Recommendation Annotation PA166301447", - "alternateDrugAvailable" : false, - "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Ultrarapid Metabolizer"}, + "id" : "PA166298674", + "name" : "Recommendation PA166298674", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981565059, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Normal metabolism of TCAs" + ], + "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, + "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452095786, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "id" : 1452061276, + "html" : "

Avoid trimipramine use. If trimipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298604", - "name" : "Recommendation PA166298604", - "alternateDrugAvailable" : false, + "id" : "PA166298680", + "name" : "Recommendation PA166298680", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -91044,10 +92161,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -91055,26 +92172,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061206, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452061282, + "html" : "

Avoid trimipramine use. If a trimipramine is warranted, consider a 50% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298749", - "name" : "Recommendation PA166298749", + "id" : "PA166298681", + "name" : "Recommendation PA166298681", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -91087,10 +92204,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -91098,26 +92215,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061351, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452061283, + "html" : "

Avoid trimipramine use. If a trimipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298701", - "name" : "Recommendation PA166298701", + "id" : "PA166298682", + "name" : "Recommendation PA166298682", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -91130,10 +92247,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -91141,18 +92258,18 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061303, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", + "id" : 1452061284, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 @@ -91184,14 +92301,14 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { "id" : 1452061285, @@ -91202,8 +92319,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298780", - "name" : "Recommendation PA166298780", + "id" : "PA166298684", + "name" : "Recommendation PA166298684", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -91216,10 +92333,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -91227,27 +92344,27 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061382, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452061286, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298639", - "name" : "Recommendation PA166298639", - "alternateDrugAvailable" : false, + "id" : "PA166298685", + "name" : "Recommendation PA166298685", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -91257,12 +92374,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: n/a", + "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -91270,26 +92387,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061241, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452061287, + "html" : "

Avoid tricyclic use due to potential for side effects. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298736", - "name" : "Recommendation PA166298736", + "id" : "PA166298686", + "name" : "Recommendation PA166298686", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -91302,10 +92419,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -91313,26 +92430,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061338, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452061288, + "html" : "

Avoid trimipramine use. If a trimipramine is warranted, consider a 50% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298670", - "name" : "Recommendation PA166298670", + "id" : "PA166298687", + "name" : "Recommendation PA166298687", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -91346,9 +92463,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -91356,26 +92473,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061272, - "html" : "

Avoid trimipramine use. If trimipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452061289, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298762", - "name" : "Recommendation PA166298762", + "id" : "PA166298688", + "name" : "Recommendation PA166298688", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -91388,10 +92505,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: n/a", + "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -91399,42 +92516,42 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061364, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061290, + "html" : "

Avoid tricyclic use due to potential for side effects. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298665", - "name" : "Recommendation PA166298665", - "alternateDrugAvailable" : false, + "id" : "PA166298689", + "name" : "Recommendation PA166298689", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -91442,26 +92559,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061267, - "html" : "

No recommendation

\n", + "id" : 1452061291, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298718", - "name" : "Recommendation PA166298718", + "id" : "PA166298690", + "name" : "Recommendation PA166298690", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -91474,10 +92591,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -91485,27 +92602,27 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061320, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061292, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298797", - "name" : "Recommendation PA166298797", - "alternateDrugAvailable" : false, + "id" : "PA166298691", + "name" : "Recommendation PA166298691", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -91515,12 +92632,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: n/a" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -91528,26 +92645,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061399, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452061293, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298652", - "name" : "Recommendation PA166298652", + "id" : "PA166298693", + "name" : "Recommendation PA166298693", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -91560,10 +92677,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -91571,26 +92688,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061254, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452061295, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298608", - "name" : "Recommendation PA166298608", + "id" : "PA166298694", + "name" : "Recommendation PA166298694", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -91603,10 +92720,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -91614,56 +92731,69 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061210, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061296, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301443", - "name" : "Recommendation Annotation PA166301443", - "alternateDrugAvailable" : false, - "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Likely Intermediate Metabolizer"}, + "id" : "PA166298695", + "name" : "Recommendation PA166298695", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981565059, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + ], + "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, + "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452095782, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "id" : 1452061297, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298705", - "name" : "Recommendation PA166298705", + "id" : "PA166298696", + "name" : "Recommendation PA166298696", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -91676,10 +92806,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -91687,26 +92817,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061307, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", + "id" : 1452061298, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298784", - "name" : "Recommendation PA166298784", + "id" : "PA166298697", + "name" : "Recommendation PA166298697", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -91719,10 +92849,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -91730,26 +92860,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061386, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452061299, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298687", - "name" : "Recommendation PA166298687", + "id" : "PA166298699", + "name" : "Recommendation PA166298699", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -91762,10 +92892,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -91773,27 +92903,27 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061289, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061301, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298802", - "name" : "Recommendation PA166298802", - "alternateDrugAvailable" : false, + "id" : "PA166298700", + "name" : "Recommendation PA166298700", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -91803,12 +92933,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: n/a" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -91816,26 +92946,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061404, - "html" : "

No recommendation

\n", + "id" : 1452061302, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298771", - "name" : "Recommendation PA166298771", + "id" : "PA166298701", + "name" : "Recommendation PA166298701", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -91848,10 +92978,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Normal metabolism of tertiary amines", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -91859,26 +92989,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061373, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061303, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298674", - "name" : "Recommendation PA166298674", + "id" : "PA166298702", + "name" : "Recommendation PA166298702", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -91891,10 +93021,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -91902,26 +93032,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061276, - "html" : "

Avoid trimipramine use. If trimipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452061304, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298779", - "name" : "Recommendation PA166298779", + "id" : "PA166298704", + "name" : "Recommendation PA166298704", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -91934,10 +93064,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Normal metabolism of tertiary amines", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -91945,26 +93075,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061381, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452061306, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298766", - "name" : "Recommendation PA166298766", + "id" : "PA166298705", + "name" : "Recommendation PA166298705", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -91977,10 +93107,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: Normal metabolism of tertiary amines", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -91988,27 +93118,27 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061368, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061307, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298621", - "name" : "Recommendation PA166298621", - "alternateDrugAvailable" : false, + "id" : "PA166298706", + "name" : "Recommendation PA166298706", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -92020,10 +93150,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -92031,27 +93161,27 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061223, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452061308, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298669", - "name" : "Recommendation PA166298669", - "alternateDrugAvailable" : false, + "id" : "PA166298707", + "name" : "Recommendation PA166298707", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -92061,12 +93191,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -92074,26 +93204,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061271, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452061309, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298753", - "name" : "Recommendation PA166298753", + "id" : "PA166298698", + "name" : "Recommendation PA166298698", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -92106,10 +93236,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -92117,26 +93247,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061355, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452061300, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298656", - "name" : "Recommendation PA166298656", + "id" : "PA166298703", + "name" : "Recommendation PA166298703", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -92149,10 +93279,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -92160,42 +93290,42 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061258, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452061305, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298709", - "name" : "Recommendation PA166298709", - "alternateDrugAvailable" : true, + "id" : "PA166298679", + "name" : "Recommendation PA166298679", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: n/a", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -92203,27 +93333,27 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061311, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", + "id" : 1452061281, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298788", - "name" : "Recommendation PA166298788", - "alternateDrugAvailable" : true, + "id" : "PA166298657", + "name" : "Recommendation PA166298657", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -92233,12 +93363,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -92246,42 +93376,42 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061390, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452061259, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298740", - "name" : "Recommendation PA166298740", - "alternateDrugAvailable" : true, + "id" : "PA166298665", + "name" : "Recommendation PA166298665", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: n/a", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -92289,26 +93419,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061342, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452061267, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298643", - "name" : "Recommendation PA166298643", + "id" : "PA166298678", + "name" : "Recommendation PA166298678", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -92321,10 +93451,10 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", + "CYP2C19: n/a", "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -92332,27 +93462,27 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061245, + "id" : 1452061280, "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298775", - "name" : "Recommendation PA166298775", - "alternateDrugAvailable" : true, + "id" : "PA166298669", + "name" : "Recommendation PA166298669", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -92362,12 +93492,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -92375,26 +93505,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061377, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061271, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298678", - "name" : "Recommendation PA166298678", + "id" : "PA166298664", + "name" : "Recommendation PA166298664", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -92410,7 +93540,7 @@ "CYP2C19: n/a", "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -92418,42 +93548,42 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061280, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452061266, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298630", - "name" : "Recommendation PA166298630", - "alternateDrugAvailable" : true, + "id" : "PA166298677", + "name" : "Recommendation PA166298677", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: n/a", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -92461,26 +93591,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061232, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061279, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298638", - "name" : "Recommendation PA166298638", + "id" : "PA166298668", + "name" : "Recommendation PA166298668", "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, @@ -92496,7 +93626,7 @@ "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -92504,42 +93634,42 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061240, + "id" : 1452061270, "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298735", - "name" : "Recommendation PA166298735", - "alternateDrugAvailable" : true, + "id" : "PA166298663", + "name" : "Recommendation PA166298663", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: n/a", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -92547,42 +93677,42 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061337, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452061265, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298722", - "name" : "Recommendation PA166298722", - "alternateDrugAvailable" : true, + "id" : "PA166298676", + "name" : "Recommendation PA166298676", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: n/a", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -92590,26 +93720,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061324, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452061278, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298625", - "name" : "Recommendation PA166298625", + "id" : "PA166298667", + "name" : "Recommendation PA166298667", "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, @@ -92620,12 +93750,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -92633,42 +93763,42 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061227, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061269, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298612", - "name" : "Recommendation PA166298612", - "alternateDrugAvailable" : true, + "id" : "PA166298662", + "name" : "Recommendation PA166298662", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: n/a", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -92676,27 +93806,70 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061214, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061264, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298757", - "name" : "Recommendation PA166298757", - "alternateDrugAvailable" : true, + "id" : "PA166298675", + "name" : "Recommendation PA166298675", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501930, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : false, + "implications" : [ + "CYP2C19: n/a", + "CYP2D6: Normal metabolism of TCAs" + ], + "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "No Result"}, + "otherPrescribingGuidance" : false, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA451791", + "name" : "trimipramine", + "version" : 29 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166105001", + "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", + "version" : 96 + }, + "text" : { + "id" : 1452061277, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "version" : 0 + }, + "version" : 1 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166298666", + "name" : "Recommendation PA166298666", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -92706,12 +93879,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -92719,42 +93892,42 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061359, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061268, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298744", - "name" : "Recommendation PA166298744", - "alternateDrugAvailable" : true, + "id" : "PA166298661", + "name" : "Recommendation PA166298661", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -92762,26 +93935,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061346, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452061263, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298691", - "name" : "Recommendation PA166298691", + "id" : "PA166298708", + "name" : "Recommendation PA166298708", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -92797,7 +93970,7 @@ "CYP2C19: Normal metabolism of tertiary amines", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -92805,17 +93978,17 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061293, + "id" : 1452061310, "html" : "

Avoid trimipramine use; If trimipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", "version" : 0 }, @@ -92823,8 +93996,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298647", - "name" : "Recommendation PA166298647", + "id" : "PA166298710", + "name" : "Recommendation PA166298710", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -92837,10 +94010,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -92848,26 +94021,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061249, - "html" : "

Avoid trimipramine use. If trimipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452061312, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298731", - "name" : "Recommendation PA166298731", + "id" : "PA166298711", + "name" : "Recommendation PA166298711", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -92880,10 +94053,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -92891,27 +94064,27 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061333, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452061313, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298634", - "name" : "Recommendation PA166298634", - "alternateDrugAvailable" : false, + "id" : "PA166298712", + "name" : "Recommendation PA166298712", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -92923,10 +94096,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -92934,26 +94107,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061236, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452061314, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298618", - "name" : "Recommendation PA166298618", + "id" : "PA166298714", + "name" : "Recommendation PA166298714", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -92966,10 +94139,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -92977,18 +94150,18 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061220, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061316, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 @@ -93020,14 +94193,14 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { "id" : 1452061317, @@ -93038,8 +94211,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298697", - "name" : "Recommendation PA166298697", + "id" : "PA166298716", + "name" : "Recommendation PA166298716", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -93052,10 +94225,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -93063,27 +94236,27 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061299, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061318, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298794", - "name" : "Recommendation PA166298794", - "alternateDrugAvailable" : false, + "id" : "PA166298717", + "name" : "Recommendation PA166298717", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -93093,12 +94266,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: n/a" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -93106,27 +94279,27 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061396, - "html" : "

No recommendation

\n", + "id" : 1452061319, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298605", - "name" : "Recommendation PA166298605", - "alternateDrugAvailable" : false, + "id" : "PA166298718", + "name" : "Recommendation PA166298718", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -93138,10 +94311,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -93149,26 +94322,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061207, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452061320, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298702", - "name" : "Recommendation PA166298702", + "id" : "PA166298720", + "name" : "Recommendation PA166298720", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -93181,10 +94354,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -93192,26 +94365,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061304, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", + "id" : 1452061322, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298684", - "name" : "Recommendation PA166298684", + "id" : "PA166298721", + "name" : "Recommendation PA166298721", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -93224,10 +94397,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -93235,26 +94408,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061286, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061323, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298781", - "name" : "Recommendation PA166298781", + "id" : "PA166298722", + "name" : "Recommendation PA166298722", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -93267,10 +94440,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -93278,26 +94451,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061383, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452061324, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298737", - "name" : "Recommendation PA166298737", + "id" : "PA166298723", + "name" : "Recommendation PA166298723", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -93313,7 +94486,7 @@ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -93321,17 +94494,17 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061339, + "id" : 1452061325, "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, @@ -93339,8 +94512,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298671", - "name" : "Recommendation PA166298671", + "id" : "PA166298725", + "name" : "Recommendation PA166298725", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -93353,10 +94526,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -93364,27 +94537,27 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061273, - "html" : "

Avoid trimipramine use. If trimipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452061327, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298627", - "name" : "Recommendation PA166298627", - "alternateDrugAvailable" : false, + "id" : "PA166298726", + "name" : "Recommendation PA166298726", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -93396,10 +94569,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -93407,56 +94580,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166105001", - "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 - }, - "text" : { - "id" : 1452061229, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166301446", - "name" : "Recommendation Annotation PA166301446", - "alternateDrugAvailable" : false, - "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Normal Metabolizer"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA451791", - "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452095785, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "id" : 1452061328, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298724", - "name" : "Recommendation PA166298724", + "id" : "PA166298727", + "name" : "Recommendation PA166298727", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -93472,7 +94615,7 @@ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -93480,17 +94623,17 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061326, + "id" : 1452061329, "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, @@ -93498,8 +94641,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298711", - "name" : "Recommendation PA166298711", + "id" : "PA166298728", + "name" : "Recommendation PA166298728", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -93512,10 +94655,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -93523,26 +94666,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061313, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061330, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298719", - "name" : "Recommendation PA166298719", + "id" : "PA166298729", + "name" : "Recommendation PA166298729", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -93555,53 +94698,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Poor Metabolizer"}, - "otherPrescribingGuidance" : false, - "population" : "general", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA451791", - "name" : "trimipramine", - "version" : 8 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166105001", - "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 - }, - "text" : { - "id" : 1452061321, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166298798", - "name" : "Recommendation PA166298798", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 981501930, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: n/a" - ], - "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -93609,26 +94709,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061400, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452061331, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298750", - "name" : "Recommendation PA166298750", + "id" : "PA166298731", + "name" : "Recommendation PA166298731", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -93641,10 +94741,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -93652,26 +94752,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061352, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452061333, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298653", - "name" : "Recommendation PA166298653", + "id" : "PA166298732", + "name" : "Recommendation PA166298732", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -93685,9 +94785,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -93695,26 +94795,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061255, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452061334, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298609", - "name" : "Recommendation PA166298609", + "id" : "PA166298733", + "name" : "Recommendation PA166298733", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -93727,10 +94827,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -93738,26 +94838,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061211, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061335, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298706", - "name" : "Recommendation PA166298706", + "id" : "PA166298734", + "name" : "Recommendation PA166298734", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -93770,10 +94870,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -93781,26 +94881,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061308, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", + "id" : 1452061336, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298785", - "name" : "Recommendation PA166298785", + "id" : "PA166298736", + "name" : "Recommendation PA166298736", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -93813,10 +94913,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -93824,26 +94924,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061387, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452061338, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298688", - "name" : "Recommendation PA166298688", + "id" : "PA166298737", + "name" : "Recommendation PA166298737", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -93856,10 +94956,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -93867,27 +94967,27 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061290, - "html" : "

Avoid tricyclic use due to potential for side effects. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452061339, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298803", - "name" : "Recommendation PA166298803", - "alternateDrugAvailable" : false, + "id" : "PA166298738", + "name" : "Recommendation PA166298738", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -93897,12 +94997,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: n/a" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -93910,27 +95010,27 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061405, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452061340, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298640", - "name" : "Recommendation PA166298640", - "alternateDrugAvailable" : false, + "id" : "PA166298739", + "name" : "Recommendation PA166298739", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -93940,12 +95040,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -93953,26 +95053,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061242, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452061341, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298772", - "name" : "Recommendation PA166298772", + "id" : "PA166298740", + "name" : "Recommendation PA166298740", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -93985,10 +95085,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -93996,42 +95096,42 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061374, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061342, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298675", - "name" : "Recommendation PA166298675", - "alternateDrugAvailable" : false, + "id" : "PA166298742", + "name" : "Recommendation PA166298742", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -94039,26 +95139,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061277, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452061344, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298728", - "name" : "Recommendation PA166298728", + "id" : "PA166298743", + "name" : "Recommendation PA166298743", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -94074,7 +95174,7 @@ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -94082,17 +95182,17 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061330, + "id" : 1452061345, "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, @@ -94100,54 +95200,24 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301442", - "name" : "Recommendation Annotation PA166301442", - "alternateDrugAvailable" : false, - "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Intermediate Metabolizer"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA451791", - "name" : "trimipramine", - "version" : 8 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166105001", - "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 - }, - "text" : { - "id" : 1452095781, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166298662", - "name" : "Recommendation PA166298662", - "alternateDrugAvailable" : false, + "id" : "PA166298744", + "name" : "Recommendation PA166298744", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ "CYP2C19: n/a", - "CYP2D6: Normal metabolism of TCAs" + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -94155,56 +95225,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061264, - "html" : "

No recommendation

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166301441", - "name" : "Recommendation Annotation PA166301441", - "alternateDrugAvailable" : false, - "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Indeterminate"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA451791", - "name" : "trimipramine", - "version" : 8 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166105001", - "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 - }, - "text" : { - "id" : 1452095780, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "id" : 1452061346, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298767", - "name" : "Recommendation PA166298767", + "id" : "PA166298745", + "name" : "Recommendation PA166298745", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -94217,10 +95257,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -94228,26 +95268,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061369, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061347, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298754", - "name" : "Recommendation PA166298754", + "id" : "PA166298747", + "name" : "Recommendation PA166298747", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -94263,7 +95303,7 @@ "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -94271,17 +95311,17 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061356, + "id" : 1452061349, "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, @@ -94289,9 +95329,9 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298657", - "name" : "Recommendation PA166298657", - "alternateDrugAvailable" : false, + "id" : "PA166298749", + "name" : "Recommendation PA166298749", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -94301,12 +95341,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: n/a", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -94314,26 +95354,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061259, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452061351, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298741", - "name" : "Recommendation PA166298741", + "id" : "PA166298750", + "name" : "Recommendation PA166298750", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -94346,53 +95386,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Ultrarapid Metabolizer"}, - "otherPrescribingGuidance" : false, - "population" : "general", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA451791", - "name" : "trimipramine", - "version" : 8 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166105001", - "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 - }, - "text" : { - "id" : 1452061343, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166298644", - "name" : "Recommendation PA166298644", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 981501930, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Normal metabolism of TCAs" - ], - "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -94400,27 +95397,27 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061246, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452061352, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298789", - "name" : "Recommendation PA166298789", - "alternateDrugAvailable" : false, + "id" : "PA166298751", + "name" : "Recommendation PA166298751", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -94430,12 +95427,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: n/a" + "CYP2C19: n/a", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -94443,26 +95440,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061391, - "html" : "

No recommendation

\n", + "id" : 1452061353, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298776", - "name" : "Recommendation PA166298776", + "id" : "PA166298752", + "name" : "Recommendation PA166298752", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -94475,10 +95472,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -94486,26 +95483,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061378, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061354, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298631", - "name" : "Recommendation PA166298631", + "id" : "PA166298754", + "name" : "Recommendation PA166298754", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -94518,10 +95515,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: n/a", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -94529,42 +95526,42 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061233, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061356, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298679", - "name" : "Recommendation PA166298679", - "alternateDrugAvailable" : false, + "id" : "PA166298755", + "name" : "Recommendation PA166298755", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ "CYP2C19: n/a", - "CYP2D6: Normal metabolism of TCAs" + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -94572,26 +95569,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061281, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452061357, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298763", - "name" : "Recommendation PA166298763", + "id" : "PA166298756", + "name" : "Recommendation PA166298756", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -94607,7 +95604,7 @@ "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -94615,17 +95612,17 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061365, + "id" : 1452061358, "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, @@ -94633,9 +95630,9 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298666", - "name" : "Recommendation PA166298666", - "alternateDrugAvailable" : false, + "id" : "PA166298757", + "name" : "Recommendation PA166298757", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -94645,12 +95642,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Normal metabolism of TCAs" + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -94658,27 +95655,27 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061268, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452061359, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298626", - "name" : "Recommendation PA166298626", - "alternateDrugAvailable" : false, + "id" : "PA166298759", + "name" : "Recommendation PA166298759", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -94691,9 +95688,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -94701,26 +95698,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061228, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061361, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298723", - "name" : "Recommendation PA166298723", + "id" : "PA166298760", + "name" : "Recommendation PA166298760", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -94733,10 +95730,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -94744,26 +95741,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061325, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452061362, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298710", - "name" : "Recommendation PA166298710", + "id" : "PA166298761", + "name" : "Recommendation PA166298761", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -94776,10 +95773,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -94787,26 +95784,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061312, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", + "id" : 1452061363, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298613", - "name" : "Recommendation PA166298613", + "id" : "PA166298762", + "name" : "Recommendation PA166298762", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -94819,10 +95816,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -94830,26 +95827,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061215, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061364, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298758", - "name" : "Recommendation PA166298758", + "id" : "PA166298763", + "name" : "Recommendation PA166298763", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -94865,7 +95862,7 @@ "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -94873,17 +95870,17 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061360, + "id" : 1452061365, "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, @@ -94891,9 +95888,9 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298600", - "name" : "Recommendation PA166298600", - "alternateDrugAvailable" : false, + "id" : "PA166298765", + "name" : "Recommendation PA166298765", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -94906,9 +95903,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -94916,26 +95913,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061202, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061367, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298692", - "name" : "Recommendation PA166298692", + "id" : "PA166298766", + "name" : "Recommendation PA166298766", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -94951,7 +95948,7 @@ "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -94959,17 +95956,17 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061294, + "id" : 1452061368, "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, @@ -94977,8 +95974,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298648", - "name" : "Recommendation PA166298648", + "id" : "PA166298767", + "name" : "Recommendation PA166298767", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -94992,9 +95989,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.0", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -95002,26 +95999,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061250, - "html" : "

Avoid trimipramine use. If trimipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452061369, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298745", - "name" : "Recommendation PA166298745", + "id" : "PA166298768", + "name" : "Recommendation PA166298768", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -95034,10 +96031,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -95045,26 +96042,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061347, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452061370, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298732", - "name" : "Recommendation PA166298732", + "id" : "PA166298713", + "name" : "Recommendation PA166298713", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -95077,10 +96074,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -95088,27 +96085,27 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061334, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452061315, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298635", - "name" : "Recommendation PA166298635", - "alternateDrugAvailable" : false, + "id" : "PA166298719", + "name" : "Recommendation PA166298719", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -95120,10 +96117,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -95131,27 +96128,27 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061237, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452061321, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298622", - "name" : "Recommendation PA166298622", - "alternateDrugAvailable" : false, + "id" : "PA166298724", + "name" : "Recommendation PA166298724", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -95163,10 +96160,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.5", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -95174,57 +96171,27 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166105001", - "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 - }, - "text" : { - "id" : 1452061224, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166301449", - "name" : "Recommendation Annotation PA166301449", - "alternateDrugAvailable" : false, - "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Poor Metabolizer"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA451791", - "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452095788, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "id" : 1452061326, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298606", - "name" : "Recommendation PA166298606", - "alternateDrugAvailable" : false, + "id" : "PA166298730", + "name" : "Recommendation PA166298730", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -95236,10 +96203,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -95247,26 +96214,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061208, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452061332, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298703", - "name" : "Recommendation PA166298703", + "id" : "PA166298735", + "name" : "Recommendation PA166298735", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -95279,10 +96246,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -95290,26 +96257,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061305, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", + "id" : 1452061337, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298685", - "name" : "Recommendation PA166298685", + "id" : "PA166298746", + "name" : "Recommendation PA166298746", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -95323,9 +96290,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: n/a", - "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -95333,26 +96300,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061287, - "html" : "

Avoid tricyclic use due to potential for side effects. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452061348, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298800", - "name" : "Recommendation PA166298800", + "id" : "PA166298753", + "name" : "Recommendation PA166298753", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -95365,10 +96332,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: n/a" + "CYP2C19: n/a", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -95376,26 +96343,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061402, - "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. If a tertiary amine is warranted, utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452061355, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298782", - "name" : "Recommendation PA166298782", + "id" : "PA166298758", + "name" : "Recommendation PA166298758", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -95408,10 +96375,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -95419,26 +96386,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061384, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452061360, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { - "objCls" : "Recommendation Annotation", - "id" : "PA166298738", - "name" : "Recommendation PA166298738", + "objCls" : "Recommendation Annotation", + "id" : "PA166298764", + "name" : "Recommendation PA166298764", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -95451,10 +96418,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -95462,27 +96429,27 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061340, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452061366, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298672", - "name" : "Recommendation PA166298672", - "alternateDrugAvailable" : true, + "id" : "PA166298748", + "name" : "Recommendation PA166298748", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -95492,12 +96459,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: n/a", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -95505,27 +96472,27 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061274, - "html" : "

Avoid trimipramine use. If trimipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452061350, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298628", - "name" : "Recommendation PA166298628", - "alternateDrugAvailable" : false, + "id" : "PA166298770", + "name" : "Recommendation PA166298770", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -95537,10 +96504,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -95548,26 +96515,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061230, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061372, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298725", - "name" : "Recommendation PA166298725", + "id" : "PA166298771", + "name" : "Recommendation PA166298771", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -95580,10 +96547,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -95591,26 +96558,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061327, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452061373, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298615", - "name" : "Recommendation PA166298615", + "id" : "PA166298772", + "name" : "Recommendation PA166298772", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -95623,10 +96590,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -95634,26 +96601,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061217, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061374, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298712", - "name" : "Recommendation PA166298712", + "id" : "PA166298773", + "name" : "Recommendation PA166298773", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -95669,7 +96636,7 @@ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -95677,17 +96644,17 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061314, + "id" : 1452061375, "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, @@ -95695,8 +96662,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298694", - "name" : "Recommendation PA166298694", + "id" : "PA166298774", + "name" : "Recommendation PA166298774", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -95709,10 +96676,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -95720,26 +96687,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061296, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061376, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298791", - "name" : "Recommendation PA166298791", + "id" : "PA166298776", + "name" : "Recommendation PA166298776", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -95753,9 +96720,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: n/a" + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -95763,56 +96730,69 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061393, - "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. For tertiary amines, consider a 50% reduction of the recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452061378, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301445", - "name" : "Recommendation Annotation PA166301445", - "alternateDrugAvailable" : false, - "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "No Result"}, + "id" : "PA166298777", + "name" : "Recommendation PA166298777", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981565059, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : true, + "implications" : [ + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + ], + "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, + "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452095784, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "id" : 1452061379, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298707", - "name" : "Recommendation PA166298707", + "id" : "PA166298778", + "name" : "Recommendation PA166298778", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -95825,10 +96805,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", + "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -95836,26 +96816,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061309, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", + "id" : 1452061380, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298804", - "name" : "Recommendation PA166298804", + "id" : "PA166298779", + "name" : "Recommendation PA166298779", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -95868,10 +96848,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: n/a" + "CYP2C19: n/a", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -95879,26 +96859,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061406, - "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. For tertiary amines, consider a 50% reduction of the recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452061381, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298786", - "name" : "Recommendation PA166298786", + "id" : "PA166298781", + "name" : "Recommendation PA166298781", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -95914,7 +96894,7 @@ "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -95922,17 +96902,17 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061388, + "id" : 1452061383, "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, @@ -95940,8 +96920,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298689", - "name" : "Recommendation PA166298689", + "id" : "PA166298782", + "name" : "Recommendation PA166298782", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -95954,10 +96934,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -95965,27 +96945,27 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061291, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061384, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298641", - "name" : "Recommendation PA166298641", - "alternateDrugAvailable" : false, + "id" : "PA166298783", + "name" : "Recommendation PA166298783", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -95995,12 +96975,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: n/a", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -96008,26 +96988,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061243, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452061385, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298773", - "name" : "Recommendation PA166298773", + "id" : "PA166298784", + "name" : "Recommendation PA166298784", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -96040,10 +97020,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -96051,42 +97031,42 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061375, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061386, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298676", - "name" : "Recommendation PA166298676", - "alternateDrugAvailable" : false, + "id" : "PA166298785", + "name" : "Recommendation PA166298785", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ "CYP2C19: n/a", - "CYP2D6: Normal metabolism of TCAs" + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "No Result"}, + "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -96094,26 +97074,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061278, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452061387, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298729", - "name" : "Recommendation PA166298729", + "id" : "PA166298787", + "name" : "Recommendation PA166298787", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -96126,10 +97106,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥4.0", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -96137,26 +97117,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061331, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452061389, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298760", - "name" : "Recommendation PA166298760", + "id" : "PA166298788", + "name" : "Recommendation PA166298788", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -96169,10 +97149,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.0", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -96180,42 +97160,42 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061362, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061390, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298663", - "name" : "Recommendation PA166298663", - "alternateDrugAvailable" : false, + "id" : "PA166298791", + "name" : "Recommendation PA166298791", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -96223,26 +97203,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061265, - "html" : "

No recommendation

\n", + "id" : 1452061393, + "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. For tertiary amines, consider a 50% reduction of the recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298619", - "name" : "Recommendation PA166298619", + "id" : "PA166298792", + "name" : "Recommendation PA166298792", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -96256,9 +97236,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -96266,26 +97246,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061221, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061394, + "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. If a tertiary amine is warranted, utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298716", - "name" : "Recommendation PA166298716", + "id" : "PA166298793", + "name" : "Recommendation PA166298793", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -96298,10 +97278,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "≥3.25", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -96309,27 +97289,27 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061318, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061395, + "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. If a tertiary amine is warranted, utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298795", - "name" : "Recommendation PA166298795", - "alternateDrugAvailable" : false, + "id" : "PA166298796", + "name" : "Recommendation PA166298796", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -96339,12 +97319,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -96352,26 +97332,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061397, - "html" : "

No recommendation

\n", + "id" : 1452061398, + "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. For tertiary amines, consider a 50% reduction of the recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298698", - "name" : "Recommendation PA166298698", + "id" : "PA166298799", + "name" : "Recommendation PA166298799", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -96384,10 +97364,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -96395,26 +97375,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061300, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061401, + "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. For tertiary amines, consider a 50% reduction of the recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298650", - "name" : "Recommendation PA166298650", + "id" : "PA166298800", + "name" : "Recommendation PA166298800", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -96428,9 +97408,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -96438,26 +97418,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061252, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452061402, + "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. If a tertiary amine is warranted, utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298658", - "name" : "Recommendation PA166298658", + "id" : "PA166298801", + "name" : "Recommendation PA166298801", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -96471,9 +97451,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -96481,26 +97461,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061260, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452061403, + "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. If a tertiary amine is warranted, utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298742", - "name" : "Recommendation PA166298742", + "id" : "PA166298804", + "name" : "Recommendation PA166298804", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -96513,10 +97493,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -96524,26 +97504,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061344, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452061406, + "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. For tertiary amines, consider a 50% reduction of the recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298645", - "name" : "Recommendation PA166298645", + "id" : "PA166298769", + "name" : "Recommendation PA166298769", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -96557,9 +97537,9 @@ "dosingInformation" : true, "implications" : [ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.25", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -96567,26 +97547,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061247, - "html" : "

Avoid trimipramine use. If trimipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452061371, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298777", - "name" : "Recommendation PA166298777", + "id" : "PA166298775", + "name" : "Recommendation PA166298775", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -96602,7 +97582,7 @@ "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -96610,26 +97590,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061379, + "id" : 1452061377, "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298632", - "name" : "Recommendation PA166298632", + "id" : "PA166298780", + "name" : "Recommendation PA166298780", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -96642,10 +97622,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: n/a", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -96653,26 +97633,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061234, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061382, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298764", - "name" : "Recommendation PA166298764", + "id" : "PA166298786", + "name" : "Recommendation PA166298786", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -96685,10 +97665,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2C19: n/a", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -96696,42 +97676,42 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061366, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061388, + "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298667", - "name" : "Recommendation PA166298667", + "id" : "PA166298790", + "name" : "Recommendation PA166298790", "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "1.5", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -96739,27 +97719,27 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061269, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452061392, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298799", - "name" : "Recommendation PA166298799", - "alternateDrugAvailable" : true, + "id" : "PA166298795", + "name" : "Recommendation PA166298795", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -96769,12 +97749,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -96782,27 +97762,27 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061401, - "html" : "

Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. For tertiary amines, consider a 50% reduction of the recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452061397, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298751", - "name" : "Recommendation PA166298751", - "alternateDrugAvailable" : true, + "id" : "PA166298789", + "name" : "Recommendation PA166298789", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -96812,12 +97792,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "≥3.5", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -96825,27 +97805,27 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061353, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452061391, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298654", - "name" : "Recommendation PA166298654", - "alternateDrugAvailable" : true, + "id" : "PA166298794", + "name" : "Recommendation PA166298794", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -96855,12 +97835,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: n/a", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -96868,42 +97848,42 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061256, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452061396, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298614", - "name" : "Recommendation PA166298614", - "alternateDrugAvailable" : true, + "id" : "PA166298798", + "name" : "Recommendation PA166298798", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -96911,27 +97891,27 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061216, - "html" : "

Consider alternative drug not metabolized by CYP2C19; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061400, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298759", - "name" : "Recommendation PA166298759", - "alternateDrugAvailable" : true, + "id" : "PA166298803", + "name" : "Recommendation PA166298803", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -96941,12 +97921,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -96954,27 +97934,27 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061361, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061405, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298693", - "name" : "Recommendation PA166298693", - "alternateDrugAvailable" : true, + "id" : "PA166298797", + "name" : "Recommendation PA166298797", + "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, "parents" : [], @@ -96984,12 +97964,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "4.0", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -96997,26 +97977,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061295, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061399, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298601", - "name" : "Recommendation PA166298601", + "id" : "PA166298802", + "name" : "Recommendation PA166298802", "alternateDrugAvailable" : false, "classification" : { "id" : 981565059, @@ -97027,12 +98007,12 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: n/a", + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2D6": "No Result", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -97040,284 +98020,296 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061203, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061404, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298790", - "name" : "Recommendation PA166298790", + "id" : "PA166301441", + "name" : "Recommendation Annotation PA166301441", "alternateDrugAvailable" : false, - "classification" : { - "id" : 981501930, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", - "valid" : true, - "version" : 0 - }, "dosingInformation" : false, - "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: n/a" - ], - "lookupKey" : {"CYP2D6": "n/a", "CYP2C19": "Normal Metabolizer"}, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, - "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061392, - "html" : "

No recommendation

\n", + "id" : 1452095780, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298649", - "name" : "Recommendation PA166298649", - "alternateDrugAvailable" : true, - "classification" : { - "id" : 981565059, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : true, - "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Normal metabolism of TCAs" - ], - "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Poor Metabolizer"}, + "id" : "PA166301442", + "name" : "Recommendation Annotation PA166301442", + "alternateDrugAvailable" : false, + "dosingInformation" : false, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, - "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061251, - "html" : "

Avoid trimipramine use. If trimipramine is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452095781, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298746", - "name" : "Recommendation PA166298746", - "alternateDrugAvailable" : true, - "classification" : { - "id" : 981565059, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : true, - "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" - ], - "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Indeterminate"}, + "id" : "PA166301443", + "name" : "Recommendation Annotation PA166301443", + "alternateDrugAvailable" : false, + "dosingInformation" : false, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, - "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061348, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452095782, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298733", - "name" : "Recommendation PA166298733", - "alternateDrugAvailable" : true, - "classification" : { - "id" : 981565059, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", - "valid" : true, + "id" : "PA166301444", + "name" : "Recommendation Annotation PA166301444", + "alternateDrugAvailable" : false, + "dosingInformation" : false, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Likely Poor Metabolizer"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA451791", + "name" : "trimipramine", + "version" : 29 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166105001", + "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", + "version" : 96 + }, + "text" : { + "id" : 1452095783, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", "version" : 0 }, - "dosingInformation" : true, - "implications" : [ - "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" - ], - "lookupKey" : {"CYP2D6": "2.5", "CYP2C19": "Ultrarapid Metabolizer"}, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166301445", + "name" : "Recommendation Annotation PA166301445", + "alternateDrugAvailable" : false, + "dosingInformation" : false, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "No Result"}, "otherPrescribingGuidance" : false, - "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061335, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", + "id" : 1452095784, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298680", - "name" : "Recommendation PA166298680", - "alternateDrugAvailable" : true, - "classification" : { - "id" : 981565059, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", - "valid" : true, + "id" : "PA166301446", + "name" : "Recommendation Annotation PA166301446", + "alternateDrugAvailable" : false, + "dosingInformation" : false, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Normal Metabolizer"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA451791", + "name" : "trimipramine", + "version" : 29 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166105001", + "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", + "version" : 96 + }, + "text" : { + "id" : 1452095785, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", "version" : 0 }, - "dosingInformation" : true, - "implications" : [ - "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", - "CYP2D6: Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" - ], - "lookupKey" : {"CYP2D6": "0.0", "CYP2C19": "Intermediate Metabolizer"}, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166301447", + "name" : "Recommendation Annotation PA166301447", + "alternateDrugAvailable" : false, + "dosingInformation" : false, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, - "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061282, - "html" : "

Avoid trimipramine use. If a trimipramine is warranted, consider a 50% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452095786, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298636", - "name" : "Recommendation PA166298636", + "id" : "PA166301448", + "name" : "Recommendation Annotation PA166301448", "alternateDrugAvailable" : false, - "classification" : { - "id" : 981565059, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", - "valid" : true, + "dosingInformation" : false, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Rapid Metabolizer"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA451791", + "name" : "trimipramine", + "version" : 29 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166105001", + "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", + "version" : 96 + }, + "text" : { + "id" : 1452095787, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", "version" : 0 }, - "dosingInformation" : true, - "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" - ], - "lookupKey" : {"CYP2D6": "1.0", "CYP2C19": "No Result"}, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166301449", + "name" : "Recommendation Annotation PA166301449", + "alternateDrugAvailable" : false, + "dosingInformation" : false, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations", "CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, - "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061238, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452095788, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298720", - "name" : "Recommendation PA166298720", + "id" : "PA166298692", + "name" : "Recommendation PA166298692", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -97330,10 +98322,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "≥5.0", "CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "2.75", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -97341,27 +98333,27 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061322, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061294, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298623", - "name" : "Recommendation PA166298623", - "alternateDrugAvailable" : false, + "id" : "PA166298709", + "name" : "Recommendation PA166298709", + "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, "parents" : [], @@ -97373,10 +98365,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "0.75", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -97384,26 +98376,26 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061225, - "html" : "

Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

\n", + "id" : 1452061311, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustment.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298768", - "name" : "Recommendation PA166298768", + "id" : "PA166298741", + "name" : "Recommendation PA166298741", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -97416,10 +98408,10 @@ }, "dosingInformation" : true, "implications" : [ - "CYP2C19: Greatly reduced metabolism of tertiary amines compared to normal metabolizers; Decreased conversion of tertiary amines to secondary amines may affect response or side effects", + "CYP2C19: Increased metabolism of tertiary amines compared to normal metabolizers; Greater conversion of tertiary amines to secondary amines may affect response or side effects", "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" ], - "lookupKey" : {"CYP2D6": "3.0", "CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2D6": "≥3.75", "CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -97427,42 +98419,42 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061370, - "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", + "id" : 1452061343, + "html" : "

Avoid trimipramine use; If trimipramine is warranted, utilize therapeutic drug monitoring to guide dose adjustment. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations\nfor conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, intermediate, or poor metabolism is strongly recommended

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298755", - "name" : "Recommendation PA166298755", - "alternateDrugAvailable" : true, + "id" : "PA166298644", + "name" : "Recommendation PA166298644", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: n/a", - "CYP2D6: Increased metabolism of TCAs to less active compounds compared to normal metabolizers; Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure" + "CYP2C19: Normal metabolism of tertiary amines", + "CYP2D6: Normal metabolism of TCAs" ], - "lookupKey" : {"CYP2D6": "≥6.0", "CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2D6": "2.25", "CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -97470,42 +98462,42 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061357, - "html" : "

Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

\n", + "id" : 1452061246, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298610", - "name" : "Recommendation PA166298610", + "id" : "PA166298599", + "name" : "Recommendation PA166298599", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal metabolism of tertiary amines", - "CYP2D6: Normal metabolism of TCAs" + "CYP2C19: Reduced metabolism of tertiary amines compared to normal metabolizers", + "CYP2D6: Reduced metabolism of TCAs to less active compounds compared to normal metabolizers; Higher plasma concentrations of active drug will increase the probability of side effects" ], - "lookupKey" : {"CYP2D6": "1.75", "CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2D6": "0.25", "CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -97513,21 +98505,21 @@ "objCls" : "Chemical", "id" : "PA451791", "name" : "trimipramine", - "version" : 8 + "version" : 29 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166105001", "name" : "Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6", - "version" : 51 + "version" : 96 }, "text" : { - "id" : 1452061212, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

\n", + "id" : 1452061201, + "html" : "

Consider a 25% reduction of recommended starting dose. Utilizing therapeutic drug monitoring to guide dose adjustments is strongly recommended.

\n

Other Considerations

\n

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain. Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166105001" @@ -97691,7 +98683,7 @@ "objCls" : "Chemical", "id" : "PA161925594", "name" : "tropisetron", - "version" : 10 + "version" : 20 } ], "relatedGenes" : [ @@ -97700,7 +98692,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "CPIC", @@ -97713,16 +98705,46 @@ "textMarkdown" : { "id" : 1451433620, "html" : "

This annotation is based on the CPIC® guideline for ondansetron and tropisetron and CYP2D6.

\n

October 2019 Update

\n

CYP2D6 genotype to phenotype translation changes: Up until August 2019, there were a few inconsistencies in the translation of CYP2D6 genotype to phenotype translation across guidelines (i.e. CPIC and DPWG) and between clinical genetic testing laboratories. CPIC recently conducted a modified-Delphi project to obtain consensus for a uniform system for translating CYP2D6 genotype to phenotype among a panel of international CYP2D6 experts more information. Modifications to CPIC’s prior system include downgrading the value assigned to the CYP2D6*10 allele for activity score calculation from 0.5 to 0.25 and changing the phenotype assignment for an activity score of 1 from normal metabolizer to intermediate metabolizer (table of all previous and new phenotype groupings).

\n

As a result, the following changes have been made in the CYP2D6 allele functionality table, CYP2D6 genotype to phenotype table (access tables below):

\n\n

December 2016

\n\n

Table 1: Dosing recommendations for tropisetron based on CYP2D6 phenotype/genotype

\n

Adapted from Tables 1 and 2 of the 2016 guideline manuscript.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
CYP2D6 PhenotypeActivity scoreCYP2D6 GenotypesaExamples of diplotypesImplicationsTherapeutic recommendationsClassification of RecommendationsbConsideration for alternative 5-HT3 receptor antagonists antiemeticsc
Ultrarapid metabolizer>2.0An individual carrying duplications of function alleles*1/*1xN, *1/*2xN, *2/*2xNdIncreased metabolism to less active compounds when compared to normal metabolizers and is associated with decreased response to ondansetron and tropisetron (i.e. vomiting).Select and alternative drug not predominantly metabolized by CYP2D6 (i.e. granisetron).eModerateDolasetron, palonosetron, and ramosetron are also metabolized by CYP2D6. Limited evidence is available regarding the utilization of CYP2D6 genetic variation to guide use of these drugs.
Normal metabolizer2.0-1.0fAn individual carrying two normal function alleles, or two decreased function alleles, or one normal function and one no function allele, or one normal function and one decreased function allele, or combinations of duplicated alleles that result in an activity score of 1.0-2.0*1/*1, *1/*2, *1/*4, *1/*5, *1/*9, *1/*41, *2/*2,*41/*41Normal metabolismInitiate therapy with recommended starting dose.Strong
Intermediate metabolizer0.5An individual carrying one decreased function and one no function allele*4/*10,*4/*41, *5/*9Very limited data available for CYP2D6 intermediate metabolizersInsufficient evidence demonstrating clinical impact based on CYP2D6 genotype. Initiate therapy with recommended starting dose.No recommendation
Poor metabolizer0An individual carrying no functional alleles*3/*4,*4/*4, *5/*5, *5/*6Very limited data available for CYP2D6 poor metabolizersInsufficient evidence demonstrating clinical impact based on CYP2D6 genotype. Initiate therapy with recommended starting dose.No recommendation
\n

a Assignment of allele function and citations for allele function can be found on PharmGKB: CYP2D6 Allele Definition Table and CYP2D6 Allele Functionality Table.

\n

b Rating scheme is described in the 2016 Supplement

\n

c CPIC strength of recommendation: No Recommendation. See rating scheme described in the Supplement.

\n

d Where xN represents the number of CYP2D6 gene copies. For individuals with CYP2D6 duplications or multiplications, see supplemental data for additional information on how to translate diplotypes into phenotypes.

\n

e Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy.

\n

f Patients with an activity score of 1.0 may be classified as intermediate metabolizers by some reference laboratories.

\n", - "version" : 1 + "version" : 2 }, "userId" : "carrillo", - "version" : 34 + "version" : 87 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166298325", - "name" : "Recommendation PA166298325", + "id" : "PA166301330", + "name" : "Recommendation Annotation PA166301330", + "alternateDrugAvailable" : false, + "dosingInformation" : false, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA161925594", + "name" : "tropisetron", + "version" : 20 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166161955", + "name" : "Annotation of CPIC Guideline for tropisetron and CYP2D6", + "version" : 87 + }, + "text" : { + "id" : 1452095649, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166298315", + "name" : "Recommendation PA166298315", "alternateDrugAvailable" : true, "classification" : { "id" : 981501931, @@ -97737,7 +98759,7 @@ "implications" : [ "CYP2D6: Increased metabolism to less active compounds when compared to normal metabolizers and is associated with decreased response to ondansetron and tropisetron (i.e. vomiting)." ], - "lookupKey" : {"CYP2D6": "2.5"}, + "lookupKey" : {"CYP2D6": "≥6.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -97745,17 +98767,17 @@ "objCls" : "Chemical", "id" : "PA161925594", "name" : "tropisetron", - "version" : 10 + "version" : 20 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161955", "name" : "Annotation of CPIC Guideline for tropisetron and CYP2D6", - "version" : 34 + "version" : 87 }, "text" : { - "id" : 1452060927, + "id" : 1452060917, "html" : "

Select alternative drug not predominantly metabolized by CYP2D6 (i.e., granisetron).

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy. Dolasetron, palonosetron, and ramosetron are also metabolized by CYP2D6. Limited evidence is available regarding the utilization of CYP2D6 genetic variation to guide use of these drugs.

\n", "version" : 0 }, @@ -97763,8 +98785,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298321", - "name" : "Recommendation PA166298321", + "id" : "PA166298316", + "name" : "Recommendation PA166298316", "alternateDrugAvailable" : true, "classification" : { "id" : 981501931, @@ -97779,7 +98801,7 @@ "implications" : [ "CYP2D6: Increased metabolism to less active compounds when compared to normal metabolizers and is associated with decreased response to ondansetron and tropisetron (i.e. vomiting)." ], - "lookupKey" : {"CYP2D6": "≥3.0"}, + "lookupKey" : {"CYP2D6": "≥5.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -97787,17 +98809,17 @@ "objCls" : "Chemical", "id" : "PA161925594", "name" : "tropisetron", - "version" : 10 + "version" : 20 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161955", "name" : "Annotation of CPIC Guideline for tropisetron and CYP2D6", - "version" : 34 + "version" : 87 }, "text" : { - "id" : 1452060923, + "id" : 1452060918, "html" : "

Select alternative drug not predominantly metabolized by CYP2D6 (i.e., granisetron).

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy. Dolasetron, palonosetron, and ramosetron are also metabolized by CYP2D6. Limited evidence is available regarding the utilization of CYP2D6 genetic variation to guide use of these drugs.

\n", "version" : 0 }, @@ -97805,23 +98827,23 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298334", - "name" : "Recommendation PA166298334", - "alternateDrugAvailable" : false, + "id" : "PA166298318", + "name" : "Recommendation PA166298318", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Very limited data available for CYP2D6 intermediate metabolizers" + "CYP2D6: Increased metabolism to less active compounds when compared to normal metabolizers and is associated with decreased response to ondansetron and tropisetron (i.e. vomiting)." ], - "lookupKey" : {"CYP2D6": "0.25"}, + "lookupKey" : {"CYP2D6": "≥4.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -97829,26 +98851,26 @@ "objCls" : "Chemical", "id" : "PA161925594", "name" : "tropisetron", - "version" : 10 + "version" : 20 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161955", "name" : "Annotation of CPIC Guideline for tropisetron and CYP2D6", - "version" : 34 + "version" : 87 }, "text" : { - "id" : 1452060936, - "html" : "

Insufficient evidence demonstrating clinical impact based on CYP2D6 genotype. Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy.

\n", + "id" : 1452060920, + "html" : "

Select alternative drug not predominantly metabolized by CYP2D6 (i.e., granisetron).

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy. Dolasetron, palonosetron, and ramosetron are also metabolized by CYP2D6. Limited evidence is available regarding the utilization of CYP2D6 genetic variation to guide use of these drugs.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298316", - "name" : "Recommendation PA166298316", + "id" : "PA166298319", + "name" : "Recommendation PA166298319", "alternateDrugAvailable" : true, "classification" : { "id" : 981501931, @@ -97863,7 +98885,7 @@ "implications" : [ "CYP2D6: Increased metabolism to less active compounds when compared to normal metabolizers and is associated with decreased response to ondansetron and tropisetron (i.e. vomiting)." ], - "lookupKey" : {"CYP2D6": "≥5.0"}, + "lookupKey" : {"CYP2D6": "≥3.5"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -97871,17 +98893,17 @@ "objCls" : "Chemical", "id" : "PA161925594", "name" : "tropisetron", - "version" : 10 + "version" : 20 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161955", "name" : "Annotation of CPIC Guideline for tropisetron and CYP2D6", - "version" : 34 + "version" : 87 }, "text" : { - "id" : 1452060918, + "id" : 1452060921, "html" : "

Select alternative drug not predominantly metabolized by CYP2D6 (i.e., granisetron).

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy. Dolasetron, palonosetron, and ramosetron are also metabolized by CYP2D6. Limited evidence is available regarding the utilization of CYP2D6 genetic variation to guide use of these drugs.

\n", "version" : 0 }, @@ -97889,23 +98911,23 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298329", - "name" : "Recommendation PA166298329", - "alternateDrugAvailable" : false, + "id" : "PA166298320", + "name" : "Recommendation PA166298320", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Normal metabolism" + "CYP2D6: Increased metabolism to less active compounds when compared to normal metabolizers and is associated with decreased response to ondansetron and tropisetron (i.e. vomiting)." ], - "lookupKey" : {"CYP2D6": "1.5"}, + "lookupKey" : {"CYP2D6": "≥3.25"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -97913,41 +98935,41 @@ "objCls" : "Chemical", "id" : "PA161925594", "name" : "tropisetron", - "version" : 10 + "version" : 20 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161955", "name" : "Annotation of CPIC Guideline for tropisetron and CYP2D6", - "version" : 34 + "version" : 87 }, "text" : { - "id" : 1452060931, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy.

\n", + "id" : 1452060922, + "html" : "

Select alternative drug not predominantly metabolized by CYP2D6 (i.e., granisetron).

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy. Dolasetron, palonosetron, and ramosetron are also metabolized by CYP2D6. Limited evidence is available regarding the utilization of CYP2D6 genetic variation to guide use of these drugs.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298335", - "name" : "Recommendation PA166298335", - "alternateDrugAvailable" : false, + "id" : "PA166298321", + "name" : "Recommendation PA166298321", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Very limited data available for CYP2D6 poor metabolizers" + "CYP2D6: Increased metabolism to less active compounds when compared to normal metabolizers and is associated with decreased response to ondansetron and tropisetron (i.e. vomiting)." ], - "lookupKey" : {"CYP2D6": "0.0"}, + "lookupKey" : {"CYP2D6": "≥3.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -97955,41 +98977,41 @@ "objCls" : "Chemical", "id" : "PA161925594", "name" : "tropisetron", - "version" : 10 + "version" : 20 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161955", "name" : "Annotation of CPIC Guideline for tropisetron and CYP2D6", - "version" : 34 + "version" : 87 }, "text" : { - "id" : 1452060937, - "html" : "

Insufficient evidence demonstrating clinical impact based on CYP2D6 genotype. Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy.

\n", + "id" : 1452060923, + "html" : "

Select alternative drug not predominantly metabolized by CYP2D6 (i.e., granisetron).

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy. Dolasetron, palonosetron, and ramosetron are also metabolized by CYP2D6. Limited evidence is available regarding the utilization of CYP2D6 genetic variation to guide use of these drugs.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298326", - "name" : "Recommendation PA166298326", - "alternateDrugAvailable" : false, + "id" : "PA166298322", + "name" : "Recommendation PA166298322", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Normal metabolism" + "CYP2D6: Increased metabolism to less active compounds when compared to normal metabolizers and is associated with decreased response to ondansetron and tropisetron (i.e. vomiting)." ], - "lookupKey" : {"CYP2D6": "2.25"}, + "lookupKey" : {"CYP2D6": "4.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -97997,41 +99019,41 @@ "objCls" : "Chemical", "id" : "PA161925594", "name" : "tropisetron", - "version" : 10 + "version" : 20 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161955", "name" : "Annotation of CPIC Guideline for tropisetron and CYP2D6", - "version" : 34 + "version" : 87 }, "text" : { - "id" : 1452060928, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy.

\n", + "id" : 1452060924, + "html" : "

Select alternative drug not predominantly metabolized by CYP2D6 (i.e., granisetron).

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy. Dolasetron, palonosetron, and ramosetron are also metabolized by CYP2D6. Limited evidence is available regarding the utilization of CYP2D6 genetic variation to guide use of these drugs.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298331", - "name" : "Recommendation PA166298331", - "alternateDrugAvailable" : false, + "id" : "PA166298324", + "name" : "Recommendation PA166298324", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Very limited data available for CYP2D6 intermediate metabolizers" + "CYP2D6: Increased metabolism to less active compounds when compared to normal metabolizers and is associated with decreased response to ondansetron and tropisetron (i.e. vomiting)." ], - "lookupKey" : {"CYP2D6": "1.0"}, + "lookupKey" : {"CYP2D6": "3.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -98039,26 +99061,26 @@ "objCls" : "Chemical", "id" : "PA161925594", "name" : "tropisetron", - "version" : 10 + "version" : 20 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161955", "name" : "Annotation of CPIC Guideline for tropisetron and CYP2D6", - "version" : 34 + "version" : 87 }, "text" : { - "id" : 1452060933, - "html" : "

Insufficient evidence demonstrating clinical impact based on CYP2D6 genotype. Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy.

\n", + "id" : 1452060926, + "html" : "

Select alternative drug not predominantly metabolized by CYP2D6 (i.e., granisetron).

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy. Dolasetron, palonosetron, and ramosetron are also metabolized by CYP2D6. Limited evidence is available regarding the utilization of CYP2D6 genetic variation to guide use of these drugs.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298322", - "name" : "Recommendation PA166298322", + "id" : "PA166298325", + "name" : "Recommendation PA166298325", "alternateDrugAvailable" : true, "classification" : { "id" : 981501931, @@ -98073,7 +99095,7 @@ "implications" : [ "CYP2D6: Increased metabolism to less active compounds when compared to normal metabolizers and is associated with decreased response to ondansetron and tropisetron (i.e. vomiting)." ], - "lookupKey" : {"CYP2D6": "4.0"}, + "lookupKey" : {"CYP2D6": "2.5"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -98081,17 +99103,17 @@ "objCls" : "Chemical", "id" : "PA161925594", "name" : "tropisetron", - "version" : 10 + "version" : 20 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161955", "name" : "Annotation of CPIC Guideline for tropisetron and CYP2D6", - "version" : 34 + "version" : 87 }, "text" : { - "id" : 1452060924, + "id" : 1452060927, "html" : "

Select alternative drug not predominantly metabolized by CYP2D6 (i.e., granisetron).

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy. Dolasetron, palonosetron, and ramosetron are also metabolized by CYP2D6. Limited evidence is available regarding the utilization of CYP2D6 genetic variation to guide use of these drugs.

\n", "version" : 0 }, @@ -98099,8 +99121,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298330", - "name" : "Recommendation PA166298330", + "id" : "PA166298326", + "name" : "Recommendation PA166298326", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -98115,7 +99137,7 @@ "implications" : [ "CYP2D6: Normal metabolism" ], - "lookupKey" : {"CYP2D6": "1.25"}, + "lookupKey" : {"CYP2D6": "2.25"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -98123,41 +99145,41 @@ "objCls" : "Chemical", "id" : "PA161925594", "name" : "tropisetron", - "version" : 10 + "version" : 20 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161955", "name" : "Annotation of CPIC Guideline for tropisetron and CYP2D6", - "version" : 34 + "version" : 87 }, "text" : { - "id" : 1452060932, + "id" : 1452060928, "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298317", - "name" : "Recommendation PA166298317", - "alternateDrugAvailable" : true, + "id" : "PA166298327", + "name" : "Recommendation PA166298327", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Increased metabolism to less active compounds when compared to normal metabolizers and is associated with decreased response to ondansetron and tropisetron (i.e. vomiting)." + "CYP2D6: Normal metabolism" ], - "lookupKey" : {"CYP2D6": "≥3.75"}, + "lookupKey" : {"CYP2D6": "2.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -98165,41 +99187,41 @@ "objCls" : "Chemical", "id" : "PA161925594", "name" : "tropisetron", - "version" : 10 + "version" : 20 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161955", "name" : "Annotation of CPIC Guideline for tropisetron and CYP2D6", - "version" : 34 + "version" : 87 }, "text" : { - "id" : 1452060919, - "html" : "

Select alternative drug not predominantly metabolized by CYP2D6 (i.e., granisetron).

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy. Dolasetron, palonosetron, and ramosetron are also metabolized by CYP2D6. Limited evidence is available regarding the utilization of CYP2D6 genetic variation to guide use of these drugs.

\n", + "id" : 1452060929, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298323", - "name" : "Recommendation PA166298323", - "alternateDrugAvailable" : true, + "id" : "PA166298328", + "name" : "Recommendation PA166298328", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Increased metabolism to less active compounds when compared to normal metabolizers and is associated with decreased response to ondansetron and tropisetron (i.e. vomiting)." + "CYP2D6: Normal metabolism" ], - "lookupKey" : {"CYP2D6": "2.75"}, + "lookupKey" : {"CYP2D6": "1.75"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -98207,41 +99229,41 @@ "objCls" : "Chemical", "id" : "PA161925594", "name" : "tropisetron", - "version" : 10 + "version" : 20 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161955", "name" : "Annotation of CPIC Guideline for tropisetron and CYP2D6", - "version" : 34 + "version" : 87 }, "text" : { - "id" : 1452060925, - "html" : "

Select alternative drug not predominantly metabolized by CYP2D6 (i.e., granisetron).

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy. Dolasetron, palonosetron, and ramosetron are also metabolized by CYP2D6. Limited evidence is available regarding the utilization of CYP2D6 genetic variation to guide use of these drugs.

\n", + "id" : 1452060930, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298336", - "name" : "Recommendation PA166298336", + "id" : "PA166298329", + "name" : "Recommendation PA166298329", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: n/a" + "CYP2D6: Normal metabolism" ], - "lookupKey" : {"CYP2D6": "n/a"}, + "lookupKey" : {"CYP2D6": "1.5"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -98249,26 +99271,26 @@ "objCls" : "Chemical", "id" : "PA161925594", "name" : "tropisetron", - "version" : 10 + "version" : 20 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161955", "name" : "Annotation of CPIC Guideline for tropisetron and CYP2D6", - "version" : 34 + "version" : 87 }, "text" : { - "id" : 1452060938, - "html" : "

No recommendation

\n", + "id" : 1452060931, + "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298327", - "name" : "Recommendation PA166298327", + "id" : "PA166298330", + "name" : "Recommendation PA166298330", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -98283,7 +99305,7 @@ "implications" : [ "CYP2D6: Normal metabolism" ], - "lookupKey" : {"CYP2D6": "2.0"}, + "lookupKey" : {"CYP2D6": "1.25"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -98291,26 +99313,26 @@ "objCls" : "Chemical", "id" : "PA161925594", "name" : "tropisetron", - "version" : 10 + "version" : 20 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161955", "name" : "Annotation of CPIC Guideline for tropisetron and CYP2D6", - "version" : 34 + "version" : 87 }, "text" : { - "id" : 1452060929, + "id" : 1452060932, "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298332", - "name" : "Recommendation PA166298332", + "id" : "PA166298331", + "name" : "Recommendation PA166298331", "alternateDrugAvailable" : false, "classification" : { "id" : 1448526251, @@ -98325,7 +99347,7 @@ "implications" : [ "CYP2D6: Very limited data available for CYP2D6 intermediate metabolizers" ], - "lookupKey" : {"CYP2D6": "0.75"}, + "lookupKey" : {"CYP2D6": "1.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -98333,41 +99355,41 @@ "objCls" : "Chemical", "id" : "PA161925594", "name" : "tropisetron", - "version" : 10 + "version" : 20 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161955", "name" : "Annotation of CPIC Guideline for tropisetron and CYP2D6", - "version" : 34 + "version" : 87 }, "text" : { - "id" : 1452060934, + "id" : 1452060933, "html" : "

Insufficient evidence demonstrating clinical impact based on CYP2D6 genotype. Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298318", - "name" : "Recommendation PA166298318", - "alternateDrugAvailable" : true, + "id" : "PA166298332", + "name" : "Recommendation PA166298332", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Increased metabolism to less active compounds when compared to normal metabolizers and is associated with decreased response to ondansetron and tropisetron (i.e. vomiting)." + "CYP2D6: Very limited data available for CYP2D6 intermediate metabolizers" ], - "lookupKey" : {"CYP2D6": "≥4.0"}, + "lookupKey" : {"CYP2D6": "0.75"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -98375,41 +99397,41 @@ "objCls" : "Chemical", "id" : "PA161925594", "name" : "tropisetron", - "version" : 10 + "version" : 20 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161955", "name" : "Annotation of CPIC Guideline for tropisetron and CYP2D6", - "version" : 34 + "version" : 87 }, "text" : { - "id" : 1452060920, - "html" : "

Select alternative drug not predominantly metabolized by CYP2D6 (i.e., granisetron).

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy. Dolasetron, palonosetron, and ramosetron are also metabolized by CYP2D6. Limited evidence is available regarding the utilization of CYP2D6 genetic variation to guide use of these drugs.

\n", + "id" : 1452060934, + "html" : "

Insufficient evidence demonstrating clinical impact based on CYP2D6 genotype. Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298320", - "name" : "Recommendation PA166298320", - "alternateDrugAvailable" : true, + "id" : "PA166298333", + "name" : "Recommendation PA166298333", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Increased metabolism to less active compounds when compared to normal metabolizers and is associated with decreased response to ondansetron and tropisetron (i.e. vomiting)." + "CYP2D6: Very limited data available for CYP2D6 intermediate metabolizers" ], - "lookupKey" : {"CYP2D6": "≥3.25"}, + "lookupKey" : {"CYP2D6": "0.5"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -98417,41 +99439,41 @@ "objCls" : "Chemical", "id" : "PA161925594", "name" : "tropisetron", - "version" : 10 + "version" : 20 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161955", "name" : "Annotation of CPIC Guideline for tropisetron and CYP2D6", - "version" : 34 + "version" : 87 }, "text" : { - "id" : 1452060922, - "html" : "

Select alternative drug not predominantly metabolized by CYP2D6 (i.e., granisetron).

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy. Dolasetron, palonosetron, and ramosetron are also metabolized by CYP2D6. Limited evidence is available regarding the utilization of CYP2D6 genetic variation to guide use of these drugs.

\n", + "id" : 1452060935, + "html" : "

Insufficient evidence demonstrating clinical impact based on CYP2D6 genotype. Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298324", - "name" : "Recommendation PA166298324", - "alternateDrugAvailable" : true, + "id" : "PA166298334", + "name" : "Recommendation PA166298334", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Increased metabolism to less active compounds when compared to normal metabolizers and is associated with decreased response to ondansetron and tropisetron (i.e. vomiting)." + "CYP2D6: Very limited data available for CYP2D6 intermediate metabolizers" ], - "lookupKey" : {"CYP2D6": "3.0"}, + "lookupKey" : {"CYP2D6": "0.25"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -98459,26 +99481,26 @@ "objCls" : "Chemical", "id" : "PA161925594", "name" : "tropisetron", - "version" : 10 + "version" : 20 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161955", "name" : "Annotation of CPIC Guideline for tropisetron and CYP2D6", - "version" : 34 + "version" : 87 }, "text" : { - "id" : 1452060926, - "html" : "

Select alternative drug not predominantly metabolized by CYP2D6 (i.e., granisetron).

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy. Dolasetron, palonosetron, and ramosetron are also metabolized by CYP2D6. Limited evidence is available regarding the utilization of CYP2D6 genetic variation to guide use of these drugs.

\n", + "id" : 1452060936, + "html" : "

Insufficient evidence demonstrating clinical impact based on CYP2D6 genotype. Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298333", - "name" : "Recommendation PA166298333", + "id" : "PA166298335", + "name" : "Recommendation PA166298335", "alternateDrugAvailable" : false, "classification" : { "id" : 1448526251, @@ -98491,9 +99513,9 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Very limited data available for CYP2D6 intermediate metabolizers" + "CYP2D6: Very limited data available for CYP2D6 poor metabolizers" ], - "lookupKey" : {"CYP2D6": "0.5"}, + "lookupKey" : {"CYP2D6": "0.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -98501,71 +99523,41 @@ "objCls" : "Chemical", "id" : "PA161925594", "name" : "tropisetron", - "version" : 10 + "version" : 20 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161955", "name" : "Annotation of CPIC Guideline for tropisetron and CYP2D6", - "version" : 34 + "version" : 87 }, "text" : { - "id" : 1452060935, + "id" : 1452060937, "html" : "

Insufficient evidence demonstrating clinical impact based on CYP2D6 genotype. Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301330", - "name" : "Recommendation Annotation PA166301330", + "id" : "PA166298336", + "name" : "Recommendation PA166298336", "alternateDrugAvailable" : false, - "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA161925594", - "name" : "tropisetron", - "version" : 10 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166161955", - "name" : "Annotation of CPIC Guideline for tropisetron and CYP2D6", - "version" : 34 - }, - "text" : { - "id" : 1452095649, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166298315", - "name" : "Recommendation PA166298315", - "alternateDrugAvailable" : true, "classification" : { - "id" : 981501931, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Increased metabolism to less active compounds when compared to normal metabolizers and is associated with decreased response to ondansetron and tropisetron (i.e. vomiting)." + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "≥6.0"}, + "lookupKey" : {"CYP2D6": "n/a"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -98573,41 +99565,41 @@ "objCls" : "Chemical", "id" : "PA161925594", "name" : "tropisetron", - "version" : 10 + "version" : 20 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161955", "name" : "Annotation of CPIC Guideline for tropisetron and CYP2D6", - "version" : 34 + "version" : 87 }, "text" : { - "id" : 1452060917, - "html" : "

Select alternative drug not predominantly metabolized by CYP2D6 (i.e., granisetron).

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy. Dolasetron, palonosetron, and ramosetron are also metabolized by CYP2D6. Limited evidence is available regarding the utilization of CYP2D6 genetic variation to guide use of these drugs.

\n", + "id" : 1452060938, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298328", - "name" : "Recommendation PA166298328", - "alternateDrugAvailable" : false, + "id" : "PA166298317", + "name" : "Recommendation PA166298317", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Normal metabolism" + "CYP2D6: Increased metabolism to less active compounds when compared to normal metabolizers and is associated with decreased response to ondansetron and tropisetron (i.e. vomiting)." ], - "lookupKey" : {"CYP2D6": "1.75"}, + "lookupKey" : {"CYP2D6": "≥3.75"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -98615,26 +99607,26 @@ "objCls" : "Chemical", "id" : "PA161925594", "name" : "tropisetron", - "version" : 10 + "version" : 20 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161955", "name" : "Annotation of CPIC Guideline for tropisetron and CYP2D6", - "version" : 34 + "version" : 87 }, "text" : { - "id" : 1452060930, - "html" : "

Initiate therapy with recommended starting dose.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy.

\n", + "id" : 1452060919, + "html" : "

Select alternative drug not predominantly metabolized by CYP2D6 (i.e., granisetron).

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy. Dolasetron, palonosetron, and ramosetron are also metabolized by CYP2D6. Limited evidence is available regarding the utilization of CYP2D6 genetic variation to guide use of these drugs.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298319", - "name" : "Recommendation PA166298319", + "id" : "PA166298323", + "name" : "Recommendation PA166298323", "alternateDrugAvailable" : true, "classification" : { "id" : 981501931, @@ -98649,7 +99641,7 @@ "implications" : [ "CYP2D6: Increased metabolism to less active compounds when compared to normal metabolizers and is associated with decreased response to ondansetron and tropisetron (i.e. vomiting)." ], - "lookupKey" : {"CYP2D6": "≥3.5"}, + "lookupKey" : {"CYP2D6": "2.75"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -98657,21 +99649,21 @@ "objCls" : "Chemical", "id" : "PA161925594", "name" : "tropisetron", - "version" : 10 + "version" : 20 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161955", "name" : "Annotation of CPIC Guideline for tropisetron and CYP2D6", - "version" : 34 + "version" : 87 }, "text" : { - "id" : 1452060921, + "id" : 1452060925, "html" : "

Select alternative drug not predominantly metabolized by CYP2D6 (i.e., granisetron).

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy. Dolasetron, palonosetron, and ramosetron are also metabolized by CYP2D6. Limited evidence is available regarding the utilization of CYP2D6 genetic variation to guide use of these drugs.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166161955" @@ -98745,6 +99737,7 @@ "alternateDrugAvailable" : true, "cancerGenome" : false, "crossReferences" : [], + "descriptiveVideoId" : "XczE0gkH11o", "dosingInformation" : false, "hasTestingInfo" : false, "history" : [ @@ -98761,6 +99754,13 @@ "description" : "changed table header to include \"venlafaxine\"", "type" : "Correction", "version" : 0 + }, + { + "id" : 1452508580, + "date" : "2024-06-26T05:52:29.920-07:00", + "description" : "Added video", + "type" : "Update", + "version" : 0 } ], "literature" : [ @@ -98771,7 +99771,7 @@ "pediatricMarkdown" : { "id" : 1452004104, "html" : "

Excerpts: "Citalopram, escitalopram, and sertraline had the most pharmacogenetic data supporting potential genotype-guided prescribing changes in children. Based on this evidence, the recommendations for these drugs are relevant to pediatric patients and are consistent with smaller pharmacokinetic studies available for this population." ..... "The generalizability of other recommendations to pediatric patients needs to be established. As such, clinicians treating children and adolescents should determine their applicability to younger patients while considering the unique and more limited evidence base for these medications in youth, as well as pediatric-specific differences in tolerability (e.g., activation)and disorder-specific response trajectory. Because CYP2D6, CYP2C19, and CYP2B6 activity reach adult levels by early childhood, it may be appropriate to extrapolate genotype-guided recommendations for antidepressants related to CYP2D6, CYP2C19 and CYP2B6 to adolescents or possibly younger children with close monitoring."

\n", - "version" : 0 + "version" : 1 }, "recommendation" : true, "relatedAlleles" : [], @@ -98780,7 +99780,7 @@ "objCls" : "Chemical", "id" : "PA451866", "name" : "venlafaxine", - "version" : 8 + "version" : 40 } ], "relatedGenes" : [ @@ -98789,7 +99789,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "CPIC", @@ -98802,12 +99802,96 @@ "textMarkdown" : { "id" : 1452004103, "html" : "

This annotation is based on the CPIC® guideline for CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A Genotypes and Serotonin Reuptake Inhibitor Antidepressants.

\n

February 2023

\n\n

Table 1: Dosing recommendations for venlafaxine based on CYP2D6 phenotype

\n

Adapted from Tables 1 and 2c of the guideline.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
PhenotypeActivity score
range		Activity scoreExamplesImplicationsTherapeutic
Recommendations		Classification of
recommendationa		Considerations
CYP2D6 ultrarapid metabolizer>2.25>2.25*1/*1xN, *1/*2xN, *2/*2xNcIncreased metabolism of venlafaxine to the active metabolite O-desmethylvenlafaxine (desvenlafaxine) and increased O-desmethylvenlafaxine : venlafaxine ratio as compared to CYP2D6 normal metabolizers. There is insufficient evidence supporting the clinical impact of increased O-desmethylvenlafaxine : venlafaxine ratio in CYP2D6 ultrarapid metabolizers.No action recommended based on genotype for venlafaxine because of minimal evidence regarding the impact on efficacy or side effects.No recommendation
CYP2D6 normal metabolizer1.25 <= x <= 2.251.25
1.5
1.75
2.0
2.25		*1/*10
*1/*41, *1/*9
*10/*41x3
*1/*1, *1/*2
*2x2/*10		Normal metabolism.Initiate therapy with recommended starting dose.Strong
CYP2D6 intermediate metabolizer0 < x < 1.250.25
0.5
0.75
1.0		*4/*10
*4/*41, *10/*10
*10/*41
*41/*41, *1/*5		Decreased metabolism of venlafaxine to active metabolite O-desmethylvenlafaxine (desvenlafaxine) and decreased O-desmethylvenlafaxine : venlafaxine ratio as compared to CYP2D6 normal metabolizers. There is insufficient evidence supporting the clinical impact of the decreased O-desmethylvenlafaxine:venlafaxine ratio in CYP2D6 intermediate metabolizers.No action recommended based on genotype for venlafaxine because of minimal evidence regarding the impact on efficacy or side effects.No recommendation
CYP2D6 poor metabolizer00*3/*4, *4/*4, *5/*5, *5/*6Decreased metabolism of venlafaxine to the active metabolite O-desmethylvenlafaxine (desvenlafaxine) and greatly decreased O-desmethylvenlafaxine : venlafaxine ratio as compared to CYP2D6 normal and intermediate metabolizers. The clinical impact of increased venlafaxine and decreased O-desmethylvenlafaxine:venlafaxine ratio in CYP2D6 poor metabolizers is unclear, but CYP2D6 PM genotype has been associated with adverse effects.Consider a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2D6.OptionalDrug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when adjusting dose or selecting an alternative therapy.
CYP2D6 Indeterminaten/aAn individual carrying one or two unknown or uncertain function alleles*1/*22, *1/*25, *22/*25No recommendationNo recommendation
\n

a Rating scheme described in Supplemental Materials.

\n", - "version" : 1 + "version" : 3 }, "userId" : "katrin", - "version" : 3 + "version" : 11 }, "recommendations" : [ + { + "objCls" : "Recommendation Annotation", + "id" : "PA166300947", + "name" : "Recommendation PA166300947", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 1448526251, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : false, + "implications" : [ + "CYP2D6: Increased metabolism of venlafaxine to the active metabolite O-desmethylvenlafaxine (desvenlafaxine) and increased O-desmethylvenlafaxine:venlafaxine ratio as compared to CYP2D6 normal metabolizers. There is insufficient evidence supporting the clinical impact of increased O-desmethylvenlafaxine:venlafaxine ratio in CYP2D6 ultrarapid metabolizers." + ], + "lookupKey" : {"CYP2D6": "≥3.5"}, + "otherPrescribingGuidance" : false, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA451866", + "name" : "venlafaxine", + "version" : 40 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166288201", + "name" : "Annotation of CPIC Guideline for venlafaxine and CYP2D6", + "version" : 11 + }, + "text" : { + "id" : 1452093927, + "html" : "

No action recommended based on genotype for venlafaxine because of minimal evidence regarding the impact on efficacy or side effects.

\n", + "version" : 0 + }, + "version" : 2 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166300948", + "name" : "Recommendation PA166300948", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 1448526251, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : false, + "implications" : [ + "CYP2D6: Increased metabolism of venlafaxine to the active metabolite O-desmethylvenlafaxine (desvenlafaxine) and increased O-desmethylvenlafaxine:venlafaxine ratio as compared to CYP2D6 normal metabolizers. There is insufficient evidence supporting the clinical impact of increased O-desmethylvenlafaxine:venlafaxine ratio in CYP2D6 ultrarapid metabolizers." + ], + "lookupKey" : {"CYP2D6": "≥3.25"}, + "otherPrescribingGuidance" : false, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA451866", + "name" : "venlafaxine", + "version" : 40 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166288201", + "name" : "Annotation of CPIC Guideline for venlafaxine and CYP2D6", + "version" : 11 + }, + "text" : { + "id" : 1452093928, + "html" : "

No action recommended based on genotype for venlafaxine because of minimal evidence regarding the impact on efficacy or side effects.

\n", + "version" : 0 + }, + "version" : 2 + }, { "objCls" : "Recommendation Annotation", "id" : "PA166300949", @@ -98834,41 +99918,41 @@ "objCls" : "Chemical", "id" : "PA451866", "name" : "venlafaxine", - "version" : 8 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166288201", "name" : "Annotation of CPIC Guideline for venlafaxine and CYP2D6", - "version" : 3 + "version" : 11 }, "text" : { "id" : 1452093929, "html" : "

No action recommended based on genotype for venlafaxine because of minimal evidence regarding the impact on efficacy or side effects.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300958", - "name" : "Recommendation PA166300958", + "id" : "PA166300950", + "name" : "Recommendation PA166300950", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Normal metabolism" + "CYP2D6: Increased metabolism of venlafaxine to the active metabolite O-desmethylvenlafaxine (desvenlafaxine) and increased O-desmethylvenlafaxine:venlafaxine ratio as compared to CYP2D6 normal metabolizers. There is insufficient evidence supporting the clinical impact of increased O-desmethylvenlafaxine:venlafaxine ratio in CYP2D6 ultrarapid metabolizers." ], - "lookupKey" : {"CYP2D6": "2.25"}, + "lookupKey" : {"CYP2D6": "≥6.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -98876,26 +99960,26 @@ "objCls" : "Chemical", "id" : "PA451866", "name" : "venlafaxine", - "version" : 8 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166288201", "name" : "Annotation of CPIC Guideline for venlafaxine and CYP2D6", - "version" : 3 + "version" : 11 }, "text" : { - "id" : 1452093938, - "html" : "

Initiate therapy with recommended starting dose.

\n", + "id" : 1452093930, + "html" : "

No action recommended based on genotype for venlafaxine because of minimal evidence regarding the impact on efficacy or side effects.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300953", - "name" : "Recommendation PA166300953", + "id" : "PA166300951", + "name" : "Recommendation PA166300951", "alternateDrugAvailable" : false, "classification" : { "id" : 1448526251, @@ -98910,7 +99994,7 @@ "implications" : [ "CYP2D6: Increased metabolism of venlafaxine to the active metabolite O-desmethylvenlafaxine (desvenlafaxine) and increased O-desmethylvenlafaxine:venlafaxine ratio as compared to CYP2D6 normal metabolizers. There is insufficient evidence supporting the clinical impact of increased O-desmethylvenlafaxine:venlafaxine ratio in CYP2D6 ultrarapid metabolizers." ], - "lookupKey" : {"CYP2D6": "≥3.0"}, + "lookupKey" : {"CYP2D6": "≥5.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -98918,26 +100002,26 @@ "objCls" : "Chemical", "id" : "PA451866", "name" : "venlafaxine", - "version" : 8 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166288201", "name" : "Annotation of CPIC Guideline for venlafaxine and CYP2D6", - "version" : 3 + "version" : 11 }, "text" : { - "id" : 1452093933, + "id" : 1452093931, "html" : "

No action recommended based on genotype for venlafaxine because of minimal evidence regarding the impact on efficacy or side effects.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300966", - "name" : "Recommendation PA166300966", + "id" : "PA166300957", + "name" : "Recommendation PA166300957", "alternateDrugAvailable" : false, "classification" : { "id" : 1448526251, @@ -98950,9 +100034,9 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Decreased metabolism of venlafaxine to active metabolite O-desmethylvenlafaxine (desvenlafaxine) and decreased O-desmethylvenlafaxine:venlafaxine ratio as compared to normal metabolizers. There is insufficient evidence supporting the clinical impact of the decreased O-desmethylvenlafaxine:venlafaxine ratio in CYP2D6 intermediate metabolizers." + "CYP2D6: Increased metabolism of venlafaxine to the active metabolite O-desmethylvenlafaxine (desvenlafaxine) and increased O-desmethylvenlafaxine:venlafaxine ratio as compared to CYP2D6 normal metabolizers. There is insufficient evidence supporting the clinical impact of increased O-desmethylvenlafaxine:venlafaxine ratio in CYP2D6 ultrarapid metabolizers." ], - "lookupKey" : {"CYP2D6": "0.25"}, + "lookupKey" : {"CYP2D6": "2.5"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -98960,26 +100044,26 @@ "objCls" : "Chemical", "id" : "PA451866", "name" : "venlafaxine", - "version" : 8 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166288201", "name" : "Annotation of CPIC Guideline for venlafaxine and CYP2D6", - "version" : 3 + "version" : 11 }, "text" : { - "id" : 1452093946, + "id" : 1452093937, "html" : "

No action recommended based on genotype for venlafaxine because of minimal evidence regarding the impact on efficacy or side effects.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300962", - "name" : "Recommendation PA166300962", + "id" : "PA166300958", + "name" : "Recommendation PA166300958", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -98994,7 +100078,7 @@ "implications" : [ "CYP2D6: Normal metabolism" ], - "lookupKey" : {"CYP2D6": "1.25"}, + "lookupKey" : {"CYP2D6": "2.25"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -99002,21 +100086,21 @@ "objCls" : "Chemical", "id" : "PA451866", "name" : "venlafaxine", - "version" : 8 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166288201", "name" : "Annotation of CPIC Guideline for venlafaxine and CYP2D6", - "version" : 3 + "version" : 11 }, "text" : { - "id" : 1452093942, + "id" : 1452093938, "html" : "

Initiate therapy with recommended starting dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", @@ -99044,83 +100128,41 @@ "objCls" : "Chemical", "id" : "PA451866", "name" : "venlafaxine", - "version" : 8 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166288201", "name" : "Annotation of CPIC Guideline for venlafaxine and CYP2D6", - "version" : 3 + "version" : 11 }, "text" : { "id" : 1452093939, "html" : "

Initiate therapy with recommended starting dose.

\n", "version" : 0 }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166300967", - "name" : "Recommendation PA166300967", - "alternateDrugAvailable" : true, - "classification" : { - "id" : 981565059, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "CYP2D6: Decreased metabolism of venlafaxine to the active metabolite O-desmethylvenlafaxine (desvenlafaxine) and greatly decreased O-desmethylvenlafaxine:venlafaxine ratio as compared to CYP2D6 normal and intermediate metabolizers. The clinical impact of increased venlafaxine and decreased O-desmethylvenlafaxine:venlafaxine ratio in CYP2D6 poor metabolizers is unclear, but CYP2D6 PM genotype has been associated with adverse effects." - ], - "lookupKey" : {"CYP2D6": "0.0"}, - "otherPrescribingGuidance" : false, - "population" : "general", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA451866", - "name" : "venlafaxine", - "version" : 8 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166288201", - "name" : "Annotation of CPIC Guideline for venlafaxine and CYP2D6", - "version" : 3 - }, - "text" : { - "id" : 1452093947, - "html" : "

Consider a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2D6.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when adjusting dose or selecting an alternative therapy.

\n", - "version" : 0 - }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300954", - "name" : "Recommendation PA166300954", + "id" : "PA166300960", + "name" : "Recommendation PA166300960", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Increased metabolism of venlafaxine to the active metabolite O-desmethylvenlafaxine (desvenlafaxine) and increased O-desmethylvenlafaxine:venlafaxine ratio as compared to CYP2D6 normal metabolizers. There is insufficient evidence supporting the clinical impact of increased O-desmethylvenlafaxine:venlafaxine ratio in CYP2D6 ultrarapid metabolizers." + "CYP2D6: Normal metabolism" ], - "lookupKey" : {"CYP2D6": "4.0"}, + "lookupKey" : {"CYP2D6": "1.75"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -99128,41 +100170,41 @@ "objCls" : "Chemical", "id" : "PA451866", "name" : "venlafaxine", - "version" : 8 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166288201", "name" : "Annotation of CPIC Guideline for venlafaxine and CYP2D6", - "version" : 3 + "version" : 11 }, "text" : { - "id" : 1452093934, - "html" : "

No action recommended based on genotype for venlafaxine because of minimal evidence regarding the impact on efficacy or side effects.

\n", + "id" : 1452093940, + "html" : "

Initiate therapy with recommended starting dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300963", - "name" : "Recommendation PA166300963", + "id" : "PA166300961", + "name" : "Recommendation PA166300961", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Decreased metabolism of venlafaxine to active metabolite O-desmethylvenlafaxine (desvenlafaxine) and decreased O-desmethylvenlafaxine:venlafaxine ratio as compared to normal metabolizers. There is insufficient evidence supporting the clinical impact of the decreased O-desmethylvenlafaxine:venlafaxine ratio in CYP2D6 intermediate metabolizers." + "CYP2D6: Normal metabolism" ], - "lookupKey" : {"CYP2D6": "1.0"}, + "lookupKey" : {"CYP2D6": "1.5"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -99170,41 +100212,41 @@ "objCls" : "Chemical", "id" : "PA451866", "name" : "venlafaxine", - "version" : 8 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166288201", "name" : "Annotation of CPIC Guideline for venlafaxine and CYP2D6", - "version" : 3 + "version" : 11 }, "text" : { - "id" : 1452093943, - "html" : "

No action recommended based on genotype for venlafaxine because of minimal evidence regarding the impact on efficacy or side effects.

\n", + "id" : 1452093941, + "html" : "

Initiate therapy with recommended starting dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300950", - "name" : "Recommendation PA166300950", + "id" : "PA166300962", + "name" : "Recommendation PA166300962", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Increased metabolism of venlafaxine to the active metabolite O-desmethylvenlafaxine (desvenlafaxine) and increased O-desmethylvenlafaxine:venlafaxine ratio as compared to CYP2D6 normal metabolizers. There is insufficient evidence supporting the clinical impact of increased O-desmethylvenlafaxine:venlafaxine ratio in CYP2D6 ultrarapid metabolizers." + "CYP2D6: Normal metabolism" ], - "lookupKey" : {"CYP2D6": "≥6.0"}, + "lookupKey" : {"CYP2D6": "1.25"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -99212,26 +100254,26 @@ "objCls" : "Chemical", "id" : "PA451866", "name" : "venlafaxine", - "version" : 8 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166288201", "name" : "Annotation of CPIC Guideline for venlafaxine and CYP2D6", - "version" : 3 + "version" : 11 }, "text" : { - "id" : 1452093930, - "html" : "

No action recommended based on genotype for venlafaxine because of minimal evidence regarding the impact on efficacy or side effects.

\n", + "id" : 1452093942, + "html" : "

Initiate therapy with recommended starting dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300947", - "name" : "Recommendation PA166300947", + "id" : "PA166300963", + "name" : "Recommendation PA166300963", "alternateDrugAvailable" : false, "classification" : { "id" : 1448526251, @@ -99244,9 +100286,9 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Increased metabolism of venlafaxine to the active metabolite O-desmethylvenlafaxine (desvenlafaxine) and increased O-desmethylvenlafaxine:venlafaxine ratio as compared to CYP2D6 normal metabolizers. There is insufficient evidence supporting the clinical impact of increased O-desmethylvenlafaxine:venlafaxine ratio in CYP2D6 ultrarapid metabolizers." + "CYP2D6: Decreased metabolism of venlafaxine to active metabolite O-desmethylvenlafaxine (desvenlafaxine) and decreased O-desmethylvenlafaxine:venlafaxine ratio as compared to normal metabolizers. There is insufficient evidence supporting the clinical impact of the decreased O-desmethylvenlafaxine:venlafaxine ratio in CYP2D6 intermediate metabolizers." ], - "lookupKey" : {"CYP2D6": "≥3.5"}, + "lookupKey" : {"CYP2D6": "1.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -99254,51 +100296,21 @@ "objCls" : "Chemical", "id" : "PA451866", "name" : "venlafaxine", - "version" : 8 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166288201", "name" : "Annotation of CPIC Guideline for venlafaxine and CYP2D6", - "version" : 3 + "version" : 11 }, "text" : { - "id" : 1452093927, + "id" : 1452093943, "html" : "

No action recommended based on genotype for venlafaxine because of minimal evidence regarding the impact on efficacy or side effects.

\n", "version" : 0 }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166301331", - "name" : "Recommendation Annotation PA166301331", - "alternateDrugAvailable" : false, - "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA451866", - "name" : "venlafaxine", - "version" : 8 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166288201", - "name" : "Annotation of CPIC Guideline for venlafaxine and CYP2D6", - "version" : 3 - }, - "text" : { - "id" : 1452095650, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", - "version" : 0 - }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", @@ -99326,26 +100338,26 @@ "objCls" : "Chemical", "id" : "PA451866", "name" : "venlafaxine", - "version" : 8 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166288201", "name" : "Annotation of CPIC Guideline for venlafaxine and CYP2D6", - "version" : 3 + "version" : 11 }, "text" : { "id" : 1452093944, "html" : "

No action recommended based on genotype for venlafaxine because of minimal evidence regarding the impact on efficacy or side effects.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300968", - "name" : "Recommendation PA166300968", + "id" : "PA166300965", + "name" : "Recommendation PA166300965", "alternateDrugAvailable" : false, "classification" : { "id" : 1448526251, @@ -99358,9 +100370,9 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2D6: n/a" + "CYP2D6: Decreased metabolism of venlafaxine to active metabolite O-desmethylvenlafaxine (desvenlafaxine) and decreased O-desmethylvenlafaxine:venlafaxine ratio as compared to normal metabolizers. There is insufficient evidence supporting the clinical impact of the decreased O-desmethylvenlafaxine:venlafaxine ratio in CYP2D6 intermediate metabolizers." ], - "lookupKey" : {"CYP2D6": "n/a"}, + "lookupKey" : {"CYP2D6": "0.5"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -99368,26 +100380,26 @@ "objCls" : "Chemical", "id" : "PA451866", "name" : "venlafaxine", - "version" : 8 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166288201", "name" : "Annotation of CPIC Guideline for venlafaxine and CYP2D6", - "version" : 3 + "version" : 11 }, "text" : { - "id" : 1452093948, - "html" : "

No recommendation

\n", + "id" : 1452093945, + "html" : "

No action recommended based on genotype for venlafaxine because of minimal evidence regarding the impact on efficacy or side effects.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300955", - "name" : "Recommendation PA166300955", + "id" : "PA166300966", + "name" : "Recommendation PA166300966", "alternateDrugAvailable" : false, "classification" : { "id" : 1448526251, @@ -99400,9 +100412,9 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Increased metabolism of venlafaxine to the active metabolite O-desmethylvenlafaxine (desvenlafaxine) and increased O-desmethylvenlafaxine:venlafaxine ratio as compared to CYP2D6 normal metabolizers. There is insufficient evidence supporting the clinical impact of increased O-desmethylvenlafaxine:venlafaxine ratio in CYP2D6 ultrarapid metabolizers." + "CYP2D6: Decreased metabolism of venlafaxine to active metabolite O-desmethylvenlafaxine (desvenlafaxine) and decreased O-desmethylvenlafaxine:venlafaxine ratio as compared to normal metabolizers. There is insufficient evidence supporting the clinical impact of the decreased O-desmethylvenlafaxine:venlafaxine ratio in CYP2D6 intermediate metabolizers." ], - "lookupKey" : {"CYP2D6": "2.75"}, + "lookupKey" : {"CYP2D6": "0.25"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -99410,41 +100422,41 @@ "objCls" : "Chemical", "id" : "PA451866", "name" : "venlafaxine", - "version" : 8 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166288201", "name" : "Annotation of CPIC Guideline for venlafaxine and CYP2D6", - "version" : 3 + "version" : 11 }, "text" : { - "id" : 1452093935, + "id" : 1452093946, "html" : "

No action recommended based on genotype for venlafaxine because of minimal evidence regarding the impact on efficacy or side effects.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300960", - "name" : "Recommendation PA166300960", + "id" : "PA166300952", + "name" : "Recommendation PA166300952", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Normal metabolism" + "CYP2D6: Increased metabolism of venlafaxine to the active metabolite O-desmethylvenlafaxine (desvenlafaxine) and increased O-desmethylvenlafaxine:venlafaxine ratio as compared to CYP2D6 normal metabolizers. There is insufficient evidence supporting the clinical impact of increased O-desmethylvenlafaxine:venlafaxine ratio in CYP2D6 ultrarapid metabolizers." ], - "lookupKey" : {"CYP2D6": "1.75"}, + "lookupKey" : {"CYP2D6": "≥3.75"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -99452,26 +100464,26 @@ "objCls" : "Chemical", "id" : "PA451866", "name" : "venlafaxine", - "version" : 8 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166288201", "name" : "Annotation of CPIC Guideline for venlafaxine and CYP2D6", - "version" : 3 + "version" : 11 }, "text" : { - "id" : 1452093940, - "html" : "

Initiate therapy with recommended starting dose.

\n", + "id" : 1452093932, + "html" : "

No action recommended based on genotype for venlafaxine because of minimal evidence regarding the impact on efficacy or side effects.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300951", - "name" : "Recommendation PA166300951", + "id" : "PA166300955", + "name" : "Recommendation PA166300955", "alternateDrugAvailable" : false, "classification" : { "id" : 1448526251, @@ -99486,7 +100498,7 @@ "implications" : [ "CYP2D6: Increased metabolism of venlafaxine to the active metabolite O-desmethylvenlafaxine (desvenlafaxine) and increased O-desmethylvenlafaxine:venlafaxine ratio as compared to CYP2D6 normal metabolizers. There is insufficient evidence supporting the clinical impact of increased O-desmethylvenlafaxine:venlafaxine ratio in CYP2D6 ultrarapid metabolizers." ], - "lookupKey" : {"CYP2D6": "≥5.0"}, + "lookupKey" : {"CYP2D6": "2.75"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -99494,26 +100506,26 @@ "objCls" : "Chemical", "id" : "PA451866", "name" : "venlafaxine", - "version" : 8 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166288201", "name" : "Annotation of CPIC Guideline for venlafaxine and CYP2D6", - "version" : 3 + "version" : 11 }, "text" : { - "id" : 1452093931, + "id" : 1452093935, "html" : "

No action recommended based on genotype for venlafaxine because of minimal evidence regarding the impact on efficacy or side effects.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300957", - "name" : "Recommendation PA166300957", + "id" : "PA166300953", + "name" : "Recommendation PA166300953", "alternateDrugAvailable" : false, "classification" : { "id" : 1448526251, @@ -99528,7 +100540,7 @@ "implications" : [ "CYP2D6: Increased metabolism of venlafaxine to the active metabolite O-desmethylvenlafaxine (desvenlafaxine) and increased O-desmethylvenlafaxine:venlafaxine ratio as compared to CYP2D6 normal metabolizers. There is insufficient evidence supporting the clinical impact of increased O-desmethylvenlafaxine:venlafaxine ratio in CYP2D6 ultrarapid metabolizers." ], - "lookupKey" : {"CYP2D6": "2.5"}, + "lookupKey" : {"CYP2D6": "≥3.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -99536,26 +100548,26 @@ "objCls" : "Chemical", "id" : "PA451866", "name" : "venlafaxine", - "version" : 8 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166288201", "name" : "Annotation of CPIC Guideline for venlafaxine and CYP2D6", - "version" : 3 + "version" : 11 }, "text" : { - "id" : 1452093937, + "id" : 1452093933, "html" : "

No action recommended based on genotype for venlafaxine because of minimal evidence regarding the impact on efficacy or side effects.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300948", - "name" : "Recommendation PA166300948", + "id" : "PA166300954", + "name" : "Recommendation PA166300954", "alternateDrugAvailable" : false, "classification" : { "id" : 1448526251, @@ -99570,7 +100582,7 @@ "implications" : [ "CYP2D6: Increased metabolism of venlafaxine to the active metabolite O-desmethylvenlafaxine (desvenlafaxine) and increased O-desmethylvenlafaxine:venlafaxine ratio as compared to CYP2D6 normal metabolizers. There is insufficient evidence supporting the clinical impact of increased O-desmethylvenlafaxine:venlafaxine ratio in CYP2D6 ultrarapid metabolizers." ], - "lookupKey" : {"CYP2D6": "≥3.25"}, + "lookupKey" : {"CYP2D6": "4.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -99578,26 +100590,26 @@ "objCls" : "Chemical", "id" : "PA451866", "name" : "venlafaxine", - "version" : 8 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166288201", "name" : "Annotation of CPIC Guideline for venlafaxine and CYP2D6", - "version" : 3 + "version" : 11 }, "text" : { - "id" : 1452093928, + "id" : 1452093934, "html" : "

No action recommended based on genotype for venlafaxine because of minimal evidence regarding the impact on efficacy or side effects.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300965", - "name" : "Recommendation PA166300965", + "id" : "PA166300956", + "name" : "Recommendation PA166300956", "alternateDrugAvailable" : false, "classification" : { "id" : 1448526251, @@ -99610,9 +100622,9 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Decreased metabolism of venlafaxine to active metabolite O-desmethylvenlafaxine (desvenlafaxine) and decreased O-desmethylvenlafaxine:venlafaxine ratio as compared to normal metabolizers. There is insufficient evidence supporting the clinical impact of the decreased O-desmethylvenlafaxine:venlafaxine ratio in CYP2D6 intermediate metabolizers." + "CYP2D6: Increased metabolism of venlafaxine to the active metabolite O-desmethylvenlafaxine (desvenlafaxine) and increased O-desmethylvenlafaxine:venlafaxine ratio as compared to CYP2D6 normal metabolizers. There is insufficient evidence supporting the clinical impact of increased O-desmethylvenlafaxine:venlafaxine ratio in CYP2D6 ultrarapid metabolizers." ], - "lookupKey" : {"CYP2D6": "0.5"}, + "lookupKey" : {"CYP2D6": "3.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -99620,41 +100632,41 @@ "objCls" : "Chemical", "id" : "PA451866", "name" : "venlafaxine", - "version" : 8 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166288201", "name" : "Annotation of CPIC Guideline for venlafaxine and CYP2D6", - "version" : 3 + "version" : 11 }, "text" : { - "id" : 1452093945, + "id" : 1452093936, "html" : "

No action recommended based on genotype for venlafaxine because of minimal evidence regarding the impact on efficacy or side effects.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300952", - "name" : "Recommendation PA166300952", - "alternateDrugAvailable" : false, + "id" : "PA166300967", + "name" : "Recommendation PA166300967", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Increased metabolism of venlafaxine to the active metabolite O-desmethylvenlafaxine (desvenlafaxine) and increased O-desmethylvenlafaxine:venlafaxine ratio as compared to CYP2D6 normal metabolizers. There is insufficient evidence supporting the clinical impact of increased O-desmethylvenlafaxine:venlafaxine ratio in CYP2D6 ultrarapid metabolizers." + "CYP2D6: Decreased metabolism of venlafaxine to the active metabolite O-desmethylvenlafaxine (desvenlafaxine) and greatly decreased O-desmethylvenlafaxine:venlafaxine ratio as compared to CYP2D6 normal and intermediate metabolizers. The clinical impact of increased venlafaxine and decreased O-desmethylvenlafaxine:venlafaxine ratio in CYP2D6 poor metabolizers is unclear, but CYP2D6 PM genotype has been associated with adverse effects." ], - "lookupKey" : {"CYP2D6": "≥3.75"}, + "lookupKey" : {"CYP2D6": "0.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -99662,26 +100674,26 @@ "objCls" : "Chemical", "id" : "PA451866", "name" : "venlafaxine", - "version" : 8 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166288201", "name" : "Annotation of CPIC Guideline for venlafaxine and CYP2D6", - "version" : 3 + "version" : 11 }, "text" : { - "id" : 1452093932, - "html" : "

No action recommended based on genotype for venlafaxine because of minimal evidence regarding the impact on efficacy or side effects.

\n", + "id" : 1452093947, + "html" : "

Consider a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2D6.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when adjusting dose or selecting an alternative therapy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300956", - "name" : "Recommendation PA166300956", + "id" : "PA166300968", + "name" : "Recommendation PA166300968", "alternateDrugAvailable" : false, "classification" : { "id" : 1448526251, @@ -99694,9 +100706,9 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Increased metabolism of venlafaxine to the active metabolite O-desmethylvenlafaxine (desvenlafaxine) and increased O-desmethylvenlafaxine:venlafaxine ratio as compared to CYP2D6 normal metabolizers. There is insufficient evidence supporting the clinical impact of increased O-desmethylvenlafaxine:venlafaxine ratio in CYP2D6 ultrarapid metabolizers." + "CYP2D6: n/a" ], - "lookupKey" : {"CYP2D6": "3.0"}, + "lookupKey" : {"CYP2D6": "n/a"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -99704,60 +100716,48 @@ "objCls" : "Chemical", "id" : "PA451866", "name" : "venlafaxine", - "version" : 8 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166288201", "name" : "Annotation of CPIC Guideline for venlafaxine and CYP2D6", - "version" : 3 + "version" : 11 }, "text" : { - "id" : 1452093936, - "html" : "

No action recommended based on genotype for venlafaxine because of minimal evidence regarding the impact on efficacy or side effects.

\n", + "id" : 1452093948, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300961", - "name" : "Recommendation PA166300961", + "id" : "PA166301331", + "name" : "Recommendation Annotation PA166301331", "alternateDrugAvailable" : false, - "classification" : { - "id" : 981501930, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", - "valid" : true, - "version" : 0 - }, "dosingInformation" : false, - "implications" : [ - "CYP2D6: Normal metabolism" - ], - "lookupKey" : {"CYP2D6": "1.5"}, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations"}, "otherPrescribingGuidance" : false, - "population" : "general", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451866", "name" : "venlafaxine", - "version" : 8 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166288201", "name" : "Annotation of CPIC Guideline for venlafaxine and CYP2D6", - "version" : 3 + "version" : 11 }, "text" : { - "id" : 1452093941, - "html" : "

Initiate therapy with recommended starting dose.

\n", + "id" : 1452095650, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", "version" : 0 }, "version" : 0 @@ -99908,7 +100908,7 @@ "objCls" : "Chemical", "id" : "PA10233", "name" : "voriconazole", - "version" : 7 + "version" : 37 } ], "relatedGenes" : [ @@ -99917,14 +100917,14 @@ "id" : "PA124", "symbol" : "CYP2C19", "name" : "cytochrome P450 family 2 subfamily C member 19", - "version" : 7210 + "version" : 7266 } ], "source" : "CPIC", "summaryMarkdown" : { "id" : 1448432518, "html" : "

The CPIC dosing guideline for voriconazole recommends selecting an alternative agent that is not dependent on CYP2C19 metabolism in adults who are CYP2C19 ultrarapid metabolizers, rapid metabolizers or poor metabolizers. In pediatric patients, an alternative agent should be used in patients who are ultrarapid metabolizers or poor metabolizers. In pediatric rapid metabolizers, therapy should be initiated at recommended standard case dosing, then therapeutic dosing monitoring should be used to titrate dose to therapeutic trough concentrations.

\n", - "version" : 0 + "version" : 3 }, "terms" : [], "textMarkdown" : { @@ -99933,14 +100933,14 @@ "version" : 2 }, "userId" : "rachel", - "version" : 38 + "version" : 129 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166298810", - "name" : "Recommendation PA166298810", - "alternateDrugAvailable" : false, + "id" : "PA166298805", + "name" : "Recommendation PA166298805", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501931, "parents" : [], @@ -99952,36 +100952,36 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2C19: Higher dose-adjusted trough concentrations of voriconazole compared with normal metabolizers" + "CYP2C19: In patients for whom a rapid metabolizer genotype (*1/*17) is identified, the probability of attainment of therapeutic concentrations is modest with standard dosing" ], - "lookupKey" : {"CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2C19": "Rapid Metabolizer"}, "otherPrescribingGuidance" : false, - "population" : "pediatrics", + "population" : "adults", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA10233", "name" : "voriconazole", - "version" : 7 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161537", "name" : "Annotation of CPIC Guideline for voriconazole and CYP2C19", - "version" : 38 + "version" : 129 }, "text" : { - "id" : 1452061412, - "html" : "

Initiate therapy with recommended standard of care dosing

\n

Other Considerations

\n

Further dose adjustments or selection of alternative therapy may be necessary due to other clinical factors, such as drug interactions, hepatic function, renal function, species, site of infection, therapeutic drug monitoring, and comorbidities.

\n", + "id" : 1452061407, + "html" : "

Choose an alternative agent that is not dependent on CYP2C19 metabolism as primary therapy in lieu of voriconazole. Such agents include isavuconazole, liposomal amphotericin B, and posaconazole.

\n

Other Considerations

\n

Further dose adjustments or selection of alternative therapy may be necessary due to other clinical factors, such as drug interactions, hepatic function, renal function, species, site of infection, therapeutic drug monitoring, and comorbidities.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298814", - "name" : "Recommendation PA166298814", + "id" : "PA166298806", + "name" : "Recommendation PA166298806", "alternateDrugAvailable" : true, "classification" : { "id" : 981501931, @@ -99994,36 +100994,36 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2C19: In patients for whom an ultrarapid metabolizer genotype (*17/*17) is identified, the probability of attainment of therapeutic voriconazole concentrations is small with standard dosing" + "CYP2C19: In patients for whom an ultrarapid metabolizer genotype (*17/*17) is identified, the probability of attainment of therapeutic concentrations is small" ], "lookupKey" : {"CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, - "population" : "adults", + "population" : "pediatrics", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA10233", "name" : "voriconazole", - "version" : 7 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161537", "name" : "Annotation of CPIC Guideline for voriconazole and CYP2C19", - "version" : 38 + "version" : 129 }, "text" : { - "id" : 1452061416, - "html" : "

Choose an alternative agent that is not dependent on CYP2C19 metabolism as primary therapy in lieu of voriconazole. Such agents include isavuconazole, liposomal amphotericin B, and posaconazole.

\n

Other Considerations

\n

Further dose adjustments or selection of alternative therapy may be necessary due to other clinical factors, such as drug interactions, hepatic function, renal function, species, site of infection, therapeutic drug monitoring, and comorbidities. Recommendations based upon data extrapolated from patients with CYP2C19*1/*17 genotype.

\n", + "id" : 1452061408, + "html" : "

Choose an alternative agent that is not dependent on CYP2C19 metabolism as primary therapy in lieu of voriconazole. Such agents include liposomal amphotericin B and posaconazole.

\n

Other Considerations

\n

Further dose adjustments or selection of alternative therapy may be necessary due to other clinical factors, such as drug interactions, hepatic function, renal function, species, site of infection, therapeutic drug monitoring, and comorbidities. Achieving voriconazole therapeutic concentrations in the pediatric population with ultrarapid and rapid metabolizer phenotypes in a timely manner is difficult. As critical time may be lost in achieving therapeutic concentrations, an alternative antifungal agent is recommended in order that the child receives effective antifungal therapy as soon as possible.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298818", - "name" : "Recommendation PA166298818", + "id" : "PA166298814", + "name" : "Recommendation PA166298814", "alternateDrugAvailable" : true, "classification" : { "id" : 981501931, @@ -100034,11 +101034,11 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Higher dose-adjusted trough concentrations of voriconazole and may increase probability of adverse events" + "CYP2C19: In patients for whom an ultrarapid metabolizer genotype (*17/*17) is identified, the probability of attainment of therapeutic voriconazole concentrations is small with standard dosing" ], - "lookupKey" : {"CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "adults", "relatedChemicals" : [ @@ -100046,68 +101046,68 @@ "objCls" : "Chemical", "id" : "PA10233", "name" : "voriconazole", - "version" : 7 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161537", "name" : "Annotation of CPIC Guideline for voriconazole and CYP2C19", - "version" : 38 + "version" : 129 }, "text" : { - "id" : 1452061420, - "html" : "

Choose an alternative agent that is not dependent on CYP2C19 metabolism as primary therapy in lieu of voriconazole. Such agents include isavuconazole, liposomal amphotericin B, and posaconazole. In the event that voriconazole is considered to be the most appropriate agent, based on clinical advice, for a patient with poor metabolizer genotype, voriconazole should be administered at a preferably lower than standard dosage with careful therapeutic drug monitoring.

\n

Other Considerations

\n

Further dose adjustments or selection of alternative therapy may be necessary due to other clinical factors, such as drug interactions, hepatic function, renal function, species, site of infection, therapeutic drug monitoring, and comorbidities.

\n", + "id" : 1452061416, + "html" : "

Choose an alternative agent that is not dependent on CYP2C19 metabolism as primary therapy in lieu of voriconazole. Such agents include isavuconazole, liposomal amphotericin B, and posaconazole.

\n

Other Considerations

\n

Further dose adjustments or selection of alternative therapy may be necessary due to other clinical factors, such as drug interactions, hepatic function, renal function, species, site of infection, therapeutic drug monitoring, and comorbidities. Recommendations based upon data extrapolated from patients with CYP2C19*1/*17 genotype.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298805", - "name" : "Recommendation PA166298805", - "alternateDrugAvailable" : true, + "id" : "PA166298808", + "name" : "Recommendation PA166298808", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2C19: In patients for whom a rapid metabolizer genotype (*1/*17) is identified, the probability of attainment of therapeutic concentrations is modest with standard dosing" + "CYP2C19: Normal voriconazole metabolism" ], - "lookupKey" : {"CYP2C19": "Rapid Metabolizer"}, + "lookupKey" : {"CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, - "population" : "adults", + "population" : "pediatrics", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA10233", "name" : "voriconazole", - "version" : 7 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161537", "name" : "Annotation of CPIC Guideline for voriconazole and CYP2C19", - "version" : 38 + "version" : 129 }, "text" : { - "id" : 1452061407, - "html" : "

Choose an alternative agent that is not dependent on CYP2C19 metabolism as primary therapy in lieu of voriconazole. Such agents include isavuconazole, liposomal amphotericin B, and posaconazole.

\n

Other Considerations

\n

Further dose adjustments or selection of alternative therapy may be necessary due to other clinical factors, such as drug interactions, hepatic function, renal function, species, site of infection, therapeutic drug monitoring, and comorbidities.

\n", + "id" : 1452061410, + "html" : "

Initiate therapy with recommended standard of care dosing

\n

Other Considerations

\n

Further dose adjustments or selection of alternative therapy may be necessary due to other clinical factors, such as drug interactions, hepatic function, renal function, species, site of infection, therapeutic drug monitoring, and comorbidities.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298809", - "name" : "Recommendation PA166298809", + "id" : "PA166298807", + "name" : "Recommendation PA166298807", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -100120,37 +101120,37 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2C19: Higher dose-adjusted trough concentrations of voriconazole compared with normal metabolizers" + "CYP2C19: In patients for whom a rapid metabolizer genotype (*1/*17) is identified, the probability of attainment of therapeutic concentrations is variable." ], - "lookupKey" : {"CYP2C19": "Likely Intermediate Metabolizer"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"CYP2C19": "Rapid Metabolizer"}, + "otherPrescribingGuidance" : true, "population" : "pediatrics", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA10233", "name" : "voriconazole", - "version" : 7 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161537", "name" : "Annotation of CPIC Guideline for voriconazole and CYP2C19", - "version" : 38 + "version" : 129 }, "text" : { - "id" : 1452061411, - "html" : "

Initiate therapy with recommended standard of care dosing

\n

Other Considerations

\n

Further dose adjustments or selection of alternative therapy may be necessary due to other clinical factors, such as drug interactions, hepatic function, renal function, species, site of infection, therapeutic drug monitoring, and comorbidities.

\n", + "id" : 1452061409, + "html" : "

Initiate therapy with recommended standard of care dosing. Use therapeutic drug monitoring to titrate dose to therapeutic trough concentrations.

\n

Other Considerations

\n

Further dose adjustments or selection of alternative therapy may be necessary due to other clinical factors, such as drug interactions, hepatic function, renal function, species, site of infection, therapeutic drug monitoring (TDM), and comorbidities. Achieving voriconazole therapeutic concentrations in the pediatric population with ultrarapid and rapid metabolizer phenotypes in a timely manner is difficult. As critical time may be lost in achieving therapeutic concentrations, an alternative antifungal agent is recommended in order that the child receives effective antifungal therapy as soon as possible. Meticulous TDM is critical for rapid metabolizers. There is insufficient evidence to distinguish a CYP2C19*1/*17 and *1/*1 pediatric patient due to large variability in trough concentrations.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298811", - "name" : "Recommendation PA166298811", - "alternateDrugAvailable" : true, + "id" : "PA166298810", + "name" : "Recommendation PA166298810", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, "parents" : [], @@ -100160,11 +101160,11 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Higher dose-adjusted trough concentrations of voriconazole and may increase probability of adverse events" + "CYP2C19: Higher dose-adjusted trough concentrations of voriconazole compared with normal metabolizers" ], - "lookupKey" : {"CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "pediatrics", "relatedChemicals" : [ @@ -100172,26 +101172,26 @@ "objCls" : "Chemical", "id" : "PA10233", "name" : "voriconazole", - "version" : 7 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161537", "name" : "Annotation of CPIC Guideline for voriconazole and CYP2C19", - "version" : 38 + "version" : 129 }, "text" : { - "id" : 1452061413, - "html" : "

Choose an alternative agent that is not dependent on CYP2C19 metabolism as primary therapy in lieu of voriconazole. Such agents include liposomal amphotericin B and posaconazole. In the event that voriconazole is considered to be the most appropriate agent, based on clinical advice, for a patient with poor metabolizer genotype, voriconazole should be administered at a preferably lower than standard dosage with careful therapeutic drug monitoring.

\n

Other Considerations

\n

Further dose adjustments or selection of alternative therapy may be necessary due to other clinical factors, such as drug interactions, hepatic function, renal function, species, site of infection, therapeutic drug monitoring, and comorbidities. Recommendation based upon data extrapolated from adults.

\n", + "id" : 1452061412, + "html" : "

Initiate therapy with recommended standard of care dosing

\n

Other Considerations

\n

Further dose adjustments or selection of alternative therapy may be necessary due to other clinical factors, such as drug interactions, hepatic function, renal function, species, site of infection, therapeutic drug monitoring, and comorbidities.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298820", - "name" : "Recommendation PA166298820", + "id" : "PA166298813", + "name" : "Recommendation PA166298813", "alternateDrugAvailable" : false, "classification" : { "id" : 1448526251, @@ -100208,27 +101208,27 @@ ], "lookupKey" : {"CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, - "population" : "adults", + "population" : "pediatrics", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA10233", "name" : "voriconazole", - "version" : 7 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161537", "name" : "Annotation of CPIC Guideline for voriconazole and CYP2C19", - "version" : 38 + "version" : 129 }, "text" : { - "id" : 1452061422, + "id" : 1452061415, "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -100256,27 +101256,27 @@ "objCls" : "Chemical", "id" : "PA10233", "name" : "voriconazole", - "version" : 7 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161537", "name" : "Annotation of CPIC Guideline for voriconazole and CYP2C19", - "version" : 38 + "version" : 129 }, "text" : { "id" : 1452061417, "html" : "

Initiate therapy with recommended standard of care dosing

\n

Other Considerations

\n

Further dose adjustments or selection of alternative therapy may be necessary due to other clinical factors, such as drug interactions, hepatic function, renal function, species, site of infection, therapeutic drug monitoring, and comorbidities.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298819", - "name" : "Recommendation PA166298819", - "alternateDrugAvailable" : true, + "id" : "PA166298816", + "name" : "Recommendation PA166298816", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, "parents" : [], @@ -100286,11 +101286,11 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Higher dose-adjusted trough concentrations of voriconazole and may increase probability of adverse events" + "CYP2C19: Higher dose-adjusted trough concentrations of voriconazole compared with normal metabolizers" ], - "lookupKey" : {"CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "adults", "relatedChemicals" : [ @@ -100298,27 +101298,27 @@ "objCls" : "Chemical", "id" : "PA10233", "name" : "voriconazole", - "version" : 7 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161537", "name" : "Annotation of CPIC Guideline for voriconazole and CYP2C19", - "version" : 38 + "version" : 129 }, "text" : { - "id" : 1452061421, - "html" : "

Choose an alternative agent that is not dependent on CYP2C19 metabolism as primary therapy in lieu of voriconazole. Such agents include isavuconazole, liposomal amphotericin B, and posaconazole. In the event that voriconazole is considered to be the most appropriate agent, based on clinical advice, for a patient with poor metabolizer genotype, voriconazole should be administered at a preferably lower than standard dosage with careful therapeutic drug monitoring.

\n

Other Considerations

\n

Further dose adjustments or selection of alternative therapy may be necessary due to other clinical factors, such as drug interactions, hepatic function, renal function, species, site of infection, therapeutic drug monitoring, and comorbidities.

\n", + "id" : 1452061418, + "html" : "

Initiate therapy with recommended standard of care dosing

\n

Other Considerations

\n

Further dose adjustments or selection of alternative therapy may be necessary due to other clinical factors, such as drug interactions, hepatic function, renal function, species, site of infection, therapeutic drug monitoring, and comorbidities.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298806", - "name" : "Recommendation PA166298806", - "alternateDrugAvailable" : true, + "id" : "PA166298817", + "name" : "Recommendation PA166298817", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, "parents" : [], @@ -100330,79 +101330,79 @@ }, "dosingInformation" : false, "implications" : [ - "CYP2C19: In patients for whom an ultrarapid metabolizer genotype (*17/*17) is identified, the probability of attainment of therapeutic concentrations is small" + "CYP2C19: Higher dose-adjusted trough concentrations of voriconazole compared with normal metabolizers" ], - "lookupKey" : {"CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, - "population" : "pediatrics", + "population" : "adults", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA10233", "name" : "voriconazole", - "version" : 7 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161537", "name" : "Annotation of CPIC Guideline for voriconazole and CYP2C19", - "version" : 38 + "version" : 129 }, "text" : { - "id" : 1452061408, - "html" : "

Choose an alternative agent that is not dependent on CYP2C19 metabolism as primary therapy in lieu of voriconazole. Such agents include liposomal amphotericin B and posaconazole.

\n

Other Considerations

\n

Further dose adjustments or selection of alternative therapy may be necessary due to other clinical factors, such as drug interactions, hepatic function, renal function, species, site of infection, therapeutic drug monitoring, and comorbidities. Achieving voriconazole therapeutic concentrations in the pediatric population with ultrarapid and rapid metabolizer phenotypes in a timely manner is difficult. As critical time may be lost in achieving therapeutic concentrations, an alternative antifungal agent is recommended in order that the child receives effective antifungal therapy as soon as possible.

\n", + "id" : 1452061419, + "html" : "

Initiate therapy with recommended standard of care dosing

\n

Other Considerations

\n

Further dose adjustments or selection of alternative therapy may be necessary due to other clinical factors, such as drug interactions, hepatic function, renal function, species, site of infection, therapeutic drug monitoring, and comorbidities.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298812", - "name" : "Recommendation PA166298812", - "alternateDrugAvailable" : true, + "id" : "PA166298820", + "name" : "Recommendation PA166298820", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501931, + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2C19: Higher dose-adjusted trough concentrations of voriconazole and may increase probability of adverse events" + "CYP2C19: n/a" ], - "lookupKey" : {"CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2C19": "Indeterminate"}, "otherPrescribingGuidance" : false, - "population" : "pediatrics", + "population" : "adults", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA10233", "name" : "voriconazole", - "version" : 7 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161537", "name" : "Annotation of CPIC Guideline for voriconazole and CYP2C19", - "version" : 38 + "version" : 129 }, "text" : { - "id" : 1452061414, - "html" : "

Choose an alternative agent that is not dependent on CYP2C19 metabolism as primary therapy in lieu of voriconazole. Such agents include liposomal amphotericin B and posaconazole. In the event that voriconazole is considered to be the most appropriate agent, based on clinical advice, for a patient with poor metabolizer genotype, voriconazole should be administered at a preferably lower than standard dosage with careful therapeutic drug monitoring.

\n

Other Considerations

\n

Further dose adjustments or selection of alternative therapy may be necessary due to other clinical factors, such as drug interactions, hepatic function, renal function, species, site of infection, therapeutic drug monitoring, and comorbidities. Recommendation based upon data extrapolated from adults.

\n", + "id" : 1452061422, + "html" : "

No recommendation

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298816", - "name" : "Recommendation PA166298816", - "alternateDrugAvailable" : false, + "id" : "PA166298819", + "name" : "Recommendation PA166298819", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501931, "parents" : [], @@ -100412,11 +101412,11 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Higher dose-adjusted trough concentrations of voriconazole compared with normal metabolizers" + "CYP2C19: Higher dose-adjusted trough concentrations of voriconazole and may increase probability of adverse events" ], - "lookupKey" : {"CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "adults", "relatedChemicals" : [ @@ -100424,27 +101424,27 @@ "objCls" : "Chemical", "id" : "PA10233", "name" : "voriconazole", - "version" : 7 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161537", "name" : "Annotation of CPIC Guideline for voriconazole and CYP2C19", - "version" : 38 + "version" : 129 }, "text" : { - "id" : 1452061418, - "html" : "

Initiate therapy with recommended standard of care dosing

\n

Other Considerations

\n

Further dose adjustments or selection of alternative therapy may be necessary due to other clinical factors, such as drug interactions, hepatic function, renal function, species, site of infection, therapeutic drug monitoring, and comorbidities.

\n", + "id" : 1452061421, + "html" : "

Choose an alternative agent that is not dependent on CYP2C19 metabolism as primary therapy in lieu of voriconazole. Such agents include isavuconazole, liposomal amphotericin B, and posaconazole. In the event that voriconazole is considered to be the most appropriate agent, based on clinical advice, for a patient with poor metabolizer genotype, voriconazole should be administered at a preferably lower than standard dosage with careful therapeutic drug monitoring.

\n

Other Considerations

\n

Further dose adjustments or selection of alternative therapy may be necessary due to other clinical factors, such as drug interactions, hepatic function, renal function, species, site of infection, therapeutic drug monitoring, and comorbidities.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298807", - "name" : "Recommendation PA166298807", - "alternateDrugAvailable" : false, + "id" : "PA166298818", + "name" : "Recommendation PA166298818", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501931, "parents" : [], @@ -100454,53 +101454,53 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: In patients for whom a rapid metabolizer genotype (*1/*17) is identified, the probability of attainment of therapeutic concentrations is variable." + "CYP2C19: Higher dose-adjusted trough concentrations of voriconazole and may increase probability of adverse events" ], - "lookupKey" : {"CYP2C19": "Rapid Metabolizer"}, - "otherPrescribingGuidance" : true, - "population" : "pediatrics", + "lookupKey" : {"CYP2C19": "Likely Poor Metabolizer"}, + "otherPrescribingGuidance" : false, + "population" : "adults", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA10233", "name" : "voriconazole", - "version" : 7 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161537", "name" : "Annotation of CPIC Guideline for voriconazole and CYP2C19", - "version" : 38 + "version" : 129 }, "text" : { - "id" : 1452061409, - "html" : "

Initiate therapy with recommended standard of care dosing. Use therapeutic drug monitoring to titrate dose to therapeutic trough concentrations.

\n

Other Considerations

\n

Further dose adjustments or selection of alternative therapy may be necessary due to other clinical factors, such as drug interactions, hepatic function, renal function, species, site of infection, therapeutic drug monitoring (TDM), and comorbidities. Achieving voriconazole therapeutic concentrations in the pediatric population with ultrarapid and rapid metabolizer phenotypes in a timely manner is difficult. As critical time may be lost in achieving therapeutic concentrations, an alternative antifungal agent is recommended in order that the child receives effective antifungal therapy as soon as possible. Meticulous TDM is critical for rapid metabolizers. There is insufficient evidence to distinguish a CYP2C19*1/*17 and *1/*1 pediatric patient due to large variability in trough concentrations.

\n", + "id" : 1452061420, + "html" : "

Choose an alternative agent that is not dependent on CYP2C19 metabolism as primary therapy in lieu of voriconazole. Such agents include isavuconazole, liposomal amphotericin B, and posaconazole. In the event that voriconazole is considered to be the most appropriate agent, based on clinical advice, for a patient with poor metabolizer genotype, voriconazole should be administered at a preferably lower than standard dosage with careful therapeutic drug monitoring.

\n

Other Considerations

\n

Further dose adjustments or selection of alternative therapy may be necessary due to other clinical factors, such as drug interactions, hepatic function, renal function, species, site of infection, therapeutic drug monitoring, and comorbidities.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298813", - "name" : "Recommendation PA166298813", - "alternateDrugAvailable" : false, + "id" : "PA166298812", + "name" : "Recommendation PA166298812", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: n/a" + "CYP2C19: Higher dose-adjusted trough concentrations of voriconazole and may increase probability of adverse events" ], - "lookupKey" : {"CYP2C19": "Indeterminate"}, + "lookupKey" : {"CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "pediatrics", "relatedChemicals" : [ @@ -100508,41 +101508,41 @@ "objCls" : "Chemical", "id" : "PA10233", "name" : "voriconazole", - "version" : 7 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161537", "name" : "Annotation of CPIC Guideline for voriconazole and CYP2C19", - "version" : 38 + "version" : 129 }, "text" : { - "id" : 1452061415, - "html" : "

No recommendation

\n", + "id" : 1452061414, + "html" : "

Choose an alternative agent that is not dependent on CYP2C19 metabolism as primary therapy in lieu of voriconazole. Such agents include liposomal amphotericin B and posaconazole. In the event that voriconazole is considered to be the most appropriate agent, based on clinical advice, for a patient with poor metabolizer genotype, voriconazole should be administered at a preferably lower than standard dosage with careful therapeutic drug monitoring.

\n

Other Considerations

\n

Further dose adjustments or selection of alternative therapy may be necessary due to other clinical factors, such as drug interactions, hepatic function, renal function, species, site of infection, therapeutic drug monitoring, and comorbidities. Recommendation based upon data extrapolated from adults.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298808", - "name" : "Recommendation PA166298808", - "alternateDrugAvailable" : false, + "id" : "PA166298811", + "name" : "Recommendation PA166298811", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2C19: Normal voriconazole metabolism" + "CYP2C19: Higher dose-adjusted trough concentrations of voriconazole and may increase probability of adverse events" ], - "lookupKey" : {"CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "pediatrics", "relatedChemicals" : [ @@ -100550,26 +101550,26 @@ "objCls" : "Chemical", "id" : "PA10233", "name" : "voriconazole", - "version" : 7 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161537", "name" : "Annotation of CPIC Guideline for voriconazole and CYP2C19", - "version" : 38 + "version" : 129 }, "text" : { - "id" : 1452061410, - "html" : "

Initiate therapy with recommended standard of care dosing

\n

Other Considerations

\n

Further dose adjustments or selection of alternative therapy may be necessary due to other clinical factors, such as drug interactions, hepatic function, renal function, species, site of infection, therapeutic drug monitoring, and comorbidities.

\n", + "id" : 1452061413, + "html" : "

Choose an alternative agent that is not dependent on CYP2C19 metabolism as primary therapy in lieu of voriconazole. Such agents include liposomal amphotericin B and posaconazole. In the event that voriconazole is considered to be the most appropriate agent, based on clinical advice, for a patient with poor metabolizer genotype, voriconazole should be administered at a preferably lower than standard dosage with careful therapeutic drug monitoring.

\n

Other Considerations

\n

Further dose adjustments or selection of alternative therapy may be necessary due to other clinical factors, such as drug interactions, hepatic function, renal function, species, site of infection, therapeutic drug monitoring, and comorbidities. Recommendation based upon data extrapolated from adults.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166298817", - "name" : "Recommendation PA166298817", + "id" : "PA166298809", + "name" : "Recommendation PA166298809", "alternateDrugAvailable" : false, "classification" : { "id" : 981501931, @@ -100584,29 +101584,29 @@ "implications" : [ "CYP2C19: Higher dose-adjusted trough concentrations of voriconazole compared with normal metabolizers" ], - "lookupKey" : {"CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, - "population" : "adults", + "population" : "pediatrics", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA10233", "name" : "voriconazole", - "version" : 7 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166161537", "name" : "Annotation of CPIC Guideline for voriconazole and CYP2C19", - "version" : 38 + "version" : 129 }, "text" : { - "id" : 1452061419, + "id" : 1452061411, "html" : "

Initiate therapy with recommended standard of care dosing

\n

Other Considerations

\n

Further dose adjustments or selection of alternative therapy may be necessary due to other clinical factors, such as drug interactions, hepatic function, renal function, species, site of infection, therapeutic drug monitoring, and comorbidities.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166161537" @@ -100680,6 +101680,7 @@ "alternateDrugAvailable" : true, "cancerGenome" : false, "crossReferences" : [], + "descriptiveVideoId" : "gqSb7LarS24", "dosingInformation" : true, "hasTestingInfo" : false, "history" : [ @@ -100689,6 +101690,13 @@ "description" : "added guideline publication", "type" : "Update", "version" : 0 + }, + { + "id" : 1452509700, + "date" : "2024-06-27T00:42:37.302-07:00", + "description" : "Added video", + "type" : "Update", + "version" : 0 } ], "literature" : [ @@ -100708,7 +101716,7 @@ "objCls" : "Chemical", "id" : "PA166122595", "name" : "vortioxetine", - "version" : 5 + "version" : 10 } ], "relatedGenes" : [ @@ -100717,7 +101725,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "CPIC", @@ -100730,16 +101738,16 @@ "textMarkdown" : { "id" : 1452004141, "html" : "

This annotation is based on the CPIC® guideline for CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A Genotypes and Serotonin Reuptake Inhibitor Antidepressants.

\n

February 2023

\n\n

Table 1: Dosing recommendations for vortioxetine based on CYP2D6 phenotype

\n

Adapted from Tables 1 and 2d of the guideline.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
PhenotypeActivity score
range		Activity scoreExamplesImplicationsTherapeutic
Recommendations		Classification of
recommendationa		Considerations
CYP2D6 ultrarapid metabolizer>2.25>2.25*1/*1xN, *1/*2xN, *2/*2xNcIncreased metabolism of vortioxetine to inactive compounds when compared to CYP2D6 normal metabolizers. Lower plasma concentrations decrease the probability of clinical benefit.Select alternative drug not predominantly metabolized by CYP2D6. If vortioxetine use is warranted, initiate therapy at standard starting dose and titrate to maintenance dose based on efficacy and side effects. Increasing the target maintenance dose by 50% or more may be needed for efficacy.OptionalDrug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when selecting an alternative therapy.
CYP2D6 normal metabolizer1.25 <= x <= 2.251.25
1.5
1.75
2.0
2.25		*1/*10
*1/*41, *1/*9
*10/*41x3
*1/*1, *1/*2
*2x2/*10		Normal metabolism.Initiate therapy with recommended starting dose.Strong
CYP2D6 intermediate metabolizer0 < x < 1.250.25
0.5
0.75
1.0		*4/*10
*4/*41, *10/*10
*10/*41
*41/*41, *1/*5		Reduced metabolism of vortioxetine to less active compounds when compared to CYP2D6 normal metabolizers. Higher plasma concentrations may increase the probability of side effectsInitiate therapy with recommended starting dose.Moderate
CYP2D6 poor metabolizer00*3/*4, *4/*4, *5/*5, *5/*6Greatly reduced metabolism of vortioxetine to inactive compounds when compared to CYP2D6 normal metabolizers. Higher plasma concentrations may increase the probability of side effects.Initiate 50% of starting dose (e.g., 5 mg) and titrate to the maximum recommended dose of 10 mg or consider a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2D6.ModerateDrug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when adjusting dose or selecting an alternative therapy.
CYP2D6 Indeterminaten/aAn individual carrying one or two unknown or uncertain function alleles*1/*22, *1/*25, *22/*25No recommendationNo recommendation
\n

a Rating scheme described in Supplemental Materials.

\n", - "version" : 0 + "version" : 1 }, "userId" : "katrin", - "version" : 1 + "version" : 6 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166300980", - "name" : "Recommendation PA166300980", + "id" : "PA166300973", + "name" : "Recommendation PA166300973", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -100754,7 +101762,7 @@ "implications" : [ "CYP2D6: Increased metabolism of vortioxetine to inactive compounds when compared to CYP2D6 normal metabolizers. Lower plasma concentrations decrease the probability of clinical benefit." ], - "lookupKey" : {"CYP2D6": "≥3.0"}, + "lookupKey" : {"CYP2D6": "≥5.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -100762,41 +101770,41 @@ "objCls" : "Chemical", "id" : "PA166122595", "name" : "vortioxetine", - "version" : 5 + "version" : 10 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166288221", "name" : "Annotation of CPIC Guideline for vortioxetine and CYP2D6", - "version" : 1 + "version" : 6 }, "text" : { - "id" : 1452093961, + "id" : 1452093954, "html" : "

Select alternative drug not predominantly metabolized by CYP2D6. If vortioxetine use is warranted, initiate therapy at standard starting dose and titrate to maintenance dose based on efficacy and side effects. Increasing the target maintenance dose by 50% or more may be needed for efficacy.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when selecting an alternative therapy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300971", - "name" : "Recommendation PA166300971", - "alternateDrugAvailable" : false, + "id" : "PA166300974", + "name" : "Recommendation PA166300974", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501931, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2D6: Reduced metabolism of vortioxetine to less active compounds when compared to CYP2D6 normal metabolizers. Higher plasma concentrations may increase the probability of side effects." + "CYP2D6: Increased metabolism of vortioxetine to inactive compounds when compared to CYP2D6 normal metabolizers. Lower plasma concentrations decrease the probability of clinical benefit." ], - "lookupKey" : {"CYP2D6": "1.0"}, + "lookupKey" : {"CYP2D6": "≥3.75"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -100804,41 +101812,41 @@ "objCls" : "Chemical", "id" : "PA166122595", "name" : "vortioxetine", - "version" : 5 + "version" : 10 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166288221", "name" : "Annotation of CPIC Guideline for vortioxetine and CYP2D6", - "version" : 1 + "version" : 6 }, "text" : { - "id" : 1452093952, - "html" : "

Initiate therapy with recommended starting dose.

\n", + "id" : 1452093955, + "html" : "

Select alternative drug not predominantly metabolized by CYP2D6. If vortioxetine use is warranted, initiate therapy at standard starting dose and titrate to maintenance dose based on efficacy and side effects. Increasing the target maintenance dose by 50% or more may be needed for efficacy.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when selecting an alternative therapy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300988", - "name" : "Recommendation PA166300988", - "alternateDrugAvailable" : false, + "id" : "PA166300975", + "name" : "Recommendation PA166300975", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501931, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2D6: Reduced metabolism of vortioxetine to less active compounds when compared to CYP2D6 normal metabolizers. Higher plasma concentrations may increase the probability of side effects." + "CYP2D6: Increased metabolism of vortioxetine to inactive compounds when compared to CYP2D6 normal metabolizers. Lower plasma concentrations decrease the probability of clinical benefit." ], - "lookupKey" : {"CYP2D6": "0.25"}, + "lookupKey" : {"CYP2D6": "≥6.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -100846,26 +101854,26 @@ "objCls" : "Chemical", "id" : "PA166122595", "name" : "vortioxetine", - "version" : 5 + "version" : 10 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166288221", "name" : "Annotation of CPIC Guideline for vortioxetine and CYP2D6", - "version" : 1 + "version" : 6 }, "text" : { - "id" : 1452093969, - "html" : "

Initiate therapy with recommended starting dose.

\n", + "id" : 1452093956, + "html" : "

Select alternative drug not predominantly metabolized by CYP2D6. If vortioxetine use is warranted, initiate therapy at standard starting dose and titrate to maintenance dose based on efficacy and side effects. Increasing the target maintenance dose by 50% or more may be needed for efficacy.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when selecting an alternative therapy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300979", - "name" : "Recommendation PA166300979", + "id" : "PA166300977", + "name" : "Recommendation PA166300977", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -100880,7 +101888,7 @@ "implications" : [ "CYP2D6: Increased metabolism of vortioxetine to inactive compounds when compared to CYP2D6 normal metabolizers. Lower plasma concentrations decrease the probability of clinical benefit." ], - "lookupKey" : {"CYP2D6": "≥3.25"}, + "lookupKey" : {"CYP2D6": "≥4.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -100888,26 +101896,26 @@ "objCls" : "Chemical", "id" : "PA166122595", "name" : "vortioxetine", - "version" : 5 + "version" : 10 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166288221", "name" : "Annotation of CPIC Guideline for vortioxetine and CYP2D6", - "version" : 1 + "version" : 6 }, "text" : { - "id" : 1452093960, + "id" : 1452093958, "html" : "

Select alternative drug not predominantly metabolized by CYP2D6. If vortioxetine use is warranted, initiate therapy at standard starting dose and titrate to maintenance dose based on efficacy and side effects. Increasing the target maintenance dose by 50% or more may be needed for efficacy.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when selecting an alternative therapy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300984", - "name" : "Recommendation PA166300984", + "id" : "PA166300978", + "name" : "Recommendation PA166300978", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -100922,7 +101930,7 @@ "implications" : [ "CYP2D6: Increased metabolism of vortioxetine to inactive compounds when compared to CYP2D6 normal metabolizers. Lower plasma concentrations decrease the probability of clinical benefit." ], - "lookupKey" : {"CYP2D6": "2.5"}, + "lookupKey" : {"CYP2D6": "≥3.5"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -100930,26 +101938,26 @@ "objCls" : "Chemical", "id" : "PA166122595", "name" : "vortioxetine", - "version" : 5 + "version" : 10 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166288221", "name" : "Annotation of CPIC Guideline for vortioxetine and CYP2D6", - "version" : 1 + "version" : 6 }, "text" : { - "id" : 1452093965, + "id" : 1452093959, "html" : "

Select alternative drug not predominantly metabolized by CYP2D6. If vortioxetine use is warranted, initiate therapy at standard starting dose and titrate to maintenance dose based on efficacy and side effects. Increasing the target maintenance dose by 50% or more may be needed for efficacy.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when selecting an alternative therapy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300975", - "name" : "Recommendation PA166300975", + "id" : "PA166300979", + "name" : "Recommendation PA166300979", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -100964,7 +101972,7 @@ "implications" : [ "CYP2D6: Increased metabolism of vortioxetine to inactive compounds when compared to CYP2D6 normal metabolizers. Lower plasma concentrations decrease the probability of clinical benefit." ], - "lookupKey" : {"CYP2D6": "≥6.0"}, + "lookupKey" : {"CYP2D6": "≥3.25"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -100972,26 +101980,26 @@ "objCls" : "Chemical", "id" : "PA166122595", "name" : "vortioxetine", - "version" : 5 + "version" : 10 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166288221", "name" : "Annotation of CPIC Guideline for vortioxetine and CYP2D6", - "version" : 1 + "version" : 6 }, "text" : { - "id" : 1452093956, + "id" : 1452093960, "html" : "

Select alternative drug not predominantly metabolized by CYP2D6. If vortioxetine use is warranted, initiate therapy at standard starting dose and titrate to maintenance dose based on efficacy and side effects. Increasing the target maintenance dose by 50% or more may be needed for efficacy.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when selecting an alternative therapy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300981", - "name" : "Recommendation PA166300981", + "id" : "PA166300980", + "name" : "Recommendation PA166300980", "alternateDrugAvailable" : true, "classification" : { "id" : 981565059, @@ -101006,7 +102014,7 @@ "implications" : [ "CYP2D6: Increased metabolism of vortioxetine to inactive compounds when compared to CYP2D6 normal metabolizers. Lower plasma concentrations decrease the probability of clinical benefit." ], - "lookupKey" : {"CYP2D6": "4.0"}, + "lookupKey" : {"CYP2D6": "≥3.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -101014,41 +102022,41 @@ "objCls" : "Chemical", "id" : "PA166122595", "name" : "vortioxetine", - "version" : 5 + "version" : 10 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166288221", "name" : "Annotation of CPIC Guideline for vortioxetine and CYP2D6", - "version" : 1 + "version" : 6 }, "text" : { - "id" : 1452093962, + "id" : 1452093961, "html" : "

Select alternative drug not predominantly metabolized by CYP2D6. If vortioxetine use is warranted, initiate therapy at standard starting dose and titrate to maintenance dose based on efficacy and side effects. Increasing the target maintenance dose by 50% or more may be needed for efficacy.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when selecting an alternative therapy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300990", - "name" : "Recommendation PA166300990", - "alternateDrugAvailable" : false, + "id" : "PA166300981", + "name" : "Recommendation PA166300981", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2D6: n/a" + "CYP2D6: Increased metabolism of vortioxetine to inactive compounds when compared to CYP2D6 normal metabolizers. Lower plasma concentrations decrease the probability of clinical benefit." ], - "lookupKey" : {"CYP2D6": "n/a"}, + "lookupKey" : {"CYP2D6": "4.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -101056,71 +102064,41 @@ "objCls" : "Chemical", "id" : "PA166122595", "name" : "vortioxetine", - "version" : 5 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166288221", - "name" : "Annotation of CPIC Guideline for vortioxetine and CYP2D6", - "version" : 1 - }, - "text" : { - "id" : 1452093971, - "html" : "

No recommendation

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166301332", - "name" : "Recommendation Annotation PA166301332", - "alternateDrugAvailable" : false, - "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"CYP2D6": "xN combinations"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA166122595", - "name" : "vortioxetine", - "version" : 5 + "version" : 10 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166288221", "name" : "Annotation of CPIC Guideline for vortioxetine and CYP2D6", - "version" : 1 + "version" : 6 }, "text" : { - "id" : 1452095651, - "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", + "id" : 1452093962, + "html" : "

Select alternative drug not predominantly metabolized by CYP2D6. If vortioxetine use is warranted, initiate therapy at standard starting dose and titrate to maintenance dose based on efficacy and side effects. Increasing the target maintenance dose by 50% or more may be needed for efficacy.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when selecting an alternative therapy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300989", - "name" : "Recommendation PA166300989", + "id" : "PA166300982", + "name" : "Recommendation PA166300982", "alternateDrugAvailable" : true, "classification" : { - "id" : 981501931, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Moderate", - "termId" : "guidelineStrength:981501931", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, "dosingInformation" : true, "implications" : [ - "CYP2D6: Greatly reduced metabolism of vortioxetine to inactive compounds when compared to CYP2D6 normal metabolizers. Higher plasma concentrations may increase the probability of side effects." + "CYP2D6: Increased metabolism of vortioxetine to inactive compounds when compared to CYP2D6 normal metabolizers. Lower plasma concentrations decrease the probability of clinical benefit." ], - "lookupKey" : {"CYP2D6": "0.0"}, + "lookupKey" : {"CYP2D6": "2.75"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -101128,41 +102106,41 @@ "objCls" : "Chemical", "id" : "PA166122595", "name" : "vortioxetine", - "version" : 5 + "version" : 10 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166288221", "name" : "Annotation of CPIC Guideline for vortioxetine and CYP2D6", - "version" : 1 + "version" : 6 }, "text" : { - "id" : 1452093970, - "html" : "

Initiate 50% of starting dose (e.g., 5 mg) and titrate to the maximum recommended dose of 10 mg or consider a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2D6.

\n

Other Considerations

\n

Drug-drug interactions, indication and other patient characteristics (e.g., age, renal function, liver function) should be considered when adjusting dose or selecting an alternative therapy.

\n", + "id" : 1452093963, + "html" : "

Select alternative drug not predominantly metabolized by CYP2D6. If vortioxetine use is warranted, initiate therapy at standard starting dose and titrate to maintenance dose based on efficacy and side effects. Increasing the target maintenance dose by 50% or more may be needed for efficacy.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when selecting an alternative therapy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300976", - "name" : "Recommendation PA166300976", - "alternateDrugAvailable" : false, + "id" : "PA166300983", + "name" : "Recommendation PA166300983", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2D6: Normal metabolism." + "CYP2D6: Increased metabolism of vortioxetine to inactive compounds when compared to CYP2D6 normal metabolizers. Lower plasma concentrations decrease the probability of clinical benefit." ], - "lookupKey" : {"CYP2D6": "1.75"}, + "lookupKey" : {"CYP2D6": "3.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -101170,41 +102148,41 @@ "objCls" : "Chemical", "id" : "PA166122595", "name" : "vortioxetine", - "version" : 5 + "version" : 10 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166288221", "name" : "Annotation of CPIC Guideline for vortioxetine and CYP2D6", - "version" : 1 + "version" : 6 }, "text" : { - "id" : 1452093957, - "html" : "

Initiate therapy with recommended starting dose.

\n", + "id" : 1452093964, + "html" : "

Select alternative drug not predominantly metabolized by CYP2D6. If vortioxetine use is warranted, initiate therapy at standard starting dose and titrate to maintenance dose based on efficacy and side effects. Increasing the target maintenance dose by 50% or more may be needed for efficacy.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when selecting an alternative therapy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300985", - "name" : "Recommendation PA166300985", - "alternateDrugAvailable" : false, + "id" : "PA166300984", + "name" : "Recommendation PA166300984", + "alternateDrugAvailable" : true, "classification" : { - "id" : 981501930, + "id" : 981565059, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Optional", + "termId" : "guidelineStrength:981565059", "valid" : true, "version" : 0 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "CYP2D6: Normal metabolism." + "CYP2D6: Increased metabolism of vortioxetine to inactive compounds when compared to CYP2D6 normal metabolizers. Lower plasma concentrations decrease the probability of clinical benefit." ], - "lookupKey" : {"CYP2D6": "2.25"}, + "lookupKey" : {"CYP2D6": "2.5"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -101212,27 +102190,27 @@ "objCls" : "Chemical", "id" : "PA166122595", "name" : "vortioxetine", - "version" : 5 + "version" : 10 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166288221", "name" : "Annotation of CPIC Guideline for vortioxetine and CYP2D6", - "version" : 1 + "version" : 6 }, "text" : { - "id" : 1452093966, - "html" : "

Initiate therapy with recommended starting dose.

\n", + "id" : 1452093965, + "html" : "

Select alternative drug not predominantly metabolized by CYP2D6. If vortioxetine use is warranted, initiate therapy at standard starting dose and titrate to maintenance dose based on efficacy and side effects. Increasing the target maintenance dose by 50% or more may be needed for efficacy.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when selecting an alternative therapy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300972", - "name" : "Recommendation PA166300972", - "alternateDrugAvailable" : false, + "id" : "PA166300989", + "name" : "Recommendation PA166300989", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501931, "parents" : [], @@ -101242,53 +102220,11 @@ "valid" : true, "version" : 0 }, - "dosingInformation" : false, - "implications" : [ - "CYP2D6: Reduced metabolism of vortioxetine to less active compounds when compared to CYP2D6 normal metabolizers. Higher plasma concentrations may increase the probability of side effects." - ], - "lookupKey" : {"CYP2D6": "0.75"}, - "otherPrescribingGuidance" : false, - "population" : "general", - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA166122595", - "name" : "vortioxetine", - "version" : 5 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166288221", - "name" : "Annotation of CPIC Guideline for vortioxetine and CYP2D6", - "version" : 1 - }, - "text" : { - "id" : 1452093953, - "html" : "

Initiate therapy with recommended starting dose.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166300982", - "name" : "Recommendation PA166300982", - "alternateDrugAvailable" : true, - "classification" : { - "id" : 981565059, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", - "valid" : true, - "version" : 0 - }, "dosingInformation" : true, "implications" : [ - "CYP2D6: Increased metabolism of vortioxetine to inactive compounds when compared to CYP2D6 normal metabolizers. Lower plasma concentrations decrease the probability of clinical benefit." + "CYP2D6: Greatly reduced metabolism of vortioxetine to inactive compounds when compared to CYP2D6 normal metabolizers. Higher plasma concentrations may increase the probability of side effects." ], - "lookupKey" : {"CYP2D6": "2.75"}, + "lookupKey" : {"CYP2D6": "0.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -101296,21 +102232,21 @@ "objCls" : "Chemical", "id" : "PA166122595", "name" : "vortioxetine", - "version" : 5 + "version" : 10 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166288221", "name" : "Annotation of CPIC Guideline for vortioxetine and CYP2D6", - "version" : 1 + "version" : 6 }, "text" : { - "id" : 1452093963, - "html" : "

Select alternative drug not predominantly metabolized by CYP2D6. If vortioxetine use is warranted, initiate therapy at standard starting dose and titrate to maintenance dose based on efficacy and side effects. Increasing the target maintenance dose by 50% or more may be needed for efficacy.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when selecting an alternative therapy.

\n", + "id" : 1452093970, + "html" : "

Initiate 50% of starting dose (e.g., 5 mg) and titrate to the maximum recommended dose of 10 mg or consider a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2D6.

\n

Other Considerations

\n

Drug-drug interactions, indication and other patient characteristics (e.g., age, renal function, liver function) should be considered when adjusting dose or selecting an alternative therapy.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -101338,41 +102274,41 @@ "objCls" : "Chemical", "id" : "PA166122595", "name" : "vortioxetine", - "version" : 5 + "version" : 10 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166288221", "name" : "Annotation of CPIC Guideline for vortioxetine and CYP2D6", - "version" : 1 + "version" : 6 }, "text" : { "id" : 1452093950, "html" : "

Initiate therapy with recommended starting dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300977", - "name" : "Recommendation PA166300977", - "alternateDrugAvailable" : true, + "id" : "PA166300970", + "name" : "Recommendation PA166300970", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2D6: Increased metabolism of vortioxetine to inactive compounds when compared to CYP2D6 normal metabolizers. Lower plasma concentrations decrease the probability of clinical benefit." + "CYP2D6: Normal metabolism." ], - "lookupKey" : {"CYP2D6": "≥4.0"}, + "lookupKey" : {"CYP2D6": "1.25"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -101380,41 +102316,41 @@ "objCls" : "Chemical", "id" : "PA166122595", "name" : "vortioxetine", - "version" : 5 + "version" : 10 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166288221", "name" : "Annotation of CPIC Guideline for vortioxetine and CYP2D6", - "version" : 1 + "version" : 6 }, "text" : { - "id" : 1452093958, - "html" : "

Select alternative drug not predominantly metabolized by CYP2D6. If vortioxetine use is warranted, initiate therapy at standard starting dose and titrate to maintenance dose based on efficacy and side effects. Increasing the target maintenance dose by 50% or more may be needed for efficacy.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when selecting an alternative therapy.

\n", + "id" : 1452093951, + "html" : "

Initiate therapy with recommended starting dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300973", - "name" : "Recommendation PA166300973", - "alternateDrugAvailable" : true, + "id" : "PA166300971", + "name" : "Recommendation PA166300971", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2D6: Increased metabolism of vortioxetine to inactive compounds when compared to CYP2D6 normal metabolizers. Lower plasma concentrations decrease the probability of clinical benefit." + "CYP2D6: Reduced metabolism of vortioxetine to less active compounds when compared to CYP2D6 normal metabolizers. Higher plasma concentrations may increase the probability of side effects." ], - "lookupKey" : {"CYP2D6": "≥5.0"}, + "lookupKey" : {"CYP2D6": "1.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -101422,41 +102358,41 @@ "objCls" : "Chemical", "id" : "PA166122595", "name" : "vortioxetine", - "version" : 5 + "version" : 10 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166288221", "name" : "Annotation of CPIC Guideline for vortioxetine and CYP2D6", - "version" : 1 + "version" : 6 }, "text" : { - "id" : 1452093954, - "html" : "

Select alternative drug not predominantly metabolized by CYP2D6. If vortioxetine use is warranted, initiate therapy at standard starting dose and titrate to maintenance dose based on efficacy and side effects. Increasing the target maintenance dose by 50% or more may be needed for efficacy.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when selecting an alternative therapy.

\n", + "id" : 1452093952, + "html" : "

Initiate therapy with recommended starting dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300986", - "name" : "Recommendation PA166300986", + "id" : "PA166300972", + "name" : "Recommendation PA166300972", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501930, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Strong", - "termId" : "guidelineStrength:981501930", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, "dosingInformation" : false, "implications" : [ - "CYP2D6: Normal metabolism." + "CYP2D6: Reduced metabolism of vortioxetine to less active compounds when compared to CYP2D6 normal metabolizers. Higher plasma concentrations may increase the probability of side effects." ], - "lookupKey" : {"CYP2D6": "2.0"}, + "lookupKey" : {"CYP2D6": "0.75"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -101464,41 +102400,41 @@ "objCls" : "Chemical", "id" : "PA166122595", "name" : "vortioxetine", - "version" : 5 + "version" : 10 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166288221", "name" : "Annotation of CPIC Guideline for vortioxetine and CYP2D6", - "version" : 1 + "version" : 6 }, "text" : { - "id" : 1452093967, + "id" : 1452093953, "html" : "

Initiate therapy with recommended starting dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300983", - "name" : "Recommendation PA166300983", - "alternateDrugAvailable" : true, + "id" : "PA166300976", + "name" : "Recommendation PA166300976", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2D6: Increased metabolism of vortioxetine to inactive compounds when compared to CYP2D6 normal metabolizers. Lower plasma concentrations decrease the probability of clinical benefit." + "CYP2D6: Normal metabolism." ], - "lookupKey" : {"CYP2D6": "3.0"}, + "lookupKey" : {"CYP2D6": "1.75"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -101506,26 +102442,26 @@ "objCls" : "Chemical", "id" : "PA166122595", "name" : "vortioxetine", - "version" : 5 + "version" : 10 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166288221", "name" : "Annotation of CPIC Guideline for vortioxetine and CYP2D6", - "version" : 1 + "version" : 6 }, "text" : { - "id" : 1452093964, - "html" : "

Select alternative drug not predominantly metabolized by CYP2D6. If vortioxetine use is warranted, initiate therapy at standard starting dose and titrate to maintenance dose based on efficacy and side effects. Increasing the target maintenance dose by 50% or more may be needed for efficacy.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when selecting an alternative therapy.

\n", + "id" : 1452093957, + "html" : "

Initiate therapy with recommended starting dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300970", - "name" : "Recommendation PA166300970", + "id" : "PA166300985", + "name" : "Recommendation PA166300985", "alternateDrugAvailable" : false, "classification" : { "id" : 981501930, @@ -101540,7 +102476,7 @@ "implications" : [ "CYP2D6: Normal metabolism." ], - "lookupKey" : {"CYP2D6": "1.25"}, + "lookupKey" : {"CYP2D6": "2.25"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -101548,41 +102484,41 @@ "objCls" : "Chemical", "id" : "PA166122595", "name" : "vortioxetine", - "version" : 5 + "version" : 10 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166288221", "name" : "Annotation of CPIC Guideline for vortioxetine and CYP2D6", - "version" : 1 + "version" : 6 }, "text" : { - "id" : 1452093951, + "id" : 1452093966, "html" : "

Initiate therapy with recommended starting dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300978", - "name" : "Recommendation PA166300978", - "alternateDrugAvailable" : true, + "id" : "PA166300986", + "name" : "Recommendation PA166300986", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501930, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Strong", + "termId" : "guidelineStrength:981501930", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2D6: Increased metabolism of vortioxetine to inactive compounds when compared to CYP2D6 normal metabolizers. Lower plasma concentrations decrease the probability of clinical benefit." + "CYP2D6: Normal metabolism." ], - "lookupKey" : {"CYP2D6": "≥3.5"}, + "lookupKey" : {"CYP2D6": "2.0"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -101590,21 +102526,21 @@ "objCls" : "Chemical", "id" : "PA166122595", "name" : "vortioxetine", - "version" : 5 + "version" : 10 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166288221", "name" : "Annotation of CPIC Guideline for vortioxetine and CYP2D6", - "version" : 1 + "version" : 6 }, "text" : { - "id" : 1452093959, - "html" : "

Select alternative drug not predominantly metabolized by CYP2D6. If vortioxetine use is warranted, initiate therapy at standard starting dose and titrate to maintenance dose based on efficacy and side effects. Increasing the target maintenance dose by 50% or more may be needed for efficacy.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when selecting an alternative therapy.

\n", + "id" : 1452093967, + "html" : "

Initiate therapy with recommended starting dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", @@ -101632,41 +102568,41 @@ "objCls" : "Chemical", "id" : "PA166122595", "name" : "vortioxetine", - "version" : 5 + "version" : 10 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166288221", "name" : "Annotation of CPIC Guideline for vortioxetine and CYP2D6", - "version" : 1 + "version" : 6 }, "text" : { "id" : 1452093968, "html" : "

Initiate therapy with recommended starting dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166300974", - "name" : "Recommendation PA166300974", - "alternateDrugAvailable" : true, + "id" : "PA166300988", + "name" : "Recommendation PA166300988", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981565059, + "id" : 981501931, "parents" : [], "resource" : "Guideline Strength", - "term" : "Optional", - "termId" : "guidelineStrength:981565059", + "term" : "Moderate", + "termId" : "guidelineStrength:981501931", "valid" : true, "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "CYP2D6: Increased metabolism of vortioxetine to inactive compounds when compared to CYP2D6 normal metabolizers. Lower plasma concentrations decrease the probability of clinical benefit." + "CYP2D6: Reduced metabolism of vortioxetine to less active compounds when compared to CYP2D6 normal metabolizers. Higher plasma concentrations may increase the probability of side effects." ], - "lookupKey" : {"CYP2D6": "≥3.75"}, + "lookupKey" : {"CYP2D6": "0.25"}, "otherPrescribingGuidance" : false, "population" : "general", "relatedChemicals" : [ @@ -101674,18 +102610,90 @@ "objCls" : "Chemical", "id" : "PA166122595", "name" : "vortioxetine", - "version" : 5 + "version" : 10 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166288221", "name" : "Annotation of CPIC Guideline for vortioxetine and CYP2D6", - "version" : 1 + "version" : 6 }, "text" : { - "id" : 1452093955, - "html" : "

Select alternative drug not predominantly metabolized by CYP2D6. If vortioxetine use is warranted, initiate therapy at standard starting dose and titrate to maintenance dose based on efficacy and side effects. Increasing the target maintenance dose by 50% or more may be needed for efficacy.

\n

Other Considerations

\n

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when selecting an alternative therapy.

\n", + "id" : 1452093969, + "html" : "

Initiate therapy with recommended starting dose.

\n", + "version" : 0 + }, + "version" : 2 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166300990", + "name" : "Recommendation PA166300990", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 1448526251, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : false, + "implications" : [ + "CYP2D6: n/a" + ], + "lookupKey" : {"CYP2D6": "n/a"}, + "otherPrescribingGuidance" : false, + "population" : "general", + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA166122595", + "name" : "vortioxetine", + "version" : 10 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166288221", + "name" : "Annotation of CPIC Guideline for vortioxetine and CYP2D6", + "version" : 6 + }, + "text" : { + "id" : 1452093971, + "html" : "

No recommendation

\n", + "version" : 0 + }, + "version" : 2 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166301332", + "name" : "Recommendation Annotation PA166301332", + "alternateDrugAvailable" : false, + "dosingInformation" : false, + "implications" : [], + "lookupKey" : {"CYP2D6": "xN combinations"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA166122595", + "name" : "vortioxetine", + "version" : 10 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166288221", + "name" : "Annotation of CPIC Guideline for vortioxetine and CYP2D6", + "version" : 6 + }, + "text" : { + "id" : 1452095651, + "html" : "

xN is not a valid input for CYP2D6 copy number alleles. Please select a copy number representation as outlined below.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
xN AllelePossible selection
*1xN*1x2 or *1x≥3
*2xN*2x2 or *2x≥3
*3xN*3x2
*4xN*4x2 or *4x≥3
*6xN*6x2
*35xN*35x2
*36xN*36x2
*43xN*43x2
*45xN*45x2
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GuidelineCNV AlleleFunctionActivity
value		Other Allele
Function		Activity
value		CYP2D6 ASPhenotype
CPIC or DPWG*1x2Increased2No function02Normal metabolizer
CPIC or DPWG*1x2Increased2Decreased function0.252.25Normal metabolizer
CPIC*1x2Increased2Decreased function0.52.5Ultrarapid metabolizer
DPWG*1x2Increased2Decreased function0.52.5Normal metabolizer
CPIC or DPWG*1x2Increased2Normal function1.03.0Ultrarapid metabolizer
CPIC or DPWG*1x≥3Increased≥3≥3Ultrarapid metabolizer
\n", "version" : 0 }, "version" : 0 @@ -101947,6 +102955,13 @@ "description" : "Updated warfarin flow chart Figure 2 to be consistent with the manuscript", "type" : "Update", "version" : 0 + }, + { + "id" : 1452515660, + "date" : "2024-07-04T13:41:20.308-07:00", + "description" : "change image host for figure 2 from CPIC to PGKB", + "type" : "Note", + "version" : 0 } ], "literature" : [ @@ -101967,63 +102982,63 @@ "id" : "PA165816552", "symbol" : "CYP2C9*11", "name" : "*11", - "version" : 23 + "version" : 50 }, { "objCls" : "Haplotype", "id" : "PA165816543", "symbol" : "CYP2C9*2", "name" : "*2", - "version" : 23 + "version" : 52 }, { "objCls" : "Haplotype", "id" : "PA165816544", "symbol" : "CYP2C9*3", "name" : "*3", - "version" : 25 + "version" : 55 }, { "objCls" : "Haplotype", "id" : "PA165816546", "symbol" : "CYP2C9*5", "name" : "*5", - "version" : 23 + "version" : 50 }, { "objCls" : "Haplotype", "id" : "PA165816547", "symbol" : "CYP2C9*6", "name" : "*6", - "version" : 24 + "version" : 52 }, { "objCls" : "Haplotype", "id" : "PA165816549", "symbol" : "CYP2C9*8", "name" : "*8", - "version" : 25 + "version" : 52 }, { "objCls" : "Variant", "id" : "PA166154157", "symbol" : "rs12777823", "name" : "rs12777823", - "version" : 5 + "version" : 6 }, { "objCls" : "Variant", "id" : "PA166155381", "symbol" : "rs2108622", "name" : "rs2108622", - "version" : 5 + "version" : 6 }, { "objCls" : "Variant", "id" : "PA166155091", "symbol" : "rs9923231", "name" : "rs9923231", - "version" : 5 + "version" : 10 } ], "relatedChemicals" : [ @@ -102031,7 +103046,7 @@ "objCls" : "Chemical", "id" : "PA451906", "name" : "warfarin", - "version" : 17 + "version" : 70 } ], "relatedGenes" : [ @@ -102040,37 +103055,37 @@ "id" : "PA126", "symbol" : "CYP2C9", "name" : "cytochrome P450 family 2 subfamily C member 9", - "version" : 7877 + "version" : 7952 }, { "objCls" : "Gene", "id" : "PA27121", "symbol" : "CYP4F2", "name" : "cytochrome P450 family 4 subfamily F member 2", - "version" : 16 + "version" : 55 }, { "objCls" : "Gene", "id" : "PA133787052", "symbol" : "VKORC1", "name" : "vitamin K epoxide reductase complex subunit 1", - "version" : 16 + "version" : 52 } ], "source" : "CPIC", "summaryMarkdown" : { "id" : 1447981868, "html" : "

The updated guideline for pharmacogenetics-guided warfarin dosing is published by the Clinical Pharmacogenetics Implementation Consortium. The recommendations for dosing are for adult and pediatric patients that are specific to continental ancestry, and are based on genotypes from CYP2C9, VKORC1, CYP4F2, and rs12777823.

\n", - "version" : 3 + "version" : 11 }, "terms" : [], "textMarkdown" : { "id" : 1451433628, - "html" : "

This annotation is based on the CPIC® guideline for pharmacogenetics-guided warfarin dosing.

\n

February 2017 Update

\n\n

Figure 2. Dosing recommendations for Warfarin dosing based on genotype for adult patients

\n

Adapted from Figure 2 of the 2017 guideline manuscript

\n

\"Fig2\"

\n

Figure 3. Dosing recommendations for Warfarin dosing based on genotype for pediatric patients

\n

Adapted from Figure 3 of the 2017 guideline manuscript

\n

\"Fig3\"

\n

Figure 3 Legend: aData strongest for European ancestry populations and consistent in most Japanese studies.
\nb“Dose clinically” means to dose without genetic information, which may include use of a clinical dosing algorithm or standard dose approach
\ncValidated published pediatric pharmacogenetic algorithms include Hamberg et al.[Article:24330000] and Biss et al.[Article:22010099]
\ndNo studies in children included CYP2C9*5, *6, *8, or *11 genotyping.

\n

November 2013 Update

\n

CPIC guideline authors are aware of several recently published studies on warfarin pharmacogenetics [Articles:24251361, 24251363, 24251360]. These papers have prompted several opinion pieces [Articles:24328463, 24251364]. The authors are evaluating the information, which will be incorporated into the next update of the CPIC guideline on warfarin.

\n

October 2011

\n

Advance online publication September 2011.

\n\n

Figure 2. Frequency histograms of stable therapeutic warfarin doses in mg/week, stratified by VKORC1 -1639G>A genotype.

\n

Adapted from Figure 2 of the 2011 guideline manuscript

\n

\"CPIC

\n

Figure 2 Legend: Frequency histograms of stable therapeutic warfarin doses in mg/week, stratified by VKORC1 -1639G>A genotype in 3,616 patients recruited by the International Warfarin Pharmacogenetics Consortium (IWPC) who did not carry the CYP2C9*2 or *3 allele (i.e., coded as *1/*1 for US Food and Drug Administration (FDA) table and algorithm dosing). The range of doses within each genotype group recommended on the FDA table is shown via the shaded rectangle. The range of doses predicted using the IWPC dosing algorithm in these 3,616 patients is shown by the solid lines.

\n

Figure 2 demonstrates that the range of individuals covered by the FDA table is much narrower than that of the algorithm. The article and supplement detail important variables that are not covered by the table that should also be taken into consideration.

\n\n

Adapted from Table 1 of the 2011 guideline manuscript

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
VKORC1 Genotype (-1639G>A, rs9923231)CYP2C9*1/*1CYP2C9*1/*2CYP2C9*1/*3CYP2C9*2/*2CYP2C9*2/*3CYP2C9*3/*3
GG5-75-73-43-43-40.5-2
GA5-73-43-43-40.5-20.5-2
AA3-43-40.5-20.5-20.5-20.5-2
\n

Reproduced from updated warfarin (Coumadin) product label.

\n

Supplemental Table S1. Genotypes that constitute the * alleles for CYP2C9

\n

Adapted from Table S1 of the 2011 guideline supplement

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
AlleleConstituted by genotypes at:Amino acid changesEnzymatic Activity
*1reference allele at all positionsNormal
*2C>T at rs1799853R144CDecreased
*3A>C at rs1057910I359LDecreased
\n", - "version" : 4 + "html" : "

This annotation is based on the CPIC® guideline for pharmacogenetics-guided warfarin dosing.

\n

February 2017 Update

\n\n

Figure 2. Dosing recommendations for Warfarin dosing based on genotype for adult patients

\n

Adapted from Figure 2 of the 2017 guideline manuscript

\n

\"Figure

\n

Figure 3. Dosing recommendations for Warfarin dosing based on genotype for pediatric patients

\n

Adapted from Figure 3 of the 2017 guideline manuscript

\n

\"Figure

\n

Figure 3 Legend: aData strongest for European ancestry populations and consistent in most Japanese studies.
\nb“Dose clinically” means to dose without genetic information, which may include use of a clinical dosing algorithm or standard dose approach
\ncValidated published pediatric pharmacogenetic algorithms include Hamberg et al.[Article:24330000] and Biss et al.[Article:22010099]
\ndNo studies in children included CYP2C9*5, *6, *8, or *11 genotyping.

\n

November 2013 Update

\n

CPIC guideline authors are aware of several recently published studies on warfarin pharmacogenetics [Articles:24251361, 24251363, 24251360]. These papers have prompted several opinion pieces [Articles:24328463, 24251364]. The authors are evaluating the information, which will be incorporated into the next update of the CPIC guideline on warfarin.

\n

October 2011

\n

Advance online publication September 2011.

\n\n

Figure 2. Frequency histograms of stable therapeutic warfarin doses in mg/week, stratified by VKORC1 -1639G>A genotype.

\n

Adapted from Figure 2 of the 2011 guideline manuscript

\n

\"CPIC

\n

Figure 2 Legend: Frequency histograms of stable therapeutic warfarin doses in mg/week, stratified by VKORC1 -1639G>A genotype in 3,616 patients recruited by the International Warfarin Pharmacogenetics Consortium (IWPC) who did not carry the CYP2C9*2 or *3 allele (i.e., coded as *1/*1 for US Food and Drug Administration (FDA) table and algorithm dosing). The range of doses within each genotype group recommended on the FDA table is shown via the shaded rectangle. The range of doses predicted using the IWPC dosing algorithm in these 3,616 patients is shown by the solid lines.

\n

Figure 2 demonstrates that the range of individuals covered by the FDA table is much narrower than that of the algorithm. The article and supplement detail important variables that are not covered by the table that should also be taken into consideration.

\n\n

Adapted from Table 1 of the 2011 guideline manuscript

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
VKORC1 Genotype (-1639G>A, rs9923231)CYP2C9*1/*1CYP2C9*1/*2CYP2C9*1/*3CYP2C9*2/*2CYP2C9*2/*3CYP2C9*3/*3
GG5-75-73-43-43-40.5-2
GA5-73-43-43-40.5-20.5-2
AA3-43-40.5-20.5-20.5-20.5-2
\n

Reproduced from updated warfarin (Coumadin) product label.

\n

Supplemental Table S1. Genotypes that constitute the * alleles for CYP2C9

\n

Adapted from Table S1 of the 2011 guideline supplement

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
AlleleConstituted by genotypes at:Amino acid changesEnzymatic Activity
*1reference allele at all positionsNormal
*2C>T at rs1799853R144CDecreased
*3A>C at rs1057910I359LDecreased
\n", + "version" : 5 }, "userId" : "carrillo", - "version" : 43 + "version" : 165 }, "recommendations" : [], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166104949" @@ -102265,7 +103280,7 @@ "id" : "PA165987830", "symbol" : "HLA-B*57:01", "name" : "*57:01", - "version" : 6 + "version" : 21 } ], "relatedChemicals" : [ @@ -102273,7 +103288,7 @@ "objCls" : "Chemical", "id" : "PA448004", "name" : "abacavir", - "version" : 11 + "version" : 41 } ], "relatedGenes" : [ @@ -102282,23 +103297,23 @@ "id" : "PA35056", "symbol" : "HLA-B", "name" : "major histocompatibility complex, class I, B", - "version" : 40 + "version" : 2920 } ], "source" : "DPWG", "summaryMarkdown" : { "id" : 1447982006, "html" : "

Avoid abacavir for patients who have the HLA-B*57:01 allele (patients who are "HLA-B*57:01-positive").

\n", - "version" : 1 + "version" : 2 }, "terms" : [], "textMarkdown" : { "id" : 1447982005, "html" : "

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

\n

August 2019 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for abacavir based on HLA-B*57:01 and recommends avoiding abacavir.

\n

Wording in table taken from the Dutch guidelines August 2019 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
HLA-B*5701abacavirHLA-B*5701-positive patients have a strongly increased risk of a hypersensitivity reaction to abacavir. 48% of the HLA-B*5701-positive patients develop a severe and potentially life-threatening hypersensitivity reaction to abacavirAbacavir is contra-indicated for HLA-B*5701-positive patients.
1. Avoid abacavir.
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for abacavir and HLA-B:

\n
\n

The KNMP Pharmacogenetics Working Group considers genotyping before starting abacavir to be essential for drug safety. Genotyping must be performed before drug therapy has been initiated to guide drug selection.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n

November 2018 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for abacavir based on HLA-B*57:01 and give the same recommendation as in 2011.

\n

Wording in table taken from the Dutch guidelines November 2018 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
HLA-B*5701abacavirHLA-B*5701-positive patients have a strongly increased risk of a hypersensitivity reaction to abacavir.Abacavir is contra-indicated for HLA-B*5701-positive patients.
1. Advise the prescriber to prescribe an alternative according to the current guidelines.
\n

2011 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for abacavir based on HLA-B*57:01 [Article:21412232]. They conclude that an alternate drug should be selected for patients who are HLA-B*57:01 positive.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GenotypeTherapeutic Dose RecommendationLevel of EvidenceClinical Relevance
HLA-B*57:01Select alternative drugPublished controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Clinical effect (S): Failure of lifesaving therapy e.g. anticipated myelosuppression; prevention of breast cancer relapse; arrhythmia; neutropenia < 0.5x109/l; leucopenia < 1.0x109/l; thrombocytopenia < 25x109/l; life-threatening complications from diarrhea.
\n\n", - "version" : 18 + "version" : 31 }, "userId" : "lester", - "version" : 39 + "version" : 78 }, "recommendations" : [ { @@ -102327,21 +103342,21 @@ "objCls" : "Chemical", "id" : "PA448004", "name" : "abacavir", - "version" : 11 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104991", "name" : "Annotation of DPWG Guideline for abacavir and HLA-B", - "version" : 39 + "version" : 78 }, "text" : { "id" : 1452061608, "html" : "

Abacavir is contra-indicated for HLA-B*57:01-positive patients.

\n
    \n
  1. Avoid abacavir.
    2. \n
\n", "version" : 0 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166104991" @@ -102575,7 +103590,7 @@ "date" : "2024-03-28T00:00:00-07:00", "description" : "Tags updated: [Alt Drug removed]", "type" : "Update", - "version" : 0 + "version" : 1 } ], "literature" : [ @@ -102597,7 +103612,7 @@ "id" : "PA166155091", "symbol" : "rs9923231", "name" : "rs9923231", - "version" : 5 + "version" : 10 } ], "relatedChemicals" : [ @@ -102605,7 +103620,7 @@ "objCls" : "Chemical", "id" : "PA452632", "name" : "acenocoumarol", - "version" : 8 + "version" : 30 } ], "relatedGenes" : [ @@ -102614,67 +103629,25 @@ "id" : "PA133787052", "symbol" : "VKORC1", "name" : "vitamin K epoxide reductase complex subunit 1", - "version" : 16 + "version" : 52 } ], "source" : "DPWG", "summaryMarkdown" : { "id" : 1447981854, "html" : "

Patients with the VKORC1 rs9923231 TT genotype (-1639 AA genotype) should be given 50% of the standard initial dose of acenocoumarol and undergo more frequent INR monitoring. There are no recommendation for patients with the VKORC1 rs9923231 CT genotype (-1639 AG genotype).

\n", - "version" : 10 + "version" : 13 }, "terms" : [], "textMarkdown" : { "id" : 1447981853, "html" : "

November 2018 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group (DPWG) has evaluated therapeutic dose recommendations for acenocoumarol based on VKORC1 genotype. They recommend that patients with the VKORC1 rs9923231 TT genotype (-1639 AA genotype) receive 50% of the standard initial dose and undergo more frequent INR monitoring.

\n

No action is needed for patients with the VKORC1 rs9923231 CT genotype (-1639 AG genotype).

\n

The annotation of the DPWG guideline for acenocoumarol and CYP2C9 can be found here.

\n

Wording in table taken from the Dutch guidelines November 2018 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
VKORC1 rs9923231 AAacenocoumarolAn INR >= 6, resulting in an increased risk of bleeding, occurs in 8-12% of these patients during the first weeks of treatment with standard regulation by the Anticoagulation Clinic. The genetic variation increases the sensitivity to acenocoumarol.Monitoring by the ANTICOAGULATION CLINIC (National INR Monitoring Service): recommend to use 50% of the standard initial dose. OTHERWISE: recommend to use 50% of the standard initial dose and recommend more frequent monitoring of the INR .The initial dose and the maintenance dose can be calculated using an algorithm. However, for patients with two or more VKORC1 and/or CYP2C9 variations, the algorithm used in EU-PACT did not result in a significant reduction in the incidence of INRs above the target range when compared to an algorithm without genetic information. We are therefore unable to recommend the use of this algorithm at this time. A (non-validated) algorithm has been prescribed for children that should result in a better prediction of the maintenance dose for AA than the current guideline used by the Anticoagulation Clinic [Article:29935043].
VKORC1 rs9923231 AGacenocoumarolThe genetic variation results in a reduction of the required dose, but with the current practice of initiating or reviewing treatment this results in little or no increased risk of bleeding or excessive anticoagulation.NO action is needed for this gene-drug interaction
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Download the algorithm used in EU-PACT provided by DPWG this is an excel file retrieved from DPWG on 3/19/2024

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for acenocoumarol and VKORC1:

\n
\n

The Dutch Pharmacogenetics Working Group considers genotyping before starting acenocoumarol to be to be beneficial for drug safety. It is advised to genotype the patient before (or directly after) drug therapy has been initiated to guide drug and dose selection.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n

2011 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for acenocoumarol based on VKORC1 genotype [Article:21412232]. They found that VKORC1 genotype contributes to dose variability. However, they make no dosing recommendations at this time "because of strict international normalized ratio monitoring by the Dutch Thrombosis Service."

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GenotypeTherapeutic Dose RecommendationLevel of EvidenceClinical Relevance
VKORC1 rs9934438 AGNonePublished controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Minor clinical effect (S): QTc prolongation (<450 ms , <470 ms ); INR increase < 4.5; Kinetic effect (S).
VKORC1 rs9934438 AACheck INR more frequently.Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Minor clinical effect (S): QTc prolongation (<450 ms , <470 ms ); INR increase < 4.5; Kinetic effect (S).
\n\n", - "version" : 22 + "version" : 32 }, "userId" : "carrillo", - "version" : 42 + "version" : 93 }, "recommendations" : [ - { - "objCls" : "Recommendation Annotation", - "id" : "PA166299301", - "name" : "Recommendation PA166299301", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 981501929, - "description" : "Not Applicable", - "parents" : [], - "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", - "valid" : true, - "version" : 1 - }, - "dosingInformation" : true, - "implications" : [ - "An INR ≥ 6, resulting in an increased risk of bleeding, occurs in 8-12% of these patients during the first weeks of treatment with standard regulation by the Anticoagulation Clinic. The genetic variation increases the sensitivity to acenocoumarol." - ], - "lookupKey" : {"VKORC1": "-1639 AA"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA452632", - "name" : "acenocoumarol", - "version" : 8 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166104938", - "name" : "Annotation of DPWG Guideline for acenocoumarol and VKORC1", - "version" : 42 - }, - "text" : { - "id" : 1452061664, - "html" : "

Monitoring by the ANTICOAGULATION CLINIC (National INR Monitoring Service):

\n\n

OTHERWISE:

\n\n", - "version" : 0 - }, - "version" : 0 - }, { "objCls" : "Recommendation Annotation", "id" : "PA166299299", @@ -102701,14 +103674,14 @@ "objCls" : "Chemical", "id" : "PA452632", "name" : "acenocoumarol", - "version" : 8 + "version" : 30 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104938", "name" : "Annotation of DPWG Guideline for acenocoumarol and VKORC1", - "version" : 42 + "version" : 93 }, "text" : { "id" : 1452061662, @@ -102742,21 +103715,63 @@ "objCls" : "Chemical", "id" : "PA452632", "name" : "acenocoumarol", - "version" : 8 + "version" : 30 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104938", "name" : "Annotation of DPWG Guideline for acenocoumarol and VKORC1", - "version" : 42 + "version" : 93 }, "text" : { "id" : 1452061663, "html" : "

The guideline does not provide a recommendation for acenocoumarol in patients with the VKORC1 rs9923231 CC genotype (-1639 GG genotype).

\n", "version" : 0 }, - "version" : 0 + "version" : 3 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166299301", + "name" : "Recommendation PA166299301", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501929, + "description" : "Not Applicable", + "parents" : [], + "resource" : "Guideline Strength", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", + "valid" : true, + "version" : 1 + }, + "dosingInformation" : true, + "implications" : [ + "An INR ≥ 6, resulting in an increased risk of bleeding, occurs in 8-12% of these patients during the first weeks of treatment with standard regulation by the Anticoagulation Clinic. The genetic variation increases the sensitivity to acenocoumarol." + ], + "lookupKey" : {"VKORC1": "-1639 AA"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA452632", + "name" : "acenocoumarol", + "version" : 30 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104938", + "name" : "Annotation of DPWG Guideline for acenocoumarol and VKORC1", + "version" : 93 + }, + "text" : { + "id" : 1452061664, + "html" : "

Monitoring by the ANTICOAGULATION CLINIC (National INR Monitoring Service):

\n\n

OTHERWISE:

\n\n", + "version" : 0 + }, + "version" : 2 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166104938" @@ -102947,7 +103962,7 @@ "id" : "PA166156544", "symbol" : "rs2231142", "name" : "rs2231142", - "version" : 4 + "version" : 7 } ], "relatedChemicals" : [ @@ -102955,7 +103970,7 @@ "objCls" : "Chemical", "id" : "PA448320", "name" : "allopurinol", - "version" : 9 + "version" : 35 } ], "relatedGenes" : [ @@ -102964,7 +103979,7 @@ "id" : "PA390", "symbol" : "ABCG2", "name" : "ATP binding cassette subfamily G member 2 (Junior blood group)", - "version" : 3596 + "version" : 3672 } ], "source" : "DPWG", @@ -102977,16 +103992,16 @@ "textMarkdown" : { "id" : 1451695863, "html" : "

Dutch pharmacogenetics working group (DPWG) guideline for the gene-drug interaction of ABCG2, HLA-B and Allopurinol, and MTHFR, folic acid and methotrexate. European journal of human genetics (2022)

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group published a paper with the guidelines as per the May 2021 guideline including more details and scoring the clinical implementation [Article:36056234]. The article includes the following mapping for the variant ABCG2 p.(Gln141Lys): rs-number: 2231142; NM_001257386.1:c.421 C > A; NP_001244315.1:p.Gln141Lys; NG_032067.2:g.105152 C > A.

\n

May 2021 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group (DPWG) has evaluated therapeutic dose recommendations for allopurinol based on ABCG2 genotype. They recommend a dose increase for patients with the GT or TT genotypes (described in the document as their equivalent amino acids GK and KK, respectively).

\n

Note: The DPWG allopurinol guideline publication [Article:36056234] includes the following mapping for the variant ABCG2 p.(Gln141Lys): rs-number: 2231142; NM_001257386.1:c.421 C > A; NP_001244315.1:p.Gln141Lys; NG_032067.2:g.105152 C > A. ABCG2 is found on the negative strand. All genotypes displayed in this annotation have been complemented to the positive strand by PharmGKB.

\n

Wording in table taken from the Dutch guidelines May 2021 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
141KK (TT genotype)aallopurinolThe effectiveness of allopurinol is reduced, meaning that a higher dose is required. The gene variation reduces the excretion of uric acid by kidneys and intestines, meaning that a stronger inhibition of the uric acid production by allopurinol is required to achieve the desired uric acid concentration.Use 1.4 times the standard dose. This equates to a dose titration schedule of 100, 300, 400, 600 and 700 mg/day instead of the usual schedule of 100, 200, 300, 400 and 500 mg/day.
141QK (GT genotype)aallopurinolThe effectiveness of allopurinol is reduced, meaning that a higher dose is required. The gene variation reduces the excretion of uric acid by kidneys and intestines, meaning that a stronger inhibition of the uric acid production by allopurinol is required to achieve the desired uric acid concentration.Use 1.25 times the standard dose. This equates to a dose titration schedule of 100, 200, 400 and 500 mg/day instead of the usual schedule of 100, 200, 300 and 400 mg/day.
\n

a These genotypes have been complemented to the positive strand, in line with standard PharmGKB procedures.

\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for allopurinol and ABCG2:

\n
\n

The KNMP Pharmacogenetics Working Group considers genotyping of ABCG2 before starting allopurinol to be potentially beneficial for drug effectiveness. Genotyping can be considered on an individual patient basis. If, however, the genotype is available, the Dutch Pharmacogenetics Working Group recommends adhering to the gene-drug guideline.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

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Use 1.25 times the standard dose.
\nThis equates to a dose titration schedule of 100, 200, 400 and 500 mg/day instead of the usual schedule of 100, 200, 300 and 400 mg/day.

\n", + "id" : 1452061469, + "html" : "

Use 1.4 times the standard dose.
\nThis equates to a dose titration schedule of 100, 300, 400, 600 and 700 mg/day instead of the usual schedule of 100, 200, 300, 400 and 500 mg/day.

\n", "version" : 0 }, - "version" : 0 + "version" : 4 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299106", - "name" : "Recommendation PA166299106", + "id" : "PA166299108", + "name" : "Recommendation PA166299108", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "The effectiveness of allopurinol is reduced, meaning that a higher dose is required. The gene variation reduces the excretion of uric acid by kidneys and intestines, meaning that a stronger inhibition of the uric acid production by allopurinol is required to achieve the desired uric acid concentration." + "The guideline does not provide a description of the impact of the ABCG2 rs2231142 GG genotype (c.421CC; p.141QQ) on allopurinol." ], - "lookupKey" : {"ABCG2": "Poor Function"}, + "lookupKey" : {"ABCG2": "Normal Function"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448320", "name" : "allopurinol", - "version" : 9 + "version" : 35 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166264961", "name" : "Annotation of DPWG Guideline for allopurinol and ABCG2", - "version" : 15 + "version" : 54 }, "text" : { - "id" : 1452061469, - "html" : "

Use 1.4 times the standard dose.
\nThis equates to a dose titration schedule of 100, 300, 400, 600 and 700 mg/day instead of the usual schedule of 100, 200, 300, 400 and 500 mg/day.

\n", + "id" : 1452061471, + "html" : "

The guideline does not provide a recommendation for allopurinol in patients with the the ABCG2 rs2231142 GG genotype (c.421CC; p.141QQ)

\n", "version" : 0 }, - "version" : 0 + "version" : 4 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299108", - "name" : "Recommendation PA166299108", + "id" : "PA166299107", + "name" : "Recommendation PA166299107", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "The guideline does not provide a description of the impact of the ABCG2 rs2231142 GG genotype (c.421CC; p.141QQ) on allopurinol." + "The effectiveness of allopurinol is reduced, meaning that a higher dose is required. The gene variation reduces the excretion of uric acid by kidneys and intestines, meaning that a stronger inhibition of the uric acid production by allopurinol is required to achieve the desired uric acid concentration." ], - "lookupKey" : {"ABCG2": "Normal Function"}, + "lookupKey" : {"ABCG2": "Decreased Function"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448320", "name" : "allopurinol", - "version" : 9 + "version" : 35 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166264961", "name" : "Annotation of DPWG Guideline for allopurinol and ABCG2", - "version" : 15 + "version" : 54 }, "text" : { - "id" : 1452061471, - "html" : "

The guideline does not provide a recommendation for allopurinol in patients with the the ABCG2 rs2231142 GG genotype (c.421CC; p.141QQ)

\n", + "id" : 1452061470, + "html" : "

Use 1.25 times the standard dose.
\nThis equates to a dose titration schedule of 100, 200, 400 and 500 mg/day instead of the usual schedule of 100, 200, 300 and 400 mg/day.

\n", "version" : 0 }, - "version" : 0 + "version" : 3 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166264961" @@ -103277,7 +104292,7 @@ "id" : "PA165987831", "symbol" : "HLA-B*58:01", "name" : "*58:01", - "version" : 4 + "version" : 21 } ], "relatedChemicals" : [ @@ -103285,7 +104300,7 @@ "objCls" : "Chemical", "id" : "PA448320", "name" : "allopurinol", - "version" : 9 + "version" : 35 } ], "relatedGenes" : [ @@ -103294,7 +104309,7 @@ "id" : "PA35056", "symbol" : "HLA-B", "name" : "major histocompatibility complex, class I, B", - "version" : 40 + "version" : 2920 } ], "source" : "DPWG", @@ -103307,10 +104322,10 @@ "textMarkdown" : { "id" : 1451697661, "html" : "

Dutch pharmacogenetics working group (DPWG) guideline for the gene-drug interaction of ABCG2, HLA-B and Allopurinol, and MTHFR, folic acid and methotrexate. European journal of human genetics (2022)

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group published a paper with the guidelines as per the May 2021 guideline including more details and scoring the clinical implementation [Article:36056234]

\n

May 2021 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group (DPWG) has evaluated therapeutic dose recommendations for allopurinol based on presence of the HLA-B*58:01 allele.

\n

Wording in table taken from the Dutch guidelines May 2021 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
HLA-B*5801allopurinolA strongly increased risk of developing the life-threatening cutaneous side effects Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and DRESS is present in patients with this genetic variation. The risk of an allopurinol-induced life-threatening cutaneous side effect (mortality 11%) in these patients is 1.6-2.0% for the entire group and 8-18% for the group with chronic renal insufficiency.1. Choose an alternative, such as febuxostat 2. Another option is to induce allopurinol tolerance first: To induce allopurinol tolerance, the allopurinol dose is increased every 3 days until a dose of 100 mg/day has been achieved on Day 28. The consecutive daily doses in the induction protocol are 50 µg, 100 µg, 200 µg, 500 µg, 1 mg, 5 mg, 10 mg, 25 mg, 50 mg and 100 mg.
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for allopurinol and HLA-B:

\n
\n

The KNMP Pharmacogenetics Working Group considers genotyping of patients before starting allopurinol to be beneficial for drug safety. It is advised to consider genotyping the patient before (or directly after) drug therapy has been initiated to guide drug and dose selection.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n", - "version" : 4 + "version" : 6 }, "userId" : "cfthorn", - "version" : 7 + "version" : 27 }, "recommendations" : [ { @@ -103339,21 +104354,21 @@ "objCls" : "Chemical", "id" : "PA448320", "name" : "allopurinol", - "version" : 9 + "version" : 35 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166265141", "name" : "Annotation of DPWG Guideline for allopurinol and HLA-B", - "version" : 7 + "version" : 27 }, "text" : { "id" : 1452061472, "html" : "\n", "version" : 0 }, - "version" : 0 + "version" : 2 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166265141" @@ -103632,7 +104647,7 @@ "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "relatedGenes" : [ @@ -103641,29 +104656,29 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "DPWG", "summaryMarkdown" : { "id" : 1447981960, "html" : "

The Dutch Pharmacogenetics Working Group Guideline for amitriptyline recommends decreasing the dose for CYP2D6 intermediate and CYP2D6 poor metabolizers and increasing the dose or using an alternative drug for CYP2D6 ultra-rapid metabolizers.

\n", - "version" : 2 + "version" : 6 }, "terms" : [], "textMarkdown" : { "id" : 1447981959, "html" : "

August 2019 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group (DPWG) has evaluated therapeutic dose recommendations for amitriptyline based on CYP2D6 genotypes. They recommend decreasing the dose for CYP2D6 intermediate and CYP2D6 poor metabolizers with plasma concentration monitoring, and increasing the dose or using an alternative drug for CYP2D6 ultra-rapid metabolizers.

\n

Wording in table taken from the Dutch guidelines August 2019 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
CYP2D6 UMamitriptylineThe risk of ineffectiveness is increased and the risk of cardiotoxic side effects may be increased. The gene variation leads to increased conversion of amitriptyline and the active metabolite nortriptyline to less active and inactive metabolites.1. increase the dose to 1.4 times the standard dose, monitor the effect and side effects or the plasma concentrations and be alert to increased plasma concentrations of the cardiotoxic Z-10-hydroxy metabolites. Plasma concentrations of Z-hydroxy nortriptyine or Z-hydroxy amitriptyline higher than 40 ng/mL are considered toxic.
2. if a dose increase is not desirable due to the cardiotoxic hydroxy metabolite: avoid amitriptyline. Anti-depressants that are not metabolised by CYP2D6, or to a lesser extent, include citalopram and sertraline.
CYP2D6 IMamitriptylineThe risk of side effects is increased, because the gene variation leads to higher plasma concentrations of the active metabolite nortriptyline and to a lesser extent of amitriptyline.Use 75% of the standard dose and monitor the efficacy and side effects or the plasma concentrations of amitriptyline and nortriptyline to adjust the maintenance dose
CYP2D6 PMamitriptylineIn theory risk of side effects is increased, because the genetic variation results in higher plasma concentrations of the active metabolite nortriptyline and to a lesser extent of amitriptyline.Use 70% of the standard dose and monitor the effect and side effects or the plasma concentrations of amitriptyline and nortriptyline to adjust the maintenance dose
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for amitriptyline and CYP2D6:

\n
\n

The Dutch Pharmacogenetics Working Group considers genotyping before starting amitriptyline to be potentially beneficial for the prevention of side effects and for drug efficacy. Genotyping can be considered on an individual patient basis. If, however, the genotype is available, the Dutch Pharmacogenetics Working Group recommends adhering to the gene-drug guideline.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n

November 2018 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for amitriptyline based on CYP2D6 genotype. They recommend to choose an alternative antidepressant if possible and in case an alternative is not an option to increase the dose for UM and decreased the dose for IM and PM together with plasma concentrations monitoring.

\n

Wording in table taken from Dutch guidelines 2018 November 2018 update

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
CYP2D6 UMamitriptylineThe genetic polymorphism leads to increased metabolic capacity of CYP2D6, which may cause a decrease in the plasma concentrations of amitriptyline and its active metabolite nortriptyline and increased plasma concentrations of the active metabolites E-10-OH- amitriptyline and E-10-OH-nortriptyline.1. Choose an alternative if possible. Antidepressants that are not metabolised via CYP2D6 - or to a lesser extent - include, for example, citalopram and sertraline.
2. If an alternative is not an option: increase the dose to 1.25 times the standard dose, monitor the plasma concentrations and be alert to potential therapy failure due to decreased amitriptyline plus nortriptyline plasma concentrations and to increased plasma concentrations of the potentially cardiotoxic, active hydroxy metabolites.
CYP2D6 IMamitriptylineThe genetic polymorphism leads to decreased metabolic capacity of CYP2D6, which may cause an increase in the plasma concentrations of amitriptyline and its active metabolite nortriptyline and decreased plasma concentrations of the active metabolites E-10-OH- amitriptyline and E-10-OH-nortriptyline.1. Choose an alternative if possible. Antidepressants that are not metabolised via CYP2D6 - or to a lesser extent - include, for example, citalopram and sertraline.
2. If an alternative is not an option: use 60% of the standard dose and monitor the plasma concentrations of amitriptyline and nortriptyline. As side effects are related to nortriptyline plasma concentrations and the efficacy to amitriptyline plus nortriptyline plasma concentrations, which are influenced to a lesser extent by CYP2D6, it is not known whether it is possible to reduce the dose to such an extent that the side effects disappear, but the efficacy is maintained.
CYP2D6 PMamitriptylineThe genetic polymorphism leads to decreased metabolic capacity of CYP2D6, which may cause an increase in the plasma concentrations of amitriptyline and its active metabolite nortriptyline and decreased plasma concentrations of the active metabolites E-10-OH- amitriptyline and E-10-OH-nortriptyline.1. Choose an alternative if possible. Antidepressants that are not metabolised via CYP2D6 - or to a lesser extent - include, for example, citalopram and sertraline.
2. If an alternative is not an option: use 50% of the standard dose and monitor the plasma concentrations of amitriptyline and nortriptyline. As side effects are related to nortriptyline plasma concentrations and the efficacy to amitriptyline plus nortriptyline plasma concentrations, which are influenced to a lesser extent by CYP2D6, it is not known whether it is possible to reduce the dose to such an extent that the side effects disappear, but the efficacy is maintained.
\n

2011 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for amitriptyline based on CYP2D6 genotypes [Article:21412232]. They recommend selecting an alternative drug or reducing the initial dose for patients carrying intermediate metabolizer alleles and selecting alternative drugs or monitor amitypityline and nortriptyline plasma concentration for patients carrying the poor metabolizer or ultrarapid metabolizer alleles.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Phenotype (Genotype)Therapeutic Dose RecommendationLevel of EvidenceClinical Relevance
PM (two inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) alleles)Insufficient data to allow calculation of dose adjustment. Select alternative drug (e.g., citalopram, sertraline) or monitor amitriptyline and nortriptyline plasma concentration.Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Minor clinical effect (S): QTc prolongation (<450 ms female, <470 ms male); INR increase < 4.5; Kinetic effect (S)
IM (two decreased-activity (*9, *10, *17, *29, *36, *41) alleles or carrying one active (*1, *2, *33, *35) and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele, or carrying one decreased-activity (*9, *10, *17, *29, *36, *41) allele and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele)Reduce dose by 25% and monitor plasma concentration or select alternative drug (e.g., citalopram, sertraline).Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Clinical effect (S): long-standing discomfort (48-168 hr) without permanent injury e.g. failure of therapy with tricyclic antidepressants, atypical antipsychotic drugs; extrapyramidal side effects; parkinsonism; ADE resulting from increased bioavailability of tricyclic antidepressants, metoprolol, propafenone (central effects e.g. dizziness); INR 4.5-6.0; neutropenia 1.0-1.5x109/l; leucopenia 2.0-3.0x109/l; thrombocytopenia 50-75x109/l
UM (a gene duplication in absence of inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) or decreased-activity (*9, *10, *17, *29, *36, *41) alleles)Insufficient data to allow calculation of dose adjustment. Select alternative drug (e.g., citalopram,sertraline) or monitor (E-10-hydroxy)amitriptyline plasma concentration.Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Clinical effect (S): long-standing discomfort (48-168 hr) without permanent injury e.g. failure of therapy with tricyclic antidepressants, atypical antipsychotic drugs; extrapyramidal side effects; parkinsonism; ADE resulting from increased bioavailability of tricyclic antidepressants, metoprolol, propafenone (central effects e.g. dizziness); INR 4.5-6.0; neutropenia 1.0-1.5x109/l; leucopenia 2.0-3.0x109/l; thrombocytopenia 50-75x109/l.
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Use 75% of the standard dose and monitor the efficacy and side effects or the plasma concentrations of amitriptyline and nortriptyline to adjust the maintenance dose

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Use 70% of the standard dose and monitor the effect and side effects or the plasma concentrations of amitriptyline and nortriptyline to adjust the maintenance dose

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301968", - "name" : "Recommendation Annotation PA166301968", - "alternateDrugAvailable" : true, + "id" : "PA166301823", + "name" : "Recommendation Annotation PA166301823", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -103719,77 +104734,78 @@ }, "dosingInformation" : true, "implications" : [ - "The risk of ineffectiveness is increased and the risk of cardiotoxic side effects may be increased. The gene variation leads to increased conversion of amitriptyline and the active metabolite nortriptyline to less active and inactive metabolites." + "The risk of side effects is increased, because the gene variation leads to higher plasma concentrations of the active metabolite nortriptyline and to a lesser extent of amitriptyline." ], - "lookupKey" : {"CYP2D6": "≥6.0"}, + "lookupKey" : {"CYP2D6": "0.25"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104982", "name" : "Annotation of DPWG Guideline for amitriptyline and CYP2D6", - "version" : 33 + "version" : 104 }, "text" : { - "id" : 1452103487, - "html" : "

Increase the dose to 1.4 times the standard dose, monitor the effect and side effects or the plasma concentrations and be alert to increased plasma concentrations of the cardiotoxic Z-10-hydroxy metabolites. Plasma concentrations of Z-hydroxy nortriptyine or Z-hydroxy amitriptyline higher than 40 ng/mL are considered toxic.\nIf a dose increase is not desirable due to the cardiotoxic hydroxy metabolite: avoid amitriptyline. Anti-depressants that are not metabolised by CYP2D6, or to a lesser extent, include citalopram and sertraline.

\n", + "id" : 1452103290, + "html" : "

Use 75% of the standard dose and monitor the efficacy and side effects or the plasma concentrations of amitriptyline and nortriptyline to adjust the maintenance dose

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301941", - "name" : "Recommendation Annotation PA166301941", + "id" : "PA166301861", + "name" : "Recommendation Annotation PA166301861", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on amitriptyline." + "The risk of side effects is increased, because the gene variation leads to higher plasma concentrations of the active metabolite nortriptyline and to a lesser extent of amitriptyline." ], - "lookupKey" : {"CYP2D6": "2.25"}, + "lookupKey" : {"CYP2D6": "0.5"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104982", "name" : "Annotation of DPWG Guideline for amitriptyline and CYP2D6", - "version" : 33 + "version" : 104 }, "text" : { - "id" : 1452103460, - "html" : "

The guideline does not provide a recommendation for amitriptyline in normal metabolizers.

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Use 75% of the standard dose and monitor the efficacy and side effects or the plasma concentrations of amitriptyline and nortriptyline to adjust the maintenance dose

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Increase the dose to 1.4 times the standard dose, monitor the effect and side effects or the plasma concentrations and be alert to increased plasma concentrations of the cardiotoxic Z-10-hydroxy metabolites. Plasma concentrations of Z-hydroxy nortriptyine or Z-hydroxy amitriptyline higher than 40 ng/mL are considered toxic.\nIf a dose increase is not desirable due to the cardiotoxic hydroxy metabolite: avoid amitriptyline. Anti-depressants that are not metabolised by CYP2D6, or to a lesser extent, include citalopram and sertraline.

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Use 75% of the standard dose and monitor the efficacy and side effects or the plasma concentrations of amitriptyline and nortriptyline to adjust the maintenance dose

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Use 75% of the standard dose and monitor the efficacy and side effects or the plasma concentrations of amitriptyline and nortriptyline to adjust the maintenance dose

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The guideline does not provide a recommendation for amitriptyline in normal metabolizers

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The guideline does not provide a recommendation for amitriptyline in normal metabolizers.

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Use 75% of the standard dose and monitor the efficacy and side effects or the plasma concentrations of amitriptyline and nortriptyline to adjust the maintenance dose

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The guideline does not provide a recommendation for amitriptyline in normal metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301967", - "name" : "Recommendation Annotation PA166301967", - "alternateDrugAvailable" : true, + "id" : "PA166301942", + "name" : "Recommendation Annotation PA166301942", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "The risk of ineffectiveness is increased and the risk of cardiotoxic side effects may be increased. The gene variation leads to increased conversion of amitriptyline and the active metabolite nortriptyline to less active and inactive metabolites." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on amitriptyline." ], - "lookupKey" : {"CYP2D6": "≥5.0"}, + "lookupKey" : {"CYP2D6": "2.5"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104982", "name" : "Annotation of DPWG Guideline for amitriptyline and CYP2D6", - "version" : 33 + "version" : 104 }, "text" : { - "id" : 1452103486, - "html" : "

Increase the dose to 1.4 times the standard dose, monitor the effect and side effects or the plasma concentrations and be alert to increased plasma concentrations of the cardiotoxic Z-10-hydroxy metabolites. Plasma concentrations of Z-hydroxy nortriptyine or Z-hydroxy amitriptyline higher than 40 ng/mL are considered toxic.\nIf a dose increase is not desirable due to the cardiotoxic hydroxy metabolite: avoid amitriptyline. Anti-depressants that are not metabolised by CYP2D6, or to a lesser extent, include citalopram and sertraline.

\n", + "id" : 1452103461, + "html" : "

The guideline does not provide a recommendation for amitriptyline in normal metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301966", - "name" : "Recommendation Annotation PA166301966", - "alternateDrugAvailable" : true, + "id" : "PA166301941", + "name" : "Recommendation Annotation PA166301941", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "The risk of ineffectiveness is increased and the risk of cardiotoxic side effects may be increased. The gene variation leads to increased conversion of amitriptyline and the active metabolite nortriptyline to less active and inactive metabolites." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on amitriptyline." ], - "lookupKey" : {"CYP2D6": "≥4.0"}, + "lookupKey" : {"CYP2D6": "2.25"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104982", "name" : "Annotation of DPWG Guideline for amitriptyline and CYP2D6", - "version" : 33 + "version" : 104 }, "text" : { - "id" : 1452103485, - "html" : "

Increase the dose to 1.4 times the standard dose, monitor the effect and side effects or the plasma concentrations and be alert to increased plasma concentrations of the cardiotoxic Z-10-hydroxy metabolites. Plasma concentrations of Z-hydroxy nortriptyine or Z-hydroxy amitriptyline higher than 40 ng/mL are considered toxic.\nIf a dose increase is not desirable due to the cardiotoxic hydroxy metabolite: avoid amitriptyline. Anti-depressants that are not metabolised by CYP2D6, or to a lesser extent, include citalopram and sertraline.

\n", + "id" : 1452103460, + "html" : "

The guideline does not provide a recommendation for amitriptyline in normal metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301962", - "name" : "Recommendation Annotation PA166301962", + "id" : "PA166301966", + "name" : "Recommendation Annotation PA166301966", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -104055,24 +105109,24 @@ "implications" : [ "The risk of ineffectiveness is increased and the risk of cardiotoxic side effects may be increased. The gene variation leads to increased conversion of amitriptyline and the active metabolite nortriptyline to less active and inactive metabolites." ], - "lookupKey" : {"CYP2D6": "4.0"}, + "lookupKey" : {"CYP2D6": "≥4.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104982", "name" : "Annotation of DPWG Guideline for amitriptyline and CYP2D6", - "version" : 33 + "version" : 104 }, "text" : { - "id" : 1452103481, + "id" : 1452103485, "html" : "

Increase the dose to 1.4 times the standard dose, monitor the effect and side effects or the plasma concentrations and be alert to increased plasma concentrations of the cardiotoxic Z-10-hydroxy metabolites. Plasma concentrations of Z-hydroxy nortriptyine or Z-hydroxy amitriptyline higher than 40 ng/mL are considered toxic.\nIf a dose increase is not desirable due to the cardiotoxic hydroxy metabolite: avoid amitriptyline. Anti-depressants that are not metabolised by CYP2D6, or to a lesser extent, include citalopram and sertraline.

\n", "version" : 0 }, @@ -104080,8 +105134,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301965", - "name" : "Recommendation Annotation PA166301965", + "id" : "PA166301961", + "name" : "Recommendation Annotation PA166301961", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -104095,26 +105149,26 @@ }, "dosingInformation" : true, "implications" : [ - "The risk of ineffectiveness is increased and the risk of cardiotoxic side effects may be increased. The gene variation leads to increased conversion of amitriptyline and the active metabolite nortriptyline to less active and inactive metabolites" + "The risk of ineffectiveness is increased and the risk of cardiotoxic side effects may be increased. The gene variation leads to increased conversion of amitriptyline and the active metabolite nortriptyline to less active and inactive metabolites." ], - "lookupKey" : {"CYP2D6": "≥3.5"}, + "lookupKey" : {"CYP2D6": "3.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104982", "name" : "Annotation of DPWG Guideline for amitriptyline and CYP2D6", - "version" : 33 + "version" : 104 }, "text" : { - "id" : 1452103484, + "id" : 1452103480, "html" : "

Increase the dose to 1.4 times the standard dose, monitor the effect and side effects or the plasma concentrations and be alert to increased plasma concentrations of the cardiotoxic Z-10-hydroxy metabolites. Plasma concentrations of Z-hydroxy nortriptyine or Z-hydroxy amitriptyline higher than 40 ng/mL are considered toxic.\nIf a dose increase is not desirable due to the cardiotoxic hydroxy metabolite: avoid amitriptyline. Anti-depressants that are not metabolised by CYP2D6, or to a lesser extent, include citalopram and sertraline.

\n", "version" : 0 }, @@ -104122,9 +105176,9 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301842", - "name" : "Recommendation Annotation PA166301842", - "alternateDrugAvailable" : false, + "id" : "PA166301962", + "name" : "Recommendation Annotation PA166301962", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -104137,35 +105191,35 @@ }, "dosingInformation" : true, "implications" : [ - "In theory risk of side effects is increased, because the genetic variation results in higher plasma concentrations of the active metabolite nortriptyline and to a lesser extent of amitriptyline." + "The risk of ineffectiveness is increased and the risk of cardiotoxic side effects may be increased. The gene variation leads to increased conversion of amitriptyline and the active metabolite nortriptyline to less active and inactive metabolites." ], - "lookupKey" : {"CYP2D6": "0.0"}, + "lookupKey" : {"CYP2D6": "4.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104982", "name" : "Annotation of DPWG Guideline for amitriptyline and CYP2D6", - "version" : 33 + "version" : 104 }, "text" : { - "id" : 1452103308, - "html" : "

Use 70% of the standard dose and monitor the effect and side effects or the plasma concentrations of amitriptyline and nortriptyline to adjust the maintenance dose

\n", + "id" : 1452103481, + "html" : "

Increase the dose to 1.4 times the standard dose, monitor the effect and side effects or the plasma concentrations and be alert to increased plasma concentrations of the cardiotoxic Z-10-hydroxy metabolites. Plasma concentrations of Z-hydroxy nortriptyine or Z-hydroxy amitriptyline higher than 40 ng/mL are considered toxic.\nIf a dose increase is not desirable due to the cardiotoxic hydroxy metabolite: avoid amitriptyline. Anti-depressants that are not metabolised by CYP2D6, or to a lesser extent, include citalopram and sertraline.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301961", - "name" : "Recommendation Annotation PA166301961", + "id" : "PA166301963", + "name" : "Recommendation Annotation PA166301963", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -104181,24 +105235,24 @@ "implications" : [ "The risk of ineffectiveness is increased and the risk of cardiotoxic side effects may be increased. The gene variation leads to increased conversion of amitriptyline and the active metabolite nortriptyline to less active and inactive metabolites." ], - "lookupKey" : {"CYP2D6": "3.0"}, + "lookupKey" : {"CYP2D6": "≥3.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104982", "name" : "Annotation of DPWG Guideline for amitriptyline and CYP2D6", - "version" : 33 + "version" : 104 }, "text" : { - "id" : 1452103480, + "id" : 1452103482, "html" : "

Increase the dose to 1.4 times the standard dose, monitor the effect and side effects or the plasma concentrations and be alert to increased plasma concentrations of the cardiotoxic Z-10-hydroxy metabolites. Plasma concentrations of Z-hydroxy nortriptyine or Z-hydroxy amitriptyline higher than 40 ng/mL are considered toxic.\nIf a dose increase is not desirable due to the cardiotoxic hydroxy metabolite: avoid amitriptyline. Anti-depressants that are not metabolised by CYP2D6, or to a lesser extent, include citalopram and sertraline.

\n", "version" : 0 }, @@ -104206,131 +105260,92 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301921", - "name" : "Recommendation Annotation PA166301921", - "alternateDrugAvailable" : false, + "id" : "PA166301964", + "name" : "Recommendation Annotation PA166301964", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on amitriptyline." + "The risk of ineffectiveness is increased and the risk of cardiotoxic side effects may be increased. The gene variation leads to increased conversion of amitriptyline and the active metabolite nortriptyline to less active and inactive metabolites." ], - "lookupKey" : {"CYP2D6": "2.0"}, + "lookupKey" : {"CYP2D6": "≥3.25"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104982", "name" : "Annotation of DPWG Guideline for amitriptyline and CYP2D6", - "version" : 33 + "version" : 104 }, "text" : { - "id" : 1452103440, - "html" : "

The guideline does not provide a recommendation for amitriptyline in normal metabolizers.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166301881", - "name" : "Recommendation Annotation PA166301881", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 1448526251, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on amitriptyline." - ], - "lookupKey" : {"CYP2D6": "1.25"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA448385", - "name" : "amitriptyline", - "version" : 8 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166104982", - "name" : "Annotation of DPWG Guideline for amitriptyline and CYP2D6", - "version" : 33 - }, - "text" : { - "id" : 1452103400, - "html" : "

The guideline does not provide a recommendation for amitriptyline in normal metabolizers

\n", + "id" : 1452103483, + "html" : "

Increase the dose to 1.4 times the standard dose, monitor the effect and side effects or the plasma concentrations and be alert to increased plasma concentrations of the cardiotoxic Z-10-hydroxy metabolites. Plasma concentrations of Z-hydroxy nortriptyine or Z-hydroxy amitriptyline higher than 40 ng/mL are considered toxic.\nIf a dose increase is not desirable due to the cardiotoxic hydroxy metabolite: avoid amitriptyline. Anti-depressants that are not metabolised by CYP2D6, or to a lesser extent, include citalopram and sertraline.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301942", - "name" : "Recommendation Annotation PA166301942", - "alternateDrugAvailable" : false, + "id" : "PA166301965", + "name" : "Recommendation Annotation PA166301965", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on amitriptyline." + "The risk of ineffectiveness is increased and the risk of cardiotoxic side effects may be increased. The gene variation leads to increased conversion of amitriptyline and the active metabolite nortriptyline to less active and inactive metabolites" ], - "lookupKey" : {"CYP2D6": "2.5"}, + "lookupKey" : {"CYP2D6": "≥3.5"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104982", "name" : "Annotation of DPWG Guideline for amitriptyline and CYP2D6", - "version" : 33 + "version" : 104 }, "text" : { - "id" : 1452103461, - "html" : "

The guideline does not provide a recommendation for amitriptyline in normal metabolizers.

\n", + "id" : 1452103484, + "html" : "

Increase the dose to 1.4 times the standard dose, monitor the effect and side effects or the plasma concentrations and be alert to increased plasma concentrations of the cardiotoxic Z-10-hydroxy metabolites. Plasma concentrations of Z-hydroxy nortriptyine or Z-hydroxy amitriptyline higher than 40 ng/mL are considered toxic.\nIf a dose increase is not desirable due to the cardiotoxic hydroxy metabolite: avoid amitriptyline. Anti-depressants that are not metabolised by CYP2D6, or to a lesser extent, include citalopram and sertraline.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301964", - "name" : "Recommendation Annotation PA166301964", + "id" : "PA166301967", + "name" : "Recommendation Annotation PA166301967", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -104346,24 +105361,24 @@ "implications" : [ "The risk of ineffectiveness is increased and the risk of cardiotoxic side effects may be increased. The gene variation leads to increased conversion of amitriptyline and the active metabolite nortriptyline to less active and inactive metabolites." ], - "lookupKey" : {"CYP2D6": "≥3.25"}, + "lookupKey" : {"CYP2D6": "≥5.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104982", "name" : "Annotation of DPWG Guideline for amitriptyline and CYP2D6", - "version" : 33 + "version" : 104 }, "text" : { - "id" : 1452103483, + "id" : 1452103486, "html" : "

Increase the dose to 1.4 times the standard dose, monitor the effect and side effects or the plasma concentrations and be alert to increased plasma concentrations of the cardiotoxic Z-10-hydroxy metabolites. Plasma concentrations of Z-hydroxy nortriptyine or Z-hydroxy amitriptyline higher than 40 ng/mL are considered toxic.\nIf a dose increase is not desirable due to the cardiotoxic hydroxy metabolite: avoid amitriptyline. Anti-depressants that are not metabolised by CYP2D6, or to a lesser extent, include citalopram and sertraline.

\n", "version" : 0 }, @@ -104371,9 +105386,9 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301863", - "name" : "Recommendation Annotation PA166301863", - "alternateDrugAvailable" : false, + "id" : "PA166301968", + "name" : "Recommendation Annotation PA166301968", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -104386,27 +105401,27 @@ }, "dosingInformation" : true, "implications" : [ - "The risk of side effects is increased, because the gene variation leads to higher plasma concentrations of the active metabolite nortriptyline and to a lesser extent of amitriptyline." + "The risk of ineffectiveness is increased and the risk of cardiotoxic side effects may be increased. The gene variation leads to increased conversion of amitriptyline and the active metabolite nortriptyline to less active and inactive metabolites." ], - "lookupKey" : {"CYP2D6": "1.0"}, + "lookupKey" : {"CYP2D6": "≥6.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448385", "name" : "amitriptyline", - "version" : 8 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104982", "name" : "Annotation of DPWG Guideline for amitriptyline and CYP2D6", - "version" : 33 + "version" : 104 }, "text" : { - "id" : 1452103322, - "html" : "

Use 75% of the standard dose and monitor the efficacy and side effects or the plasma concentrations of amitriptyline and nortriptyline to adjust the maintenance dose

\n", + "id" : 1452103487, + "html" : "

Increase the dose to 1.4 times the standard dose, monitor the effect and side effects or the plasma concentrations and be alert to increased plasma concentrations of the cardiotoxic Z-10-hydroxy metabolites. Plasma concentrations of Z-hydroxy nortriptyine or Z-hydroxy amitriptyline higher than 40 ng/mL are considered toxic.\nIf a dose increase is not desirable due to the cardiotoxic hydroxy metabolite: avoid amitriptyline. Anti-depressants that are not metabolised by CYP2D6, or to a lesser extent, include citalopram and sertraline.

\n", "version" : 0 }, "version" : 0 @@ -104791,7 +105806,7 @@ "date" : "2024-03-28T00:00:00-07:00", "description" : "Tags updated: [Alt Drug removed]", "type" : "Update", - "version" : 0 + "version" : 1 } ], "literature" : [ @@ -104809,7 +105824,7 @@ "objCls" : "Chemical", "id" : "PA10026", "name" : "aripiprazole", - "version" : 10 + "version" : 41 } ], "relatedGenes" : [ @@ -104818,23 +105833,23 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "DPWG", "summaryMarkdown" : { "id" : 1447981884, "html" : "

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group (DPWG) recommends reducing maximum dose of aripiprazole for patients carrying poor metabolizer alleles of CYP2D6.

\n", - "version" : 0 + "version" : 1 }, "terms" : [], "textMarkdown" : { "id" : 1447981883, "html" : "

Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction between CYP2D6, CYP3A4 and CYP1A2 and antipsychotics. European journal of human genetics (2023)

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group published a paper with the guidelines for aripiprazole and CYP2D6 as per the February 2022 guidelines and further details on the assessed literature [Article:37002327]. Wording in the poor metabolizer recommendation changed from "standard maximum dose of aripiprazole" to "normal maximum dose of aripiprazole" and is reflected in the table below.

\n

February 2022 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has made a minor change to their recommendation for CYP2D6 poor metabolizers and aripiprazole. These patients are now recommended to be given a maximum of 68-75% of the standard maximum dose of aripiprazole, rather than 67-75%. The table below has been updated to reflect this. See the DPWG February 2022 guidelines.

\n

November 2018 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for aripiprazole based on CYP2D6 genotype. They recommend reducing maximum dose of aripiprazole for CYP2D6 poor metabolizer (PM).

\n

Wording in table taken from the Dutch guidelines November 2018 update

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
CYP2D6 UMaripiprazole-NO action is needed for this gene-drug interaction. The genetic variation decreases the plasma concentration of the sum of aripiprazole and the active metabolite dehydroaripiprazole to a limited degree. There is no evidence that this increases the risk of reduced effectiveness.
CYP2D6 IMaripiprazole-NO action is needed for this gene-drug interaction.The genetic variation increases the plasma concentration of the sum of aripiprazole and the active metabolite dehydroaripiprazole to a limited degree. There is insufficient evidence that this increases the risk of side effects.
CYP2D6 PMaripiprazoleThe risk of side effects is increased. The genetic variation leads to an increase in the sum of the plasma concentrations of aripiprazole and the active metabolite.Administer no more than 10 mg/day or 300 mg/month (68-75% of the normal maximum dose of aripiprazole).
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for aripiprazole and CYP2D6:

\n
\n

The KNMP Pharmacogenetics Working Group considers genotyping before starting aripiprazole to be potentially beneficial for prevention of adverse events. Genotyping can be considered on an individual patient basis. If, however, the genotype is available, the KNMP Pharmacogenetics Working Group recommends adhering to the gene-drug guideline.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n

2011 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group (DPWG) has evaluated therapeutic dose recommendations for aripiprazole based on CYP2D6 genotypes [Article:21412232]. They recommend reducing maximum dose of aripiprazole for patients carrying poor metabolizer alleles of CYP2D6.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Phenotype (Genotype)Therapeutic Dose RecommendationLevel of EvidenceClinical Relevance
PM (two inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) alleles)Reduce maximum dose to 10 mg/day (67% of the maximum recommended daily dose).Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Clinical effect (S): long-standing discomfort (48-168 hr) without permanent injury e.g. failure of therapy with tricyclic antidepressants, atypical antipsychotic drugs; extrapyramidal side effects; parkinsonism; ADE resulting from increased bioavailability of tricyclic antidepressants, metoprolol, propafenone (central effects e.g. dizziness); INR 4.5-6.0; neutropenia 1.0-1.5x109/l; leucopenia 2.0-3.0x109/l; thrombocytopenia 50-75x109/l.
IM (two decreased-activity (*9, *10, *17, *29, *36, *41) alleles or carrying one active (*1, *2, *33, *35) and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele, or carrying one decreased-activity (*9, *10, *17, *29, *36, *41) allele and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele)No recommendations.Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Minor clinical effect (S): QTc prolongation (<450 ms female, <470 ms male); INR increase < 4.5; Kinetic effect (S)
UM (a gene duplication in absence of inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) or decreased-activity (*9, *10, *17, *29, *36, *41) alleles)No recommendations.----
\n\n", - "version" : 22 + "version" : 27 }, "userId" : "carrillo", - "version" : 43 + "version" : 155 }, "recommendations" : [ { @@ -104862,26 +105877,26 @@ "objCls" : "Chemical", "id" : "PA10026", "name" : "aripiprazole", - "version" : 10 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104937", "name" : "Annotation of DPWG Guideline for aripiprazole and CYP2D6", - "version" : 43 + "version" : 155 }, "text" : { "id" : 1452103500, "html" : "

The guideline does not provide a recommendation for aripiprazole in normal metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301980", - "name" : "Recommendation Annotation PA166301980", + "id" : "PA166301983", + "name" : "Recommendation Annotation PA166301983", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -104897,74 +105912,75 @@ "implications" : [ "The genetic variation decreases the plasma concentration of the sum of aripiprazole and the active metabolite dehydroaripiprazole to a limited degree. There is no evidence that this increases the risk of reduced effectiveness." ], - "lookupKey" : {"CYP2D6": "≥3.25"}, + "lookupKey" : {"CYP2D6": "≥3.5"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA10026", "name" : "aripiprazole", - "version" : 10 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104937", "name" : "Annotation of DPWG Guideline for aripiprazole and CYP2D6", - "version" : 43 + "version" : 155 }, "text" : { - "id" : 1452103499, + "id" : 1452103502, "html" : "

NO action is needed for this gene-drug interaction.

\n", - "version" : 0 + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301976", - "name" : "Recommendation Annotation PA166301976", + "id" : "PA166301982", + "name" : "Recommendation Annotation PA166301982", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, "dosingInformation" : false, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on aripiprazole." + "The genetic variation decreases the plasma concentration of the sum of aripiprazole and the active metabolite dehydroaripiprazole to a limited degree. There is no evidence that this increases the risk of reduced effectiveness." ], - "lookupKey" : {"CYP2D6": "2.0"}, + "lookupKey" : {"CYP2D6": "≥3.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA10026", "name" : "aripiprazole", - "version" : 10 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104937", "name" : "Annotation of DPWG Guideline for aripiprazole and CYP2D6", - "version" : 43 + "version" : 155 }, "text" : { - "id" : 1452103495, - "html" : "

The guideline does not provide a recommendation for aripiprazole in normal metabolizers.

\n", - "version" : 0 + "id" : 1452103501, + "html" : "

NO action is needed for this gene-drug interaction.

\n", + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301972", - "name" : "Recommendation Annotation PA166301972", + "id" : "PA166301969", + "name" : "Recommendation Annotation PA166301969", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -104976,37 +105992,37 @@ "valid" : true, "version" : 1 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "The genetic variation increases the plasma concentration of the sum of aripiprazole and the active metabolite dehydroaripiprazole to a limited degree. There is insufficient evidence that this increases the risk of side effects." + "The risk of side effects is increased. The genetic variation leads to an increase in the sum of the plasma concentrations of aripiprazole and the active metabolite." ], - "lookupKey" : {"CYP2D6": "0.75"}, + "lookupKey" : {"CYP2D6": "0.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA10026", "name" : "aripiprazole", - "version" : 10 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104937", "name" : "Annotation of DPWG Guideline for aripiprazole and CYP2D6", - "version" : 43 + "version" : 155 }, "text" : { - "id" : 1452103491, - "html" : "

NO action is needed for this gene-drug interaction.

\n", + "id" : 1452103488, + "html" : "

Administer no more than 10 mg/day or 300 mg/month (68-75% of the normal maximum dose of aripiprazole).

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302003", - "name" : "Recommendation Annotation PA166302003", + "id" : "PA166301971", + "name" : "Recommendation Annotation PA166301971", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -105020,244 +106036,241 @@ }, "dosingInformation" : false, "implications" : [ - "The genetic variation decreases the plasma concentration of the sum of aripiprazole and the active metabolite dehydroaripiprazole to a limited degree. There is no evidence that this increases the risk of reduced effectiveness." + "The genetic variation increases the plasma concentration of the sum of aripiprazole and the active metabolite dehydroaripiprazole to a limited degree. There is insufficient evidence that this increases the risk of side effects." ], - "lookupKey" : {"CYP2D6": "≥6.0"}, + "lookupKey" : {"CYP2D6": "0.5"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA10026", "name" : "aripiprazole", - "version" : 10 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104937", "name" : "Annotation of DPWG Guideline for aripiprazole and CYP2D6", - "version" : 43 + "version" : 155 }, "text" : { - "id" : 1452103522, + "id" : 1452103490, "html" : "

NO action is needed for this gene-drug interaction.

\n", - "version" : 0 + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301975", - "name" : "Recommendation Annotation PA166301975", + "id" : "PA166301970", + "name" : "Recommendation Annotation PA166301970", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, "dosingInformation" : false, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on aripiprazole." + "The genetic variation increases the plasma concentration of the sum of aripiprazole and the active metabolite dehydroaripiprazole to a limited degree. There is insufficient evidence that this increases the risk of side effects." ], - "lookupKey" : {"CYP2D6": "1.5"}, + "lookupKey" : {"CYP2D6": "0.25"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA10026", "name" : "aripiprazole", - "version" : 10 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104937", "name" : "Annotation of DPWG Guideline for aripiprazole and CYP2D6", - "version" : 43 + "version" : 155 }, "text" : { - "id" : 1452103494, - "html" : "

The guideline does not provide a recommendation for aripiprazole in normal metabolizers.

\n", - "version" : 0 + "id" : 1452103489, + "html" : "

NO action is needed for this gene-drug interaction.

\n", + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301971", - "name" : "Recommendation Annotation PA166301971", + "id" : "PA166301977", + "name" : "Recommendation Annotation PA166301977", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, "dosingInformation" : false, "implications" : [ - "The genetic variation increases the plasma concentration of the sum of aripiprazole and the active metabolite dehydroaripiprazole to a limited degree. There is insufficient evidence that this increases the risk of side effects." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on aripiprazole." ], - "lookupKey" : {"CYP2D6": "0.5"}, + "lookupKey" : {"CYP2D6": "2.5"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA10026", "name" : "aripiprazole", - "version" : 10 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104937", "name" : "Annotation of DPWG Guideline for aripiprazole and CYP2D6", - "version" : 43 + "version" : 155 }, "text" : { - "id" : 1452103490, - "html" : "

NO action is needed for this gene-drug interaction.

\n", + "id" : 1452103496, + "html" : "

The guideline does not provide a recommendation for aripiprazole in normal metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301970", - "name" : "Recommendation Annotation PA166301970", + "id" : "PA166301976", + "name" : "Recommendation Annotation PA166301976", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, "dosingInformation" : false, "implications" : [ - "The genetic variation increases the plasma concentration of the sum of aripiprazole and the active metabolite dehydroaripiprazole to a limited degree. There is insufficient evidence that this increases the risk of side effects." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on aripiprazole." ], - "lookupKey" : {"CYP2D6": "0.25"}, + "lookupKey" : {"CYP2D6": "2.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA10026", "name" : "aripiprazole", - "version" : 10 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104937", "name" : "Annotation of DPWG Guideline for aripiprazole and CYP2D6", - "version" : 43 + "version" : 155 }, "text" : { - "id" : 1452103489, - "html" : "

NO action is needed for this gene-drug interaction.

\n", + "id" : 1452103495, + "html" : "

The guideline does not provide a recommendation for aripiprazole in normal metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301979", - "name" : "Recommendation Annotation PA166301979", + "id" : "PA166301975", + "name" : "Recommendation Annotation PA166301975", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, "dosingInformation" : false, "implications" : [ - "The genetic variation decreases the plasma concentration of the sum of aripiprazole and the active metabolite dehydroaripiprazole to a limited degree. There is no evidence that this increases the risk of reduced effectiveness." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on aripiprazole." ], - "lookupKey" : {"CYP2D6": "4.0"}, + "lookupKey" : {"CYP2D6": "1.5"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA10026", "name" : "aripiprazole", - "version" : 10 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104937", "name" : "Annotation of DPWG Guideline for aripiprazole and CYP2D6", - "version" : 43 + "version" : 155 }, "text" : { - "id" : 1452103498, - "html" : "

NO action is needed for this gene-drug interaction.

\n", + "id" : 1452103494, + "html" : "

The guideline does not provide a recommendation for aripiprazole in normal metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302002", - "name" : "Recommendation Annotation PA166302002", + "id" : "PA166301974", + "name" : "Recommendation Annotation PA166301974", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, "dosingInformation" : false, "implications" : [ - "The genetic variation decreases the plasma concentration of the sum of aripiprazole and the active metabolite dehydroaripiprazole to a limited degree. There is no evidence that this increases the risk of reduced effectiveness." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on aripiprazole." ], - "lookupKey" : {"CYP2D6": "≥5.0"}, + "lookupKey" : {"CYP2D6": "1.25"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA10026", "name" : "aripiprazole", - "version" : 10 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104937", "name" : "Annotation of DPWG Guideline for aripiprazole and CYP2D6", - "version" : 43 + "version" : 155 }, "text" : { - "id" : 1452103521, - "html" : "

NO action is needed for this gene-drug interaction.

\n", + "id" : 1452103493, + "html" : "

The guideline does not provide a recommendation for aripiprazole in normal metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301978", - "name" : "Recommendation Annotation PA166301978", + "id" : "PA166302003", + "name" : "Recommendation Annotation PA166302003", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -105273,74 +106286,75 @@ "implications" : [ "The genetic variation decreases the plasma concentration of the sum of aripiprazole and the active metabolite dehydroaripiprazole to a limited degree. There is no evidence that this increases the risk of reduced effectiveness." ], - "lookupKey" : {"CYP2D6": "3.0"}, + "lookupKey" : {"CYP2D6": "≥6.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA10026", "name" : "aripiprazole", - "version" : 10 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104937", "name" : "Annotation of DPWG Guideline for aripiprazole and CYP2D6", - "version" : 43 + "version" : 155 }, "text" : { - "id" : 1452103497, + "id" : 1452103522, "html" : "

NO action is needed for this gene-drug interaction.

\n", - "version" : 0 + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301974", - "name" : "Recommendation Annotation PA166301974", + "id" : "PA166302002", + "name" : "Recommendation Annotation PA166302002", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, "dosingInformation" : false, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on aripiprazole." + "The genetic variation decreases the plasma concentration of the sum of aripiprazole and the active metabolite dehydroaripiprazole to a limited degree. There is no evidence that this increases the risk of reduced effectiveness." ], - "lookupKey" : {"CYP2D6": "1.25"}, + "lookupKey" : {"CYP2D6": "≥5.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA10026", "name" : "aripiprazole", - "version" : 10 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104937", "name" : "Annotation of DPWG Guideline for aripiprazole and CYP2D6", - "version" : 43 + "version" : 155 }, "text" : { - "id" : 1452103493, - "html" : "

The guideline does not provide a recommendation for aripiprazole in normal metabolizers.

\n", - "version" : 0 + "id" : 1452103521, + "html" : "

NO action is needed for this gene-drug interaction.

\n", + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301983", - "name" : "Recommendation Annotation PA166301983", + "id" : "PA166302001", + "name" : "Recommendation Annotation PA166302001", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -105356,33 +106370,33 @@ "implications" : [ "The genetic variation decreases the plasma concentration of the sum of aripiprazole and the active metabolite dehydroaripiprazole to a limited degree. There is no evidence that this increases the risk of reduced effectiveness." ], - "lookupKey" : {"CYP2D6": "≥3.5"}, + "lookupKey" : {"CYP2D6": "≥4.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA10026", "name" : "aripiprazole", - "version" : 10 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104937", "name" : "Annotation of DPWG Guideline for aripiprazole and CYP2D6", - "version" : 43 + "version" : 155 }, "text" : { - "id" : 1452103502, + "id" : 1452103520, "html" : "

NO action is needed for this gene-drug interaction.

\n", - "version" : 0 + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301982", - "name" : "Recommendation Annotation PA166301982", + "id" : "PA166301980", + "name" : "Recommendation Annotation PA166301980", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -105398,33 +106412,33 @@ "implications" : [ "The genetic variation decreases the plasma concentration of the sum of aripiprazole and the active metabolite dehydroaripiprazole to a limited degree. There is no evidence that this increases the risk of reduced effectiveness." ], - "lookupKey" : {"CYP2D6": "≥3.0"}, + "lookupKey" : {"CYP2D6": "≥3.25"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA10026", "name" : "aripiprazole", - "version" : 10 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104937", "name" : "Annotation of DPWG Guideline for aripiprazole and CYP2D6", - "version" : 43 + "version" : 155 }, "text" : { - "id" : 1452103501, + "id" : 1452103499, "html" : "

NO action is needed for this gene-drug interaction.

\n", - "version" : 0 + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301969", - "name" : "Recommendation Annotation PA166301969", + "id" : "PA166301979", + "name" : "Recommendation Annotation PA166301979", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -105436,37 +106450,37 @@ "valid" : true, "version" : 1 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "The risk of side effects is increased. The genetic variation leads to an increase in the sum of the plasma concentrations of aripiprazole and the active metabolite." + "The genetic variation decreases the plasma concentration of the sum of aripiprazole and the active metabolite dehydroaripiprazole to a limited degree. There is no evidence that this increases the risk of reduced effectiveness." ], - "lookupKey" : {"CYP2D6": "0.0"}, + "lookupKey" : {"CYP2D6": "4.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA10026", "name" : "aripiprazole", - "version" : 10 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104937", "name" : "Annotation of DPWG Guideline for aripiprazole and CYP2D6", - "version" : 43 + "version" : 155 }, "text" : { - "id" : 1452103488, - "html" : "

Administer no more than 10 mg/day or 300 mg/month (68-75% of the normal maximum dose of aripiprazole).

\n", - "version" : 0 + "id" : 1452103498, + "html" : "

NO action is needed for this gene-drug interaction.

\n", + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302001", - "name" : "Recommendation Annotation PA166302001", + "id" : "PA166301978", + "name" : "Recommendation Annotation PA166301978", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -105482,74 +106496,75 @@ "implications" : [ "The genetic variation decreases the plasma concentration of the sum of aripiprazole and the active metabolite dehydroaripiprazole to a limited degree. There is no evidence that this increases the risk of reduced effectiveness." ], - "lookupKey" : {"CYP2D6": "≥4.0"}, + "lookupKey" : {"CYP2D6": "3.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA10026", "name" : "aripiprazole", - "version" : 10 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104937", "name" : "Annotation of DPWG Guideline for aripiprazole and CYP2D6", - "version" : 43 + "version" : 155 }, "text" : { - "id" : 1452103520, + "id" : 1452103497, "html" : "

NO action is needed for this gene-drug interaction.

\n", - "version" : 0 + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301977", - "name" : "Recommendation Annotation PA166301977", + "id" : "PA166301973", + "name" : "Recommendation Annotation PA166301973", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, "dosingInformation" : false, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on aripiprazole." + "The genetic variation increases the plasma concentration of the sum of aripiprazole and the active metabolite dehydroaripiprazole to a limited degree. There is insufficient evidence that this increases the risk of side effects." ], - "lookupKey" : {"CYP2D6": "2.5"}, + "lookupKey" : {"CYP2D6": "1.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA10026", "name" : "aripiprazole", - "version" : 10 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104937", "name" : "Annotation of DPWG Guideline for aripiprazole and CYP2D6", - "version" : 43 + "version" : 155 }, "text" : { - "id" : 1452103496, - "html" : "

The guideline does not provide a recommendation for aripiprazole in normal metabolizers.

\n", - "version" : 0 + "id" : 1452103492, + "html" : "

NO action is needed for this gene-drug interaction.

\n", + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301973", - "name" : "Recommendation Annotation PA166301973", + "id" : "PA166301972", + "name" : "Recommendation Annotation PA166301972", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -105565,28 +106580,28 @@ "implications" : [ "The genetic variation increases the plasma concentration of the sum of aripiprazole and the active metabolite dehydroaripiprazole to a limited degree. There is insufficient evidence that this increases the risk of side effects." ], - "lookupKey" : {"CYP2D6": "1.0"}, + "lookupKey" : {"CYP2D6": "0.75"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA10026", "name" : "aripiprazole", - "version" : 10 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104937", "name" : "Annotation of DPWG Guideline for aripiprazole and CYP2D6", - "version" : 43 + "version" : 155 }, "text" : { - "id" : 1452103492, + "id" : 1452103491, "html" : "

NO action is needed for this gene-drug interaction.

\n", - "version" : 0 + "version" : 1 }, - "version" : 0 + "version" : 2 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166104937" @@ -105879,7 +106894,7 @@ "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "relatedGenes" : [ @@ -105888,108 +106903,147 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "DPWG", "summaryMarkdown" : { "id" : 1447982000, "html" : "

The Dutch Pharmacogenetics Working Group Guideline for atomoxetine states for CYP2D6 ultrarapid metabolizers, to be alert to reduced efficacy of atomoxetine or select an alternative drug as a precaution. Be alert to side effects in CYP2D6 poor metabolizers.

\n", - "version" : 2 + "version" : 5 }, "terms" : [], "textMarkdown" : { "id" : 1447981999, "html" : "

Dutch pharmacogenetics working group (DPWG) guideline for the gene-drug interaction of CYP2D6 and COMT with atomoxetine and methylphenidate. European journal of human genetics (2022)

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group published a paper with the guidelines as per table below PMID:36509836.

\n

May 2023 Update

\n

Some wording for the description and recommendation has changed, e.g. for UMs "Advise the patient to report..." compared to "Advise the patient to contact their doctor...". The table below reflects the current wording.

\n

November 2018 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for atomoxetine based on CYP2D6 genotype.

\n

Wording in table taken from Dutch guidelines May 2023 update

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
CYP2D6 UMatomoxetineEfficacy can be reduced due to the gene variation. The gene variation results in an increased conversion of atomoxetine to the active metabolite 4-hydroxyatomoxetine, which has a much lower plasma concentration. As a result, the plasma concentration of the active ingredients decreases.- Be extra alert to reduced efficacy of the treatment.
- Advise the patient to report an inadequate effect.
- An alternative can be selected as a precaution. Clonidine is not metabolised by CYP2D6.
CYP2D6 IMatomoxetineThe dose requirement can be reduced, because the genetic variation results in a higher atomoxetine plasma concentration.In the event of side effects occurring and/or a response later than 9 weeks: reduce the dose and check whether the effect is conserved The plasma concentration of atomoxetine is a factor of 2-3 times higher for IM than for NM at the same dose.
CYP2D6 PMatomoxetineThe risk of side effects is increased, because the genetic variation results in a higher atomoxetine plasma concentration.- Start with the normal initial dose, bearing in mind that an increase in this dose probably will not be required.
- Advise the patient to report side effects (such as decreased appetite, vomiting, abdominal pain, constipation, insomnia, early waking, drowsiness, irritability, pupil dilation and itching).
- If the medicine is effective, but side effects occur: reduce the dose and check whether the effect is conserved. The plasma concentration of atomoxetine is a factor of 8-11 times higher for PM than for NM at the same dose.
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for atomoxetine and CYP2D6:

\n
\n

The KNMP Pharmacogenetics Working Group considers genotyping before starting atomoxetine to be potentially\nbeneficial for the prevention of side effects and drug effectiveness. Genotyping can be considered on an individual\npatient basis. If, however, the genotype is available, the KNMP Pharmacogenetics Working Group recommends\nadhering to the gene-drug guideline.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n

2011 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for atomoxetine based on CYP2D6 genotypes [Article:21412232].

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Phenotype (Genotype)Therapeutic Dose RecommendationLevel of EvidenceClinical Relevance
PM (two inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) alleles)Standard dose. Dose increase probably not necessary; be alert to ADEs.Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Clinical effect (S): short-lived discomfort (< 48 hr) without permanent injury: e.g. reduced decrease in resting heart rate; reduction in exercise tachycardia; decreased pain relief from oxycodone; ADE resulting from increased bioavailability of atomoxetine (decreased appetite, insomnia, sleep disturbance etc); neutropenia > 1.5x109/l; leucopenia > 3.0x109/l; thrombocytopenia > 75x109/l; moderate diarrhea not affecting daily activities; reduced glucose increase following oral glucose tolerance test.
IM (two decreased-activity (*9, *10, *17, *29, *36, *41) alleles or carrying one active (*1, *2, *33, *35) and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele, or carrying one decreased-activity (*9, *10, *17, *29, *36, *41) allele and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele)No recommendations.Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Minor clinical effect (S): QTc prolongation (<450 ms female, <470 ms male); INR increase < 4.5; Kinetic effect (S).
UM (a gene duplication in absence of inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) or decreased-activity (*9, *10, *17, *29, *36, *41) alleles)Insufficient data to allow calculation of dose adjustment. Be alert to reduced efficacy or select alternative drug (e.g., methylphenidate, clonidine).----
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The guideline does not provide a recommendation for atomoxetine in normal metabolizers.

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In the event of side effects occurring and/or a response later than 9 weeks: reduce the dose and check whether the effect is conserved. The plasma concentration of atomoxetine is a factor of 2-3 times higher for IM than for EM at the same dose.

\n", + "id" : 1452103567, + "html" : "

The guideline does not provide a recommendation for atomoxetine in normal metabolizers.

\n", "version" : 0 }, - "version" : 1 + "version" : 2 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166302027", + "name" : "Recommendation Annotation PA166302027", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 1448526251, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : false, + "implications" : [ + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on atomoxetine." + ], + "lookupKey" : {"CYP2D6": "1.5"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA134688071", + "name" : "atomoxetine", + "version" : 33 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104989", + "name" : "Annotation of DPWG Guideline for atomoxetine and CYP2D6", + "version" : 120 + }, + "text" : { + "id" : 1452103566, + "html" : "

The guideline does not provide a recommendation for atomoxetine in normal metabolizers.

\n", + "version" : 0 + }, + "version" : 2 }, { "objCls" : "Recommendation Annotation", @@ -106016,26 +107070,26 @@ "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104989", "name" : "Annotation of DPWG Guideline for atomoxetine and CYP2D6", - "version" : 34 + "version" : 120 }, "text" : { "id" : 1452103565, "html" : "

The guideline does not provide a recommendation for atomoxetine in normal metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302101", - "name" : "Recommendation Annotation PA166302101", + "id" : "PA166302030", + "name" : "Recommendation Annotation PA166302030", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -106051,24 +107105,24 @@ "implications" : [ "Efficacy can be reduced due to the gene variation. The gene variation results in an increased conversion of atomoxetine to the active metabolite 4-hydroxyatomoxetine, which has a much lower plasma concentration. As a result, the plasma concentration of the active ingredients decreases." ], - "lookupKey" : {"CYP2D6": "≥5.0"}, + "lookupKey" : {"CYP2D6": "3.0"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104989", "name" : "Annotation of DPWG Guideline for atomoxetine and CYP2D6", - "version" : 34 + "version" : 120 }, "text" : { - "id" : 1452103640, + "id" : 1452103569, "html" : "\n", "version" : 1 }, @@ -106076,9 +107130,9 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302061", - "name" : "Recommendation Annotation PA166302061", - "alternateDrugAvailable" : true, + "id" : "PA166302025", + "name" : "Recommendation Annotation PA166302025", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -106089,38 +107143,38 @@ "valid" : true, "version" : 1 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "Efficacy can be reduced due to the gene variation. The gene variation results in an increased conversion of atomoxetine to the active metabolite 4-hydroxyatomoxetine, which has a much lower plasma concentration. As a result, the plasma concentration of the active ingredients decreases." + "The dose requirement can be reduced, because the genetic variation results in a higher atomoxetine plasma concentration." ], - "lookupKey" : {"CYP2D6": "≥3.5"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"CYP2D6": "1.0"}, + "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104989", "name" : "Annotation of DPWG Guideline for atomoxetine and CYP2D6", - "version" : 34 + "version" : 120 }, "text" : { - "id" : 1452103600, - "html" : "\n", + "id" : 1452103564, + "html" : "

In the event of side effects occurring and/or a response later than 9 weeks: reduce the dose and check whether the effect is conserved The plasma concentration of atomoxetine is a factor of 2-3 times higher for IM than for NM at the same dose.

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In the event of side effects occurring and/or a response later than 9 weeks: reduce the dose and check whether the effect is conserved The plasma concentration of atomoxetine is a factor of 2-3 times higher for IM than for NM at the same dose.

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In the event of side effects occurring and/or a response later than 9 weeks: reduce the dose and check whether the effect is conserved. The plasma concentration of atomoxetine is a factor of 2-3 times higher for IM than for EM at the same dose.

\n", + "version" : 0 }, "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302021", - "name" : "Recommendation Annotation PA166302021", + "id" : "PA166302022", + "name" : "Recommendation Annotation PA166302022", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -106217,35 +107271,35 @@ }, "dosingInformation" : true, "implications" : [ - "The risk of side effects is increased, because the genetic variation results in a higher atomoxetine plasma concentration." + "The dose requirement can be reduced, because the genetic variation results in a higher atomoxetine plasma concentration." ], - "lookupKey" : {"CYP2D6": "0.0"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"CYP2D6": "0.25"}, + "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104989", "name" : "Annotation of DPWG Guideline for atomoxetine and CYP2D6", - "version" : 34 + "version" : 120 }, "text" : { - "id" : 1452103560, - "html" : "\n", - "version" : 1 + "id" : 1452103561, + "html" : "

In the event of side effects occurring and/or a response later than 9 weeks: reduce the dose and check whether the effect is conserved. The plasma concentration of atomoxetine is a factor of 2-3 times higher for IM than for EM at the same dose.

\n", + "version" : 0 }, "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302025", - "name" : "Recommendation Annotation PA166302025", + "id" : "PA166302021", + "name" : "Recommendation Annotation PA166302021", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -106259,35 +107313,35 @@ }, "dosingInformation" : true, "implications" : [ - "The dose requirement can be reduced, because the genetic variation results in a higher atomoxetine plasma concentration." + "The risk of side effects is increased, because the genetic variation results in a higher atomoxetine plasma concentration." ], - "lookupKey" : {"CYP2D6": "1.0"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"CYP2D6": "0.0"}, + "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104989", "name" : "Annotation of DPWG Guideline for atomoxetine and CYP2D6", - "version" : 34 + "version" : 120 }, "text" : { - "id" : 1452103564, - "html" : "

In the event of side effects occurring and/or a response later than 9 weeks: reduce the dose and check whether the effect is conserved The plasma concentration of atomoxetine is a factor of 2-3 times higher for IM than for NM at the same dose.

\n", + "id" : 1452103560, + "html" : "\n", "version" : 1 }, - "version" : 1 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302029", - "name" : "Recommendation Annotation PA166302029", + "id" : "PA166302041", + "name" : "Recommendation Annotation PA166302041", "alternateDrugAvailable" : false, "classification" : { "id" : 1448526251, @@ -106302,28 +107356,112 @@ "implications" : [ "The guideline does not provide a description of the impact of a normal metabolizer phenotype on atomoxetine." ], - "lookupKey" : {"CYP2D6": "2.25"}, + "lookupKey" : {"CYP2D6": "2.5"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104989", "name" : "Annotation of DPWG Guideline for atomoxetine and CYP2D6", - "version" : 34 + "version" : 120 }, "text" : { - "id" : 1452103568, + "id" : 1452103580, "html" : "

The guideline does not provide a recommendation for atomoxetine in normal metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166302044", + "name" : "Recommendation Annotation PA166302044", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981501929, + "description" : "Not Applicable", + "parents" : [], + "resource" : "Guideline Strength", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", + "valid" : true, + "version" : 1 + }, + "dosingInformation" : false, + "implications" : [ + "Efficacy can be reduced due to the gene variation. The gene variation results in an increased conversion of atomoxetine to the active metabolite 4-hydroxyatomoxetine, which has a much lower plasma concentration. As a result, the plasma concentration of the active ingredients decreases." + ], + "lookupKey" : {"CYP2D6": "≥3.25"}, + "otherPrescribingGuidance" : true, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA134688071", + "name" : "atomoxetine", + "version" : 33 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104989", + "name" : "Annotation of DPWG Guideline for atomoxetine and CYP2D6", + "version" : 120 + }, + "text" : { + "id" : 1452103583, + "html" : "\n", + "version" : 1 + }, + "version" : 1 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166302043", + "name" : "Recommendation Annotation PA166302043", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981501929, + "description" : "Not Applicable", + "parents" : [], + "resource" : "Guideline Strength", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", + "valid" : true, + "version" : 1 + }, + "dosingInformation" : false, + "implications" : [ + "Efficacy can be reduced due to the gene variation. The gene variation results in an increased conversion of atomoxetine to the active metabolite 4-hydroxyatomoxetine, which has a much lower plasma concentration. As a result, the plasma concentration of the active ingredients decreases." + ], + "lookupKey" : {"CYP2D6": "≥3.0"}, + "otherPrescribingGuidance" : true, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA134688071", + "name" : "atomoxetine", + "version" : 33 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104989", + "name" : "Annotation of DPWG Guideline for atomoxetine and CYP2D6", + "version" : 120 + }, + "text" : { + "id" : 1452103582, + "html" : "\n", + "version" : 1 + }, + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -106351,14 +107489,14 @@ "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104989", "name" : "Annotation of DPWG Guideline for atomoxetine and CYP2D6", - "version" : 34 + "version" : 120 }, "text" : { "id" : 1452103581, @@ -106369,9 +107507,9 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302024", - "name" : "Recommendation Annotation PA166302024", - "alternateDrugAvailable" : false, + "id" : "PA166302061", + "name" : "Recommendation Annotation PA166302061", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -106382,29 +107520,29 @@ "valid" : true, "version" : 1 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "The dose requirement can be reduced, because the genetic variation results in a higher atomoxetine plasma concentration." + "Efficacy can be reduced due to the gene variation. The gene variation results in an increased conversion of atomoxetine to the active metabolite 4-hydroxyatomoxetine, which has a much lower plasma concentration. As a result, the plasma concentration of the active ingredients decreases." ], - "lookupKey" : {"CYP2D6": "0.75"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"CYP2D6": "≥3.5"}, + "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104989", "name" : "Annotation of DPWG Guideline for atomoxetine and CYP2D6", - "version" : 34 + "version" : 120 }, "text" : { - "id" : 1452103563, - "html" : "

In the event of side effects occurring and/or a response later than 9 weeks: reduce the dose and check whether the effect is conserved The plasma concentration of atomoxetine is a factor of 2-3 times higher for IM than for NM at the same dose.

\n", + "id" : 1452103600, + "html" : "\n", "version" : 1 }, "version" : 1 @@ -106435,14 +107573,14 @@ "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104989", "name" : "Annotation of DPWG Guideline for atomoxetine and CYP2D6", - "version" : 34 + "version" : 120 }, "text" : { "id" : 1452103620, @@ -106453,91 +107591,9 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302028", - "name" : "Recommendation Annotation PA166302028", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 1448526251, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on atomoxetine." - ], - "lookupKey" : {"CYP2D6": "2.0"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA134688071", - "name" : "atomoxetine", - "version" : 6 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166104989", - "name" : "Annotation of DPWG Guideline for atomoxetine and CYP2D6", - "version" : 34 - }, - "text" : { - "id" : 1452103567, - "html" : "

The guideline does not provide a recommendation for atomoxetine in normal metabolizers.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166302041", - "name" : "Recommendation Annotation PA166302041", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 1448526251, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on atomoxetine." - ], - "lookupKey" : {"CYP2D6": "2.5"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA134688071", - "name" : "atomoxetine", - "version" : 6 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166104989", - "name" : "Annotation of DPWG Guideline for atomoxetine and CYP2D6", - "version" : 34 - }, - "text" : { - "id" : 1452103580, - "html" : "

The guideline does not provide a recommendation for atomoxetine in normal metabolizers.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166302023", - "name" : "Recommendation Annotation PA166302023", - "alternateDrugAvailable" : false, + "id" : "PA166302102", + "name" : "Recommendation Annotation PA166302102", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -106548,78 +107604,37 @@ "valid" : true, "version" : 1 }, - "dosingInformation" : true, - "implications" : [ - "The dose requirement can be reduced, because the genetic variation results in a higher atomoxetine plasma concentration." - ], - "lookupKey" : {"CYP2D6": "0.5"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA134688071", - "name" : "atomoxetine", - "version" : 6 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166104989", - "name" : "Annotation of DPWG Guideline for atomoxetine and CYP2D6", - "version" : 34 - }, - "text" : { - "id" : 1452103562, - "html" : "

In the event of side effects occurring and/or a response later than 9 weeks: reduce the dose and check whether the effect is conserved. The plasma concentration of atomoxetine is a factor of 2-3 times higher for IM than for EM at the same dose.

\n", - "version" : 0 - }, - "version" : 1 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166302027", - "name" : "Recommendation Annotation PA166302027", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 1448526251, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", - "valid" : true, - "version" : 0 - }, "dosingInformation" : false, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on atomoxetine." + "Efficacy can be reduced due to the gene variation. The gene variation results in an increased conversion of atomoxetine to the active metabolite 4-hydroxyatomoxetine, which has a much lower plasma concentration. As a result, the plasma concentration of the active ingredients decreases." ], - "lookupKey" : {"CYP2D6": "1.5"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"CYP2D6": "≥6.0"}, + "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104989", "name" : "Annotation of DPWG Guideline for atomoxetine and CYP2D6", - "version" : 34 + "version" : 120 }, "text" : { - "id" : 1452103566, - "html" : "

The guideline does not provide a recommendation for atomoxetine in normal metabolizers.

\n", - "version" : 0 + "id" : 1452103641, + "html" : "\n", + "version" : 1 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302102", - "name" : "Recommendation Annotation PA166302102", + "id" : "PA166302101", + "name" : "Recommendation Annotation PA166302101", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -106635,24 +107650,24 @@ "implications" : [ "Efficacy can be reduced due to the gene variation. The gene variation results in an increased conversion of atomoxetine to the active metabolite 4-hydroxyatomoxetine, which has a much lower plasma concentration. As a result, the plasma concentration of the active ingredients decreases." ], - "lookupKey" : {"CYP2D6": "≥6.0"}, + "lookupKey" : {"CYP2D6": "≥5.0"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104989", "name" : "Annotation of DPWG Guideline for atomoxetine and CYP2D6", - "version" : 34 + "version" : 120 }, "text" : { - "id" : 1452103641, + "id" : 1452103640, "html" : "\n", "version" : 1 }, @@ -106678,7 +107693,7 @@ "date" : "2019-05-27T00:00:00-07:00", "description" : "Annotation current with November 2018 DPWG Guideline release", "type" : "Create", - "version" : 0 + "version" : 1 }, { "id" : 1450820770, @@ -106776,7 +107791,7 @@ "date" : "2024-03-28T00:00:00-07:00", "description" : "Tags updated: [Alt Drug added]", "type" : "Update", - "version" : 0 + "version" : 1 } ], "literature" : [ @@ -106801,7 +107816,7 @@ "objCls" : "Chemical", "id" : "PA448500", "name" : "atorvastatin", - "version" : 22 + "version" : 67 } ], "relatedGenes" : [ @@ -106810,7 +107825,7 @@ "id" : "PA134865839", "symbol" : "SLCO1B1", "name" : "solute carrier organic anion transporter family member 1B1", - "version" : 49 + "version" : 109 } ], "source" : "DPWG", @@ -106823,94 +107838,94 @@ "textMarkdown" : { "id" : 1450415242, "html" : "

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

\n

August 2020 Guideline update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for atorvastatin based on SLCO1B1 genotype. They recommend choosing an alternative for patients with the SLCO1B1 521 CC or TC (rs4149056) genotype and with ADDITIONAL SIGNIFICANT RISK FACTORS for statin-induced myopathy. For patients without additional significant risk factors for statin-induced myopathy, they advise contacting their doctor in the event of muscle symptoms.

\n

Wording in table taken from Dutch guidelines August 2020 update

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
SLCO1B1 521 CCatorvastatinThe risk of myopathy may be increased. The gene variation may lead to reduced atorvastatin transport to the liver, which may increase the atorvastatin plasma concentration.- Patient has ADDITIONAL SIGNIFICANT RISK FACTORS for statin-induced myopathy:
1. Choose an alternative.
Do not select simvastatin, as this is also affected by the SLCO1B1 gene variation. Rosuvastatin and pravastatin are influenced to a similar extent by SLCO1B1 polymorphisms, but are not influenced by CYP3A4 inhibitors such as amiodarone, verapamil and diltiazem. Fluvastatin is not influenced significantly by SLCO1B1 gene variation or CYP3A4 inhibitors.
2. If an alternative is not an option: advise the patient to contact their doctor in the event of muscle symptoms.
- Patient has NO additional significant risk factors for statin-induced myopathy:
1. Advise the patient to contact their doctor in the event of muscle symptoms.
SLCO1B1 521 TCatorvastatinThe risk of myopathy can be elevated. The gene variation may lead to reduced atorvastatin transport to the liver, which may increase atorvastatin plasma concentrations.- Patient has ADDITIONAL SIGNIFICANT RISK FACTORS for statin-induced myopathy:
1. Choose an alternative.
Rosuvastatin and pravastatin are influenced to a similar extent by the SLCO1B1 gene variation, but are not influenced by CYP3A4 inhibitors such as amiodarone, verapamil and diltiazem. Fluvastatin is not influenced significantly by the SLCO1B1 gene variation or CYP3A4 inhibitors.
2. If an alternative is not an option: advise the patient to contact their doctor in the event of muscle symptoms.
- Patient has NO additional significant risk factors for statin-induced myopathy:
1. Advise the patient to contact their doctor in the event of muscle symptoms.
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for atorvastatin and SLCO1B1:

\n
\n

The KNMP Pharmacogenetics Working Group considers genotyping before starting atorvastatin to be potentially beneficial for the prevention of side effects. Genotyping can be considered on an individual patient basis. If, however, the genotype is available, the KNMP Pharmacogenetics Working Group recommends adhering to the genedrug guideline.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n

November 2018 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for atorvastatin based on SLCO1B1 genotype. They recommend choosing an alternative for patients with the SLCO1B1 521 CC or TC (rs4149056) genotype and with ADDITIONAL SIGNIFICANT RISK FACTORS for statin-induced myopathy. For patients without additional significant risk factors for statin-induced myopathy, they advise contacting their doctor in the event of muscle symptoms.

\n

Wording in table taken from Dutch guidelines November 2018 update

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
521 CCatorvastatinThe genetic polymorphism may lead to reduced atorvastatin transport to the liver. This may increase atorvastatin plasma concentrations and therefore the risk of myopathy.- Patient has ADDITIONAL SIGNIFICANT RISK FACTORS for statin-induced myopathy:
1. Choose an alternative. Rosuvastatin and pravastatin are influenced to a similar extent by SLCO1B1 polymorphisms but are not influenced by CYP3A4 inhibitors such as amiodarone, verapamil and diltiazem. Fluvastatin is not influenced by SLCO1B1 polymorphisms or CYP3A4 inhibitors.
2. If an alternative is not an option: advise the patient to contact their doctor in the event of muscle symptoms.
- Patient has NO additional significant risk factors for statin-induced myopathy:
1. Advise the patient to contact their doctor in the event of muscle symptoms.
521 TCatorvastatinThe genetic polymorphism may lead to reduced atorvastatin transport to the liver. This may increase atorvastatin plasma concentrations and therefore the risk of myopathy.- Patient has ADDITIONAL SIGNIFICANT RISK FACTORS for statin-induced myopathy:
1. Choose an alternative. Rosuvastatin and pravastatin are influenced to a similar extent by SLCO1B1 polymorphisms but are not influenced by CYP3A4 inhibitors such as amiodarone, verapamil and diltiazem. Fluvastatin is not influenced by SLCO1B1 polymorphisms or CYP3A4 inhibitors.
2. If an alternative is not an option: advise the patient to contact their doctor in the event of muscle symptoms.
- Patient has NO additional significant risk factors for statin-induced myopathy:
1. Advise the patient to contact their doctor in the event of muscle symptoms.
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The guideline does not provide a recommendation for atorvastatin in patients with the SLCO1B1 521 TT genotype

\n", + "id" : 1452061490, + "html" : "\n
    \n
  1. Choose an alternative.\nDo not select simvastatin, as this is also affected by the SLCO1B1 gene variation. Rosuvastatin and pravastatin are influenced to a similar extent by SLCO1B1 polymorphisms, but are not influenced by CYP3A4 inhibitors such as amiodarone, verapamil and diltiazem. Fluvastatin is not influenced significantly by SLCO1B1 gene variation or CYP3A4 inhibitors.
    2. \n
  2. If an alternative is not an option: advise the patient to contact their doctor in the event of muscle symptoms.
    3. \n
\n\n
    \n
  1. Advise the patient to contact their doctor in the event of muscle symptoms.
    2. \n
\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299127", - "name" : "Recommendation PA166299127", - "alternateDrugAvailable" : true, + "id" : "PA166299128", + "name" : "Recommendation PA166299128", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, "dosingInformation" : false, "implications" : [ - "The risk of myopathy may be increased. The gene variation may lead to reduced atorvastatin transport to the liver, which may increase the atorvastatin plasma concentration." + "The guideline does not provide a description of the impact of the _SLCO1B1_ 521 TT genotype on atorvastatin." ], - "lookupKey" : {"SLCO1B1": "Poor Function"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"SLCO1B1": "Normal Function"}, + "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448500", "name" : "atorvastatin", - "version" : 22 + "version" : 67 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182843", "name" : "Annotation of DPWG Guideline for atorvastatin and SLCO1B1", - "version" : 13 + "version" : 54 }, "text" : { - "id" : 1452061490, - "html" : "\n
    \n
  1. Choose an alternative.\nDo not select simvastatin, as this is also affected by the SLCO1B1 gene variation. Rosuvastatin and pravastatin are influenced to a similar extent by SLCO1B1 polymorphisms, but are not influenced by CYP3A4 inhibitors such as amiodarone, verapamil and diltiazem. Fluvastatin is not influenced significantly by SLCO1B1 gene variation or CYP3A4 inhibitors.
    2. \n
  2. If an alternative is not an option: advise the patient to contact their doctor in the event of muscle symptoms.
    3. \n
\n\n
    \n
  1. Advise the patient to contact their doctor in the event of muscle symptoms.
    2. \n
\n", + "id" : 1452061491, + "html" : "

The guideline does not provide a recommendation for atorvastatin in patients with the SLCO1B1 521 TT genotype

\n", "version" : 0 }, - "version" : 0 + "version" : 5 }, { "objCls" : "Recommendation Annotation", @@ -106938,21 +107953,21 @@ "objCls" : "Chemical", "id" : "PA448500", "name" : "atorvastatin", - "version" : 22 + "version" : 67 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182843", "name" : "Annotation of DPWG Guideline for atorvastatin and SLCO1B1", - "version" : 13 + "version" : 54 }, "text" : { "id" : 1452061489, "html" : "\n
    \n
  1. Choose an alternative.\nRosuvastatin and pravastatin are influenced to a similar extent by the SLCO1B1 gene variation, but are not influenced by CYP3A4 inhibitors such as amiodarone, verapamil and diltiazem. Fluvastatin is not influenced significantly by the SLCO1B1 gene variation or CYP3A4 inhibitors.
    2. \n
  2. If an alternative is not an option: advise the patient to contact their doctor in the event of muscle symptoms.
    3. \n
\n\n
    \n
  1. Advise the patient to contact their doctor in the event of muscle symptoms.
    2. \n
\n", "version" : 0 }, - "version" : 0 + "version" : 3 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166182843" @@ -107060,7 +108075,7 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "relatedGenes" : [ @@ -107069,7 +108084,7 @@ "id" : "PA134963132", "symbol" : "NUDT15", "name" : "nudix hydrolase 15", - "version" : 11 + "version" : 39 } ], "source" : "DPWG", @@ -107082,52 +108097,53 @@ "textMarkdown" : { "id" : 1450821376, "html" : "

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

\n

May 2020 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for azathioprine based on NUDT15 genotype. They recommend reducing the initial dose for patients that are intermediate metabolizers and selecting an alternative drug or reducing the initial dose for patients that are poor metabolizers. They removed the sentence "Monitoring should be performed at an increased frequency." from the previous recommendation.

\n

Wording in table taken from the Dutch guidelines May 2020 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
NUDT15 IMazathioprineGrade >= 2 leukopaenia occurs in 42% of these patients with standard therapy. The gene variation increases the concentration of the fully activated metabolite of azathioprine and mercaptopurine.- IMMUNOSUPPRESSION:start with 50% of the standard dose. Adjustment of the initial dose should be performed based on toxicity (monitoring of the blood counts) and efficacy.
Note: The percentage of 50% is based on the analogy with TPMT, for which the gene variants have a comparable effect on toxicity to those of NUDT15. A percentage of < 70% was calculated for NUDT15, but there were insufficient data available to calculate the exact percentage.
Note: Dose adjustment based on the total of 6-TGN metabolites is not possible for these patients, as they develop toxicity within the therapeutic range that applies for patients without gene variants.
Note: more stringent dose reductions are necessary if the patient is also TPMT IM or TPMT PM.
NUDT15 PMazathioprineGrade >= 2 leukopaenia occurs in 96% of these patients with standard therapy. The genetic variation increases the concentration of the fully activated metabolite of azathioprine and mercaptopurine.- avoid azathioprine and mercaptopurine. If it is not possible to avoid azathioprine and mercaptopurine: use 10% of the standard dose and advise patients to seek medical attention when symptoms of myelosuppression (such as severe sore throat in combination with fever, regular nosebleeds and tendency to bruising) occur. Any adjustment of the initial dose should be guided by toxicity (monitoring of blood counts) and efficacy.
Note: The percentage of 10% is based on the analogy with TPMT, for which the gene variants have a comparable effect on toxicity to those of NUDT15. A percentage of < 20% was calculated for NUDT15 PM, but there were insufficient data available to calculate the exact percentage.
Note: Dose adjustment based on the total of 6-TGN metabolites is not possible for these patients, as they develop toxicity within the therapeutic range that applies for patients without gene variants.
\n

Read for more information about this recommendation. Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for azathioprine and NUDT15:

\n
\n

The Dutch Pharmacogenetics Working Group considers genotyping before starting azathioprine or 6-mercaptopurine to be essential for drug safety. Genotyping must be performed before drug therapy has been initiated to guide drug and dose selection.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n

August 2019 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for azathioprine based on NUDT15 genotype. They recommend reducing the initial dose for patients that are intermediate metabolizers and selecting an alternative drug or reducing the initial dose for patients that are poor metabolizers. They updated the wording for the intermediate metabolizer recommendation, reflected in the table below.

\n

Wording in table taken from the Dutch guidelines August 2019 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
NUDT15 IMazathioprineGrade = 2 leukopaenia occurs in 42% of these patients with standard therapy. The genetic variation increases the concentration of the fully activated metabolite of azathioprine and mercaptopurine.- IMMUNOSUPPRESSION:start with 50% of the standard dose. Adjustment of the initial dose should be performed based on toxicity (monitoring of the blood counts) and efficacy. Monitoring should be performed at an increased frequency.
Note: The percentage of 50% is based on the analogy with TPMT, for which the gene variants have a comparable effect on toxicity to those of NUDT15. A percentage of < 70% was calculated for NUDT15, but there were insufficient data available to calculate the exact percentage.
Note: Dose adjustment based on the total of 6-TGN metabolites is not possible for these patients, as they develop toxicity within the therapeutic range that applies for patients without gene variants.
Note: more stringent dose reductions are necessary if the patient is also TPMT IM.
NUDT15 PMazathioprineGrade = 2 leukopaenia occurs in 96% of these patients with standard therapy. The genetic variation increases the concentration of the fully activated metabolite of azathioprine and mercaptopurine.- avoid azathioprine and mercaptopurine. If it is not possible to avoid azathioprine and mercaptopurine: use 10% of the standard dose and advise patients to seek medical attention when symptoms of myelosuppression (such as severe sore throat in combination with fever, regular nosebleeds and tendency to bruising) occur. Any adjustment of the initial dose should be guided by toxicity (monitoring of blood counts) and efficacy. Monitoring should be performed at an increased frequency.
Note: The percentage of 10% is based on the analogy with TPMT, for which the gene variants have a comparable effect on toxicity to those of NUDT15. A percentage of < 20% was calculated for NUDT15 PM, but there were insufficient data available to calculate the exact percentage.
Note: Dose adjustment based on the total of 6-TGN metabolites is not possible for these patients, as they develop toxicity within the therapeutic range that applies for patients without gene variants.
\n", - "version" : 6 + "version" : 14 }, "userId" : "carrillo", - "version" : 10 + "version" : 52 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166299093", - "name" : "Recommendation PA166299093", - "alternateDrugAvailable" : false, + "id" : "PA166299094", + "name" : "Recommendation PA166299094", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on azathioprine." + "Grade >=2 leukopaenia occurs in 96% of these patients with standard therapy. The genetic variation increases the concentration of the fully activated metabolite of azathioprine and mercaptopurine." ], - "lookupKey" : {"NUDT15": "Normal Metabolizer"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"NUDT15": "Poor Metabolizer"}, + "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166184614", "name" : "Annotation of DPWG Guideline for azathioprine and NUDT15", - "version" : 10 + "version" : 52 }, "text" : { - "id" : 1452061456, - "html" : "

The guideline does not provide a recommendation for azathioprine in normal metabolizers

\n", - "version" : 0 + "id" : 1452061457, + "html" : "

Avoid azathioprine and mercaptopurine.

\n

If it is not possible to avoid azathioprine and mercaptopurine: use 10% of the standard dose and advise patients to seek medical attention when symptoms of myelosuppression (such as severe sore throat in combination with fever, regular nosebleeds and tendency to bruising) occur. Any adjustment of the initial dose should be guided by toxicity (monitoring of blood counts) and efficacy.

\n

Note: The percentage of 10% is based on the analogy with TPMT, for which the gene variants have a comparable effect on toxicity to those of NUDT15. A percentage of < 20% was calculated for NUDT15 PM, but there were insufficient data available to calculate the exact percentage.\nNote: Dose adjustment based on the total of 6-TGN metabolites is not possible for these patients, as they develop toxicity within the therapeutic range that applies for patients without gene variants.

\n", + "version" : 1 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", @@ -107155,63 +108171,62 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166184614", "name" : "Annotation of DPWG Guideline for azathioprine and NUDT15", - "version" : 10 + "version" : 52 }, "text" : { "id" : 1452061458, "html" : "

IMMUNOSUPPRESSION: Start with 50% of the standard dose. Adjustment of the initial dose should be performed based on toxicity (monitoring of the blood counts) and efficacy.

\n

Note: The percentage of 50% is based on the analogy with TPMT, for which the gene variants have a comparable effect on toxicity to those of NUDT15. A percentage of < 70% was calculated for NUDT15, but there were insufficient data available to calculate the exact percentage.\nNote: Dose adjustment based on the total of 6-TGN metabolites is not possible for these patients, as they develop toxicity within the therapeutic range that applies for patients without gene variants.\nNote: more stringent dose reductions are necessary if the patient is also TPMT IM or TPMT PM.

\n", - "version" : 0 + "version" : 3 }, - "version" : 0 + "version" : 4 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299094", - "name" : "Recommendation PA166299094", - "alternateDrugAvailable" : true, + "id" : "PA166299093", + "name" : "Recommendation PA166299093", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "Grade >=2 leukopaenia occurs in 96% of these patients with standard therapy. The genetic variation increases the concentration of the fully activated metabolite of azathioprine and mercaptopurine." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on azathioprine." ], - "lookupKey" : {"NUDT15": "Poor Metabolizer"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"NUDT15": "Normal Metabolizer"}, + "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166184614", "name" : "Annotation of DPWG Guideline for azathioprine and NUDT15", - "version" : 10 + "version" : 52 }, "text" : { - "id" : 1452061457, - "html" : "

Avoid azathioprine and mercaptopurine.

\n

If it is not possible to avoid azathioprine and mercaptopurine: use 10% of the standard dose and advise patients to seek medical attention when symptoms of myelosuppression (such as severe sore throat in combination with fever, regular nosebleeds and tendency to bruising) occur. Any adjustment of the initial dose should be guided by toxicity (monitoring of blood counts) and efficacy.

\n

Note: The percentage of 10% is based on the analogy with TPMT, for which the gene variants have a comparable effect on toxicity to those of NUDT15. A percentage of < 20% was calculated for NUDT15 PM, but there were insufficient data available to calculate the exact percentage.\nNote: Dose adjustment based on the total of 6-TGN metabolites is not possible for these patients, as they develop toxicity within the therapeutic range that applies for patients without gene variants.

\n", + "id" : 1452061456, + "html" : "

The guideline does not provide a recommendation for azathioprine in normal metabolizers

\n", "version" : 0 }, - "version" : 0 + "version" : 3 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166184614" @@ -107428,140 +108443,140 @@ "id" : "PA165819268", "symbol" : "TPMT*1", "name" : "*1", - "version" : 16 + "version" : 30 }, { "objCls" : "Haplotype", "id" : "PA165819280", "symbol" : "TPMT*10", "name" : "*10", - "version" : 15 + "version" : 31 }, { "objCls" : "Haplotype", "id" : "PA165819281", "symbol" : "TPMT*11", "name" : "*11", - "version" : 15 + "version" : 31 }, { "objCls" : "Haplotype", "id" : "PA165819282", "symbol" : "TPMT*12", "name" : "*12", - "version" : 15 + "version" : 31 }, { "objCls" : "Haplotype", "id" : "PA165819283", "symbol" : "TPMT*13", "name" : "*13", - "version" : 15 + "version" : 31 }, { "objCls" : "Haplotype", "id" : "PA165819284", "symbol" : "TPMT*14", "name" : "*14", - "version" : 14 + "version" : 30 }, { "objCls" : "Haplotype", "id" : "PA165819285", "symbol" : "TPMT*15", "name" : "*15", - "version" : 14 + "version" : 30 }, { "objCls" : "Haplotype", "id" : "PA165819286", "symbol" : "TPMT*16", "name" : "*16", - "version" : 15 + "version" : 31 }, { "objCls" : "Haplotype", "id" : "PA165819287", "symbol" : "TPMT*17", "name" : "*17", - "version" : 15 + "version" : 31 }, { "objCls" : "Haplotype", "id" : "PA165819288", "symbol" : "TPMT*18", "name" : "*18", - "version" : 15 + "version" : 31 }, { "objCls" : "Haplotype", "id" : "PA165819269", "symbol" : "TPMT*2", "name" : "*2", - "version" : 15 + "version" : 32 }, { "objCls" : "Haplotype", "id" : "PA165819270", "symbol" : "TPMT*3A", "name" : "*3A", - "version" : 16 + "version" : 33 }, { "objCls" : "Haplotype", "id" : "PA165819271", "symbol" : "TPMT*3B", "name" : "*3B", - "version" : 15 + "version" : 32 }, { "objCls" : "Haplotype", "id" : "PA165819272", "symbol" : "TPMT*3C", "name" : "*3C", - "version" : 15 + "version" : 32 }, { "objCls" : "Haplotype", "id" : "PA165819274", "symbol" : "TPMT*4", "name" : "*4", - "version" : 14 + "version" : 31 }, { "objCls" : "Haplotype", "id" : "PA165819275", "symbol" : "TPMT*5", "name" : "*5", - "version" : 15 + "version" : 31 }, { "objCls" : "Haplotype", "id" : "PA165819276", "symbol" : "TPMT*6", "name" : "*6", - "version" : 15 + "version" : 31 }, { "objCls" : "Haplotype", "id" : "PA165819277", "symbol" : "TPMT*7", "name" : "*7", - "version" : 15 + "version" : 31 }, { "objCls" : "Haplotype", "id" : "PA165819278", "symbol" : "TPMT*8", "name" : "*8", - "version" : 15 + "version" : 31 }, { "objCls" : "Haplotype", "id" : "PA165819279", "symbol" : "TPMT*9", "name" : "*9", - "version" : 15 + "version" : 31 } ], "relatedChemicals" : [ @@ -107569,7 +108584,7 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "relatedGenes" : [ @@ -107578,23 +108593,23 @@ "id" : "PA356", "symbol" : "TPMT", "name" : "thiopurine S-methyltransferase", - "version" : 7545 + "version" : 7628 } ], "source" : "DPWG", "summaryMarkdown" : { "id" : 1447981850, "html" : "

Select an alternative drug or reduce the initial dose of azathioprine for patients that are TPMT poor metabolizers and reduce initial dose for patients that are TPMT intermediate metabolizers.

\n", - "version" : 1 + "version" : 2 }, "terms" : [], "textMarkdown" : { "id" : 1447981849, "html" : "

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

\n

May 2020 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for azathioprine based on TPMT genotype. They recommend reducing the initial dose for patients that are intermediate metabolizers and selecting an alternative drug or reducing the initial dose for patients that are poor metabolizers. They removed the sentence "The frequency of monitoring should be increased." from the previous recommendation.

\n

Wording in table taken from the Dutch guidelines May 2020 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
TPMT IMazathioprineGrade ≥ 2 leukopaenia occurs in 23% of these patients with normal therapy for immunosuppression. The genetic variation increases the quantity of the active metabolites of azathioprine and mercaptopurine.-IMMUNOSUPPRESSION
Start with 50% of the standard dose
Adjustment of the initial dose should be guided by toxicity (monitoring of blood counts) and effectiveness.
Dose adjustment is not required for doses lower than 1.5 mg/kg per day for azathioprine or 0.75 mg/kg per day for mercaptopurine.
Note: more stringent dose reductions are necessary if the patient is also NUDT15 IM or NUDT15 PM.
TPMT PMazathioprineGrade ≥ 2 leukopaenia and intolerance occurred in 98% of these patients with standard therapy. The gene variation increases the quantities of the active metabolites of azathioprine and mercaptopurine.Choose an alternative or start with 10% of the standard dose.
Any adjustment of the initial dose should be guided by toxicity (monitoring of blood counts) and effectiveness.
If the dose is decreased: advise patients to seek medical attention when symptoms of myelosuppression (such as severe sore throat in combination with fever, regular nosebleeds and tendency to bruising) occur.
\n

Read for more information about this recommendation. Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for azathioprine and TPMT:

\n
\n

The Dutch Pharmacogenetics Working Group considers genotyping before starting azathioprine or 6-mercaptopurine to be essential for drug safety. Genotyping must be performed before drug therapy has been initiated to guide drug and dose selection.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n

August 2019 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for azathioprine based on TPMT genotype. They recommend reducing the initial dose for patients that are intermediate metabolizers and selecting an alternative drug or reducing the initial dose for patients that are poor metabolizers.

\n

Wording in table taken from the Dutch guidelines August 2019 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
TPMT IMazathioprineThe genetic variation reduces the conversion of azathioprine and mercaptopurine to mainly inactive metabolites. This increases the risk of serious, life-threatening adverse events such as myelosuppression.-IMMUNOSUPPRESSION
Start with 50% of the standard dose
Adjustment of the initial dose should be guided by toxicity (monitoring of blood counts) and effectiveness.
The frequency of monitoring should be increased.
Dose adjustment is not required for doses lower than 1.5 mg/kg per day for azathioprine or 0.75 mg/kg per day for mercaptopurine.
Note: more stringent dose reductions are necessary if the patient is also NUDT15 IM.
TPMT PMazathioprineThe genetic variation reduces the conversion of azathioprine and mercaptopurine to mainly inactive metabolites. This increases the risk of serious, life-threatening adverse events such as myelosuppression.1. Choose an alternative or start with 10% of the standard dose.
Any adjustment of the initial dose should be guided by toxicity (monitoring of blood counts) and effectiveness. The frequency of monitoring should be increased.
2. If the dose is decreased: advise patients to seek medical attention when symptoms of myelosuppression (such as severe sore throat in combination with fever, regular nosebleeds and tendency to bruising) occur
\n

November 2018 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for azathioprine based on TPMT genotype. They recommend reducing the initial dose for patients that are intermediate metabolizers and selecting an alternative drug or reducing the initial dose for patients that are poor metabolizers.

\n

Wording in table taken from the Dutch guidelines November 2018 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
TPMT IMazathioprineThe genetic variation reduces the conversion of azathioprine and mercaptopurine to mainly inactive metabolites. This increases the risk of serious, life-threatening adverse events such as myelosuppression.Start with 50% of the standard dose. Adjustment of the initial dose should be guided by toxicity (monitoring of blood counts) and effectiveness. The frequency of monitoring should be increased. Dose adjustment is not required for doses lower than 1.5 mg/kg per day for azathioprine or 0.75 mg/kg per day for mercaptopurine.
TPMT PMazathioprineThe genetic variation reduces the conversion of azathioprine and mercaptopurine to mainly inactive metabolites. This increases the risk of serious, life-threatening adverse events such as myelosuppression.1. Choose an alternative or start with 10% of the standard dose.Any adjustment of the initial dose should be guided by toxicity (monitoring of blood counts) and effectiveness. The frequency of monitoring should be increased. 2. If the dose is decreased: advise patients to seek medical attention when symptoms of myelosuppression (such as severe sore throat in combination with fever, regular nosebleeds and tendency to bruising) occur.
\n

2011 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for azathioprine based on TPMT genotype [Article:21412232]. They recommend selecting an alternative drug or reducing the initial dose for patients carrying inactive alleles.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Phenotype (Genotype)Therapeutic Dose RecommendationLevel of EvidenceClinical Relevance
IM (one inactive allele: *2, *3, *4-*18)Select alternative drug or reduce dose by 50%. Increase dose in response of hematologic monitoring and efficacy.Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Clinical effect (S): Failure of lifesaving therapy e.g. anticipated myelosuppression; prevention of breast cancer relapse; arrhythmia; neutropenia < 0.5x109/l; leucopenia < 1.0x109/l; thrombocytopenia < 25x109/l; life-threatening complications from diarrhea.
PM (two inactive alleles: *2, *3, *4-*18)Select alternative drug or reduce dose by 90%. Increase dose in response of hematologic monitoring and efficacy.Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Clinical effect (S): death; arrhythmia; unanticipated myelosuppression.
\n\n", - "version" : 18 + "version" : 29 }, "userId" : "jmbarbarino", - "version" : 34 + "version" : 95 }, "recommendations" : [ { @@ -107622,21 +108637,21 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104934", "name" : "Annotation of DPWG Guideline for azathioprine and TPMT", - "version" : 34 + "version" : 95 }, "text" : { "id" : 1452061530, "html" : "

The guideline does not provide a recommendation for azathioprine in normal metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 4 }, { "objCls" : "Recommendation Annotation", @@ -107664,21 +108679,21 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104934", "name" : "Annotation of DPWG Guideline for azathioprine and TPMT", - "version" : 34 + "version" : 95 }, "text" : { "id" : 1452061529, "html" : "

Choose an alternative or start with 10% of the standard dose. Any adjustment of the initial dose should be guided by toxicity (monitoring of blood counts) and effectiveness. If the dose is decreased: advise patients to seek medical attention when symptoms of myelosuppression (such as severe sore throat in combination with fever, regular nosebleeds and tendency to bruising) occur.

\n", "version" : 1 }, - "version" : 1 + "version" : 4 }, { "objCls" : "Recommendation Annotation", @@ -107706,21 +108721,21 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104934", "name" : "Annotation of DPWG Guideline for azathioprine and TPMT", - "version" : 34 + "version" : 95 }, "text" : { "id" : 1452061528, "html" : "

IMMUNOSUPPRESSION\nStart with 50% of the standard dose. Adjustment of the initial dose should be guided by toxicity (monitoring of blood counts) and effectiveness. Dose adjustment is not required for doses lower than 1.5 mg/kg per day for azathioprine or 0.75 mg/kg per day for mercaptopurine. Note: more stringent dose reductions are necessary if the patient is also NUDT15 IM or NUDT15 PM.

\n", "version" : 1 }, - "version" : 1 + "version" : 3 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166104934" @@ -107919,7 +108934,7 @@ "date" : "2024-03-28T00:00:00-07:00", "description" : "Tags updated: [Alt Drug removed]", "type" : "Update", - "version" : 0 + "version" : 1 } ], "literature" : [ @@ -107935,7 +108950,7 @@ "objCls" : "Chemical", "id" : "PA166160053", "name" : "brexpiprazole", - "version" : 5 + "version" : 8 } ], "relatedGenes" : [ @@ -107944,23 +108959,23 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "DPWG", "summaryMarkdown" : { "id" : 1450820772, "html" : "

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group (DPWG) recommends to use half of the normal dose of brexpiprazole for poor metabolizers of CYP2D6.

\n", - "version" : 1 + "version" : 2 }, "terms" : [], "textMarkdown" : { "id" : 1450820773, "html" : "

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

\n

Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction between CYP2D6, CYP3A4 and CYP1A2 and antipsychotics. European journal of human genetics (2023)

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group published a paper with the guidelines for brexpiprazole and CYP2D6 as per the August 2019 guidelines and further details on the assessed literature [Article:37002327]. Wording in the poor metabolizer recommendation changed from "standard" to "normal" and is reflected in the table below.

\n

August 2019 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for brexpiprazole based on CYP2D6 genotype. They recommend to use half of the standard dose of brexpiprazole for CYP2D6 poor metabolizer (PM).

\n

Wording in table taken from the Dutch guidelines August 2019 update

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
CYP2D6 UMbrexpiprazole-NO action is required for this gene-drug interaction. The gene variation results in a reduction of the exposure to brexpiprazole, but there are no indications supporting a decrease in efficacy.
CYP2D6 IMbrexpiprazole-NO action is required for this gene-drug interaction. There are indications supporting an increase in the exposure to brexpiprazole, but no indications supporting an increase in side effects in patients with this gene variation.
CYP2D6 PMbrexpiprazoleThe risk of side effects is theoretically increased, because the gene variation reduces the metabolism of brexpiprazole.Use half of the normal dose.
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for brexpiprazole and CYP2D6:

\n
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The Dutch Pharmacogenetics Working Group considers genotyping before starting brexpiprazole to be potentially beneficial for prevention of adverse events. Genotyping can be considered on an individual patient basis. If, however, the genotype is available, the Dutch Pharmacogenetics Working Group recommends adhering to the gene-drug guideline.

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Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n", - "version" : 5 + "version" : 7 }, "userId" : "katrin", - "version" : 13 + "version" : 99 }, "recommendations" : [ { @@ -107989,26 +109004,26 @@ "objCls" : "Chemical", "id" : "PA166160053", "name" : "brexpiprazole", - "version" : 5 + "version" : 8 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166184527", "name" : "Annotation of DPWG Guideline for brexpiprazole and CYP2D6", - "version" : 13 + "version" : 99 }, "text" : { "id" : 1452103671, "html" : "

NO action is required for this gene-drug interaction.

\n", - "version" : 0 + "version" : 1 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302136", - "name" : "Recommendation Annotation PA166302136", + "id" : "PA166302121", + "name" : "Recommendation Annotation PA166302121", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -108020,37 +109035,37 @@ "valid" : true, "version" : 1 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "The gene variation results in a reduction of the exposure to brexpiprazole, but there are no indications supporting a decrease in efficacy." + "The risk of side effects is theoretically increased, because the gene variation reduces the metabolism of brexpiprazole." ], - "lookupKey" : {"CYP2D6": "≥4.0"}, + "lookupKey" : {"CYP2D6": "0.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166160053", "name" : "brexpiprazole", - "version" : 5 + "version" : 8 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166184527", "name" : "Annotation of DPWG Guideline for brexpiprazole and CYP2D6", - "version" : 13 + "version" : 99 }, "text" : { - "id" : 1452103675, - "html" : "

NO action is required for this gene-drug interaction.

\n", + "id" : 1452103660, + "html" : "

Use half of the normal dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302123", - "name" : "Recommendation Annotation PA166302123", + "id" : "PA166302131", + "name" : "Recommendation Annotation PA166302131", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -108064,76 +109079,35 @@ }, "dosingInformation" : false, "implications" : [ - "There are indications supporting an increase in the exposure to brexpiprazole, but no indications supporting an increase in side effects in patients with this gene variation." + "The gene variation results in a reduction of the exposure to brexpiprazole, but there are no indications supporting a decrease in efficacy." ], - "lookupKey" : {"CYP2D6": "0.5"}, + "lookupKey" : {"CYP2D6": "3.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166160053", "name" : "brexpiprazole", - "version" : 5 + "version" : 8 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166184527", "name" : "Annotation of DPWG Guideline for brexpiprazole and CYP2D6", - "version" : 13 + "version" : 99 }, "text" : { - "id" : 1452103662, + "id" : 1452103670, "html" : "

NO action is required for this gene-drug interaction.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166302127", - "name" : "Recommendation Annotation PA166302127", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 1448526251, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on brexpiprazole." - ], - "lookupKey" : {"CYP2D6": "1.5"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA166160053", - "name" : "brexpiprazole", - "version" : 5 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166184527", - "name" : "Annotation of DPWG Guideline for brexpiprazole and CYP2D6", - "version" : 13 - }, - "text" : { - "id" : 1452103666, - "html" : "

The guideline does not provide a recommendation for brexpiprazole in normal metabolizers.

\n", - "version" : 0 + "version" : 1 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302131", - "name" : "Recommendation Annotation PA166302131", + "id" : "PA166302125", + "name" : "Recommendation Annotation PA166302125", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -108147,35 +109121,35 @@ }, "dosingInformation" : false, "implications" : [ - "The gene variation results in a reduction of the exposure to brexpiprazole, but there are no indications supporting a decrease in efficacy." + "There are indications supporting an increase in the exposure to brexpiprazole, but no indications supporting an increase in side effects in patients with this gene variation." ], - "lookupKey" : {"CYP2D6": "3.0"}, + "lookupKey" : {"CYP2D6": "1.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166160053", "name" : "brexpiprazole", - "version" : 5 + "version" : 8 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166184527", "name" : "Annotation of DPWG Guideline for brexpiprazole and CYP2D6", - "version" : 13 + "version" : 99 }, "text" : { - "id" : 1452103670, + "id" : 1452103664, "html" : "

NO action is required for this gene-drug interaction.

\n", - "version" : 0 + "version" : 1 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302122", - "name" : "Recommendation Annotation PA166302122", + "id" : "PA166302124", + "name" : "Recommendation Annotation PA166302124", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -108191,33 +109165,33 @@ "implications" : [ "There are indications supporting an increase in the exposure to brexpiprazole, but no indications supporting an increase in side effects in patients with this gene variation." ], - "lookupKey" : {"CYP2D6": "0.25"}, + "lookupKey" : {"CYP2D6": "0.75"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166160053", "name" : "brexpiprazole", - "version" : 5 + "version" : 8 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166184527", "name" : "Annotation of DPWG Guideline for brexpiprazole and CYP2D6", - "version" : 13 + "version" : 99 }, "text" : { - "id" : 1452103661, + "id" : 1452103663, "html" : "

NO action is required for this gene-drug interaction.

\n", - "version" : 0 + "version" : 1 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302135", - "name" : "Recommendation Annotation PA166302135", + "id" : "PA166302123", + "name" : "Recommendation Annotation PA166302123", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -108231,71 +109205,72 @@ }, "dosingInformation" : false, "implications" : [ - "The gene variation results in a reduction of the exposure to brexpiprazole, but there are no indications supporting a decrease in efficacy." + "There are indications supporting an increase in the exposure to brexpiprazole, but no indications supporting an increase in side effects in patients with this gene variation." ], - "lookupKey" : {"CYP2D6": "≥3.5"}, + "lookupKey" : {"CYP2D6": "0.5"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166160053", "name" : "brexpiprazole", - "version" : 5 + "version" : 8 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166184527", "name" : "Annotation of DPWG Guideline for brexpiprazole and CYP2D6", - "version" : 13 + "version" : 99 }, "text" : { - "id" : 1452103674, + "id" : 1452103662, "html" : "

NO action is required for this gene-drug interaction.

\n", - "version" : 0 + "version" : 1 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302126", - "name" : "Recommendation Annotation PA166302126", + "id" : "PA166302122", + "name" : "Recommendation Annotation PA166302122", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, "dosingInformation" : false, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on brexpiprazole." + "There are indications supporting an increase in the exposure to brexpiprazole, but no indications supporting an increase in side effects in patients with this gene variation." ], - "lookupKey" : {"CYP2D6": "1.25"}, + "lookupKey" : {"CYP2D6": "0.25"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166160053", "name" : "brexpiprazole", - "version" : 5 + "version" : 8 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166184527", "name" : "Annotation of DPWG Guideline for brexpiprazole and CYP2D6", - "version" : 13 + "version" : 99 }, "text" : { - "id" : 1452103665, - "html" : "

The guideline does not provide a recommendation for brexpiprazole in normal metabolizers.

\n", - "version" : 0 + "id" : 1452103661, + "html" : "

NO action is required for this gene-drug interaction.

\n", + "version" : 1 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -108322,152 +109297,190 @@ "objCls" : "Chemical", "id" : "PA166160053", "name" : "brexpiprazole", - "version" : 5 + "version" : 8 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166184527", "name" : "Annotation of DPWG Guideline for brexpiprazole and CYP2D6", - "version" : 13 + "version" : 99 }, "text" : { "id" : 1452103669, "html" : "

The guideline does not provide a recommendation for brexpiprazole in normal metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302134", - "name" : "Recommendation Annotation PA166302134", + "id" : "PA166302129", + "name" : "Recommendation Annotation PA166302129", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, "dosingInformation" : false, "implications" : [ - "The gene variation results in a reduction of the exposure to brexpiprazole, but there are no indications supporting a decrease in efficacy." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on brexpiprazole." ], - "lookupKey" : {"CYP2D6": "≥3.25"}, + "lookupKey" : {"CYP2D6": "2.25"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166160053", "name" : "brexpiprazole", - "version" : 5 + "version" : 8 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166184527", "name" : "Annotation of DPWG Guideline for brexpiprazole and CYP2D6", - "version" : 13 + "version" : 99 }, "text" : { - "id" : 1452103673, - "html" : "

NO action is required for this gene-drug interaction.

\n", + "id" : 1452103668, + "html" : "

The guideline does not provide a recommendation for brexpiprazole in normal metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302121", - "name" : "Recommendation Annotation PA166302121", + "id" : "PA166302128", + "name" : "Recommendation Annotation PA166302128", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "The risk of side effects is theoretically increased, because the gene variation reduces the metabolism of brexpiprazole." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on brexpiprazole." ], - "lookupKey" : {"CYP2D6": "0.0"}, + "lookupKey" : {"CYP2D6": "2.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166160053", "name" : "brexpiprazole", - "version" : 5 + "version" : 8 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166184527", "name" : "Annotation of DPWG Guideline for brexpiprazole and CYP2D6", - "version" : 13 + "version" : 99 }, "text" : { - "id" : 1452103660, - "html" : "

Use half of the normal dose.

\n", + "id" : 1452103667, + "html" : "

The guideline does not provide a recommendation for brexpiprazole in normal metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302138", - "name" : "Recommendation Annotation PA166302138", + "id" : "PA166302127", + "name" : "Recommendation Annotation PA166302127", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, "dosingInformation" : false, "implications" : [ - "The gene variation results in a reduction of the exposure to brexpiprazole, but there are no indications supporting a decrease in efficacy." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on brexpiprazole." ], - "lookupKey" : {"CYP2D6": "≥6.0"}, + "lookupKey" : {"CYP2D6": "1.5"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166160053", "name" : "brexpiprazole", - "version" : 5 + "version" : 8 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166184527", "name" : "Annotation of DPWG Guideline for brexpiprazole and CYP2D6", - "version" : 13 + "version" : 99 }, "text" : { - "id" : 1452103677, - "html" : "

NO action is required for this gene-drug interaction.

\n", + "id" : 1452103666, + "html" : "

The guideline does not provide a recommendation for brexpiprazole in normal metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302125", - "name" : "Recommendation Annotation PA166302125", + "id" : "PA166302126", + "name" : "Recommendation Annotation PA166302126", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 1448526251, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : false, + "implications" : [ + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on brexpiprazole." + ], + "lookupKey" : {"CYP2D6": "1.25"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA166160053", + "name" : "brexpiprazole", + "version" : 8 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166184527", + "name" : "Annotation of DPWG Guideline for brexpiprazole and CYP2D6", + "version" : 99 + }, + "text" : { + "id" : 1452103665, + "html" : "

The guideline does not provide a recommendation for brexpiprazole in normal metabolizers.

\n", + "version" : 0 + }, + "version" : 2 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166302138", + "name" : "Recommendation Annotation PA166302138", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -108481,76 +109494,77 @@ }, "dosingInformation" : false, "implications" : [ - "There are indications supporting an increase in the exposure to brexpiprazole, but no indications supporting an increase in side effects in patients with this gene variation." + "The gene variation results in a reduction of the exposure to brexpiprazole, but there are no indications supporting a decrease in efficacy." ], - "lookupKey" : {"CYP2D6": "1.0"}, + "lookupKey" : {"CYP2D6": "≥6.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166160053", "name" : "brexpiprazole", - "version" : 5 + "version" : 8 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166184527", "name" : "Annotation of DPWG Guideline for brexpiprazole and CYP2D6", - "version" : 13 + "version" : 99 }, "text" : { - "id" : 1452103664, + "id" : 1452103677, "html" : "

NO action is required for this gene-drug interaction.

\n", - "version" : 0 + "version" : 1 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302129", - "name" : "Recommendation Annotation PA166302129", + "id" : "PA166302137", + "name" : "Recommendation Annotation PA166302137", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, "dosingInformation" : false, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on brexpiprazole." + "The gene variation results in a reduction of the exposure to brexpiprazole, but there are no indications supporting a decrease in efficacy." ], - "lookupKey" : {"CYP2D6": "2.25"}, + "lookupKey" : {"CYP2D6": "≥5.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166160053", "name" : "brexpiprazole", - "version" : 5 + "version" : 8 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166184527", "name" : "Annotation of DPWG Guideline for brexpiprazole and CYP2D6", - "version" : 13 + "version" : 99 }, "text" : { - "id" : 1452103668, - "html" : "

The guideline does not provide a recommendation for brexpiprazole in normal metabolizers.

\n", - "version" : 0 + "id" : 1452103676, + "html" : "

NO action is required for this gene-drug interaction.

\n", + "version" : 1 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302133", - "name" : "Recommendation Annotation PA166302133", + "id" : "PA166302136", + "name" : "Recommendation Annotation PA166302136", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -108566,33 +109580,33 @@ "implications" : [ "The gene variation results in a reduction of the exposure to brexpiprazole, but there are no indications supporting a decrease in efficacy." ], - "lookupKey" : {"CYP2D6": "≥3.0"}, + "lookupKey" : {"CYP2D6": "≥4.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166160053", "name" : "brexpiprazole", - "version" : 5 + "version" : 8 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166184527", "name" : "Annotation of DPWG Guideline for brexpiprazole and CYP2D6", - "version" : 13 + "version" : 99 }, "text" : { - "id" : 1452103672, + "id" : 1452103675, "html" : "

NO action is required for this gene-drug interaction.

\n", - "version" : 0 + "version" : 1 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302124", - "name" : "Recommendation Annotation PA166302124", + "id" : "PA166302135", + "name" : "Recommendation Annotation PA166302135", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -108606,35 +109620,35 @@ }, "dosingInformation" : false, "implications" : [ - "There are indications supporting an increase in the exposure to brexpiprazole, but no indications supporting an increase in side effects in patients with this gene variation." + "The gene variation results in a reduction of the exposure to brexpiprazole, but there are no indications supporting a decrease in efficacy." ], - "lookupKey" : {"CYP2D6": "0.75"}, + "lookupKey" : {"CYP2D6": "≥3.5"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166160053", "name" : "brexpiprazole", - "version" : 5 + "version" : 8 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166184527", "name" : "Annotation of DPWG Guideline for brexpiprazole and CYP2D6", - "version" : 13 + "version" : 99 }, "text" : { - "id" : 1452103663, + "id" : 1452103674, "html" : "

NO action is required for this gene-drug interaction.

\n", - "version" : 0 + "version" : 1 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302137", - "name" : "Recommendation Annotation PA166302137", + "id" : "PA166302134", + "name" : "Recommendation Annotation PA166302134", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -108650,69 +109664,70 @@ "implications" : [ "The gene variation results in a reduction of the exposure to brexpiprazole, but there are no indications supporting a decrease in efficacy." ], - "lookupKey" : {"CYP2D6": "≥5.0"}, + "lookupKey" : {"CYP2D6": "≥3.25"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166160053", "name" : "brexpiprazole", - "version" : 5 + "version" : 8 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166184527", "name" : "Annotation of DPWG Guideline for brexpiprazole and CYP2D6", - "version" : 13 + "version" : 99 }, "text" : { - "id" : 1452103676, + "id" : 1452103673, "html" : "

NO action is required for this gene-drug interaction.

\n", - "version" : 0 + "version" : 1 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302128", - "name" : "Recommendation Annotation PA166302128", + "id" : "PA166302133", + "name" : "Recommendation Annotation PA166302133", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, "dosingInformation" : false, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on brexpiprazole." + "The gene variation results in a reduction of the exposure to brexpiprazole, but there are no indications supporting a decrease in efficacy." ], - "lookupKey" : {"CYP2D6": "2.0"}, + "lookupKey" : {"CYP2D6": "≥3.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166160053", "name" : "brexpiprazole", - "version" : 5 + "version" : 8 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166184527", "name" : "Annotation of DPWG Guideline for brexpiprazole and CYP2D6", - "version" : 13 + "version" : 99 }, "text" : { - "id" : 1452103667, - "html" : "

The guideline does not provide a recommendation for brexpiprazole in normal metabolizers.

\n", - "version" : 0 + "id" : 1452103672, + "html" : "

NO action is required for this gene-drug interaction.

\n", + "version" : 1 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166184527" @@ -108964,7 +109979,7 @@ "objCls" : "Chemical", "id" : "PA448771", "name" : "capecitabine", - "version" : 21 + "version" : 60 } ], "relatedGenes" : [ @@ -108973,29 +109988,29 @@ "id" : "PA145", "symbol" : "DPYD", "name" : "dihydropyrimidine dehydrogenase", - "version" : 6907 + "version" : 6956 } ], "source" : "DPWG", "summaryMarkdown" : { "id" : 1447981934, "html" : "

An alternative drug to capecitabine is recommended for patients with a DPYD activity score of 0; if an alternative drug is not possible, the DPD activity should be determined and the initial dose adjusted accordingly. For patients with a DPYD activity score of 1 or 1.5, start with 50% of the standard dose or choose an alternative drug; adjustment of subsequent doses should be guided by toxicity and effectiveness. Patients with two partially functional alleles or one non-functional and one partially functional allele or two gene variants leading to partially functional alleles or a gene variant leading to a non-functional allele and a gene variant leading to a partially functional allele should have their DPD activity determined or should avoid fluorouracil/capecitabine. Tegafur is not an alternative for capecitabine, as it is also metabolized by DPD. The DPWG evaluated DPYD genotyping as "essential" and recommend DPYD testing prior to initiating fluoropyrimidines.

\n", - "version" : 3 + "version" : 4 }, "terms" : [], "textMarkdown" : { "id" : 1447981933, "html" : "

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

\n

Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction of DPYD and fluoropyrimidines. European journal of human genetics (2019)

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group published a paper with the guidelines as per the August 2019 update including more details and scoring the clinical implementation PMID: 31745289.

\n

August 2019 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for fluorouracil and capecitabine based on DPYD genotype. An alternative drug or reduction in dose is recommended for patients with DPYD activity scores of 0, 1 and 1.5. Patients with genotypes defined by the FENO group should have their DPD activity determined or should avoid fluorouracil/capecitabine. Tegafur is not an alternative, as it is also metabolized by DPD.

\n

Wording in table taken from the Dutch guidelines August 2019 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
Activity Score 0fluorouracil/capecitabine, systemicThe gene variation increases the risk of severe, potentially fatal toxicity. A reduced conversion of fluorouracil/capecitabine to inactive metabolites means that the standard dose is a more than 100-fold overdose.1. Avoid fluorouracil and capecitabine. Tegafur is not an alternative, as this is also metabolised by DPD.
2. If if is not possible to avoid fluorouracil and capecitabine: determine the residual DPD activity in mononuclear cells from peripheral blood and adjust the initial dose accordingly. A patient with 0.5% of the normal DPD activity tolerated 0.8% of the standard dose (150 mg capecitabine every 5 days). A patient with undetectable DPD activity tolerated 0.43% of the standard dose (150 mg capecitabine every 5 days with every third dose skipped).
Activity Score 1fluorouracil/capecitabineThe gene variation increases the risk of severe, potentially fatal toxicity. A reduced conversion of fluorouracil/capecitabine to inactive metabolites means that the normal dose is an overdose.Start with 50% of the standard dose or avoid fluorouracil and capecitabine. Adjustment of the subsequent dose should be guided by toxicity and effectiveness. However, in one study involving 17 patients with gene activity 1, the average dose after titration was 57% of the standard dose. Tegafur is not an alternative, as this is also metabolised by DPD.
Activity Score 1.5fluorouracil/capecitabineThe gene variation increases the risk of severe, potentially fatal toxicity. A reduced conversion of fluorouracil/capecitabine to inactive metabolites means that the normal dose is an overdose.Start with 50% of the standard dose or avoid fluorouracil and capecitabine. After starting treatment, the dose should be adjusted based on toxicity and effectiveness. In a study involving 17 patients with genotype 1/2846T, the average dose after titration was 64% of the standard dose. For 51 patients with genotype 1/1236A, the average dose after titration was 74% of the standard dose. Tegafur is not an alternative, as this is also metabolised by DPD.
FENOfluorouracil/capecitabineThe gene variation increases the risk of severe, potentially fatal, toxicity. A reduced conversion of fluorouracil/capecitabine to inactive metabolites means that the normal dose is an overdose.It is not possible to recommend a dose adjustment for this patient based on the genotype only.
Determine the residual DPD activity in mononuclear cells from peripheral blood and adjust the initial dose based on phenotype and genotype, or avoid fluorouracil and capecitabine. Tegafur is not an alternative, as this is also metabolized by DPD.
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for capecitabine and DPYD:

\n
\n

The Dutch Pharmacogenetics Working Group considers genotyping before starting systemic fluorouracil or capecitabine to be essential for drug safety. Genotyping must be performed before drug therapy has been initiated to guide drug and dose selection.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n

November 2018 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for fluorouracil and capecitabine based on DPYD genotype. An alternative drug or reduction in dose is recommended for patients with DPYD activity scores of 0, 0.5, 1 and 1.5. Tegafur is not an alternative, as it is also metabolized by DPD.

\n

Wording in table taken from the Dutch guidelines November 2018 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
Activity Score 0fluorouracil/capecitabine, systemicGenetic variation increases the risk of severe, potentially fatal toxicity. A reduced conversion of fluorouracil/capecitabine to inactive metabolites means that the standard dose is a more than 100-fold overdose.1. Choose an alternative. Tegafur is not an alternative, as this is also metabolised by DPD.
2. If an alternative is not possible: determine the residual DPD activity in mononuclear cells from peripheral blood and adjust the initial dose accordingly. A patient with 0.5% of the normal DPD activity tolerated 0.8% of the standard dose (150 mg capecitabine every 5 days). A patient with undetectable DPD activity tolerated 0.43% of the standard dose (150 mg capecitabine every 5 days with every third dose skipped). The average Caucasian DPD activity is 9.9 nmol/hour per mg protein. Or, adjust the initial dose based on toxicity and efficacy.
NOTE: If a patient has two different genetic variations that lead to a non-functional DPD enzyme (e.g. *2A and *13), this recommendation only applies if the variations are on a different allele. If both variations are on the same allele, this patient has gene activity score 1 and the recommendation for that gene activity score should be followed. These two situations can only be distinguished by determining the enzyme activity (phenotyping).
Activity Score 0.5fluorouracil/capecitabineGenetic variation increases the risk of severe, potentially fatal toxicity. A reduced conversion of fluorouracil/capecitabine to inactive metabolites means that the normal dose is an overdose.Start with 25% of the standard dose or choose an alternative. Adjustment of the initial dose should be guided by toxicity and effectiveness. Tegafur is not an alternative, as this is also metabolised by DPD.
NOTE: This recommendation only applies if the two genetic variations are on a different allele. If both variations are on the same allele, this patient has gene activity score 1 and the recommendation for that gene activity score should be followed. These two situations can only be distinguished by determining the enzyme activity (phenotyping).
Activity Score 1fluorouracil/capecitabineGenetic variation increases the risk of severe, potentially fatal toxicity. A reduced conversion of fluorouracil/capecitabine to inactive metabolites means that the normal dose is an overdose.Start with 50% of the standard dose or choose an alternative. Adjustment of the initial dose should be guided by toxicity and effectiveness. Tegafur is not an alternative, as this is also metabolised by DPD.
NB1: The dose reduction described here is well substantiated for *1/*2A and 1236A/1236A. The dose reduction for patients with 2846T (2846T/2846T or 1236A/2846T) is based on, among other factors, the dose reductions identified for *1/2846T.
NB2: If a patient has two different genetic variations that result in a partially functional DPD enzyme (e.g. 2846T and 1236A), this recommendation applies if the variations are on a different allele. If both variations are on the same allele, the gene activity score is between 1 and 1.5, depending on whether and how the two gene variations influence each other and on other factors that influence the DPD activity. Whether a gene activity score of 1 or 1.5 needs to be assigned in the case of two different genetic variations can only be determined by measuring the enzyme activity (phenotyping).
Activity Score 1.5fluorouracil/capecitabineGenetic variation increases the risk of severe, potentially fatal toxicity. A reduced conversion of fluorouracil/capecitabine to inactive metabolites means that the normal dose is an overdose.Start with 75% of the standard dose or choose an alternative. Adjustment of the initial dose should be guided by toxicity and effectiveness. Tegafur is not an alternative, as this is also metabolised by DPD.
\n

2011 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for capecitabine (a fluorouracil prodrug) based on DPYD genotype [Article:21412232]. They recommend that an alternate drug be used for poor metabolizer patients, and a reduced dose or alternate drug for intermediate metabolizer patients.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Phenotype (Genotype)Therapeutic Dose RecommendationLevel of EvidenceClinical Relevance
PM (2 inactive alleles, 2 decreased activity alleles, or one inactive and one decreased activity alleles)Select alterantive drug. Tegafur is not a suitable alternative because this drug is also metabolized by DPD.Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Clinical effect (S): death; arrhythmia; unanticipated myelosuppression.
IM (1 active allele and 1 inactive or decreased activity allele)Reduce dose by 50% or select alternative drug. Tegafur is not a suitable alternative because this drug is also a substrate for DPD. Increase dose in response to toxicity and efficacy.Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Clinical effect (S): death; arrhythmia; unanticipated myelosuppression.
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele TypeAlleles
active*1, *4, *5, *6, *9A
decreased activity*9B, *10
inactive*2A, *3, *7, *8, *11, *12, *13, 496A>G, IVS10-15T>C, 1156G>T, 1845G>T
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Start with 50% of the standard dose or avoid fluorouracil and capecitabine.

\n

After starting treatment, the dose should be adjusted based on toxicity and effectiveness. In a study involving 17 patients with genotype 1/2846T, the average dose after titration was 64% of the standard dose. For 51 patients with genotype 1/1236A, the average dose after titration was 74% of the standard dose. Tegafur is not an alternative, as this is also metabolised by DPD.

\n", + "id" : 1452061599, + "html" : "

It is not possible to recommend a dose adjustment for this patient based on the genotype only.

\n\n", "version" : 0 }, - "version" : 0 + "version" : 7 }, { "objCls" : "Recommendation Annotation", @@ -109059,21 +110074,21 @@ "objCls" : "Chemical", "id" : "PA448771", "name" : "capecitabine", - "version" : 21 + "version" : 60 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104963", "name" : "Annotation of DPWG Guideline for capecitabine and DPYD", - "version" : 33 + "version" : 69 }, "text" : { "id" : 1452061600, "html" : "

The guideline does not provide a recommendation for capecitabine in patients with a DPYD activity score of 2.

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Start with 50% of the standard dose or avoid fluorouracil and capecitabine.

\n

Adjustment of the subsequent dose should be guided by toxicity and effectiveness. However, in one study involving 17 patients with gene activity 1, the average dose after titration was 57% of the standard dose. Tegafur is not an alternative, as this is also metabolised by DPD.

\n", - "version" : 0 + "version" : 1 }, - "version" : 0 + "version" : 4 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299236", - "name" : "Recommendation PA166299236", + "id" : "PA166299235", + "name" : "Recommendation PA166299235", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -109132,32 +110147,74 @@ "valid" : true, "version" : 1 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ "The gene variation increases the risk of severe, potentially fatal toxicity. A reduced conversion of fluorouracil/capecitabine to inactive metabolites means that the normal dose is an overdose." ], - "lookupKey" : {"DPYD": "0.5 (Phenotyping)"}, + "lookupKey" : {"DPYD": "0.0 (Poor Metabolizer)"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448771", "name" : "capecitabine", - "version" : 21 + "version" : 60 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104963", "name" : "Annotation of DPWG Guideline for capecitabine and DPYD", - "version" : 33 + "version" : 69 }, "text" : { - "id" : 1452061599, - "html" : "

It is not possible to recommend a dose adjustment for this patient based on the genotype only.

\n\n", - "version" : 0 + "id" : 1452061598, + "html" : "

Avoid fluorouracil and capecitabine. Tegafur is not an alternative, as this is also metabolised by DPD.

\n

If it is not possible to avoid fluorouracil and capecitabine: determine the residual DPD activity in mononuclear cells from peripheral blood and adjust the initial dose accordingly.

\n

A patient with 0.5% of the normal DPD activity tolerated 0.8% of the standard dose (150 mg capecitabine every 5 days). A patient with undetectable DPD activity tolerated 0.43% of the standard dose (150 mg capecitabine every 5 days with every third dose skipped).

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Start with 50% of the standard dose or avoid fluorouracil and capecitabine.

\n

After starting treatment, the dose should be adjusted based on toxicity and effectiveness. In a study involving 17 patients with genotype 1/2846T, the average dose after titration was 64% of the standard dose. For 51 patients with genotype 1/1236A, the average dose after titration was 74% of the standard dose. Tegafur is not an alternative, as this is also metabolised by DPD.

\n", + "version" : 1 + }, + "version" : 5 }, { "objCls" : "Recommendation Annotation", @@ -109185,69 +110242,83 @@ "objCls" : "Chemical", "id" : "PA448771", "name" : "capecitabine", - "version" : 21 + "version" : 60 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104963", "name" : "Annotation of DPWG Guideline for capecitabine and DPYD", - "version" : 33 + "version" : 69 }, "text" : { "id" : 1452102460, "html" : "

It is not possible to recommend a dose adjustment for this patient based on the genotype only.

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Avoid fluorouracil and capecitabine. Tegafur is not an alternative, as this is also metabolised by DPD.

\n

If it is not possible to avoid fluorouracil and capecitabine: determine the residual DPD activity in mononuclear cells from peripheral blood and adjust the initial dose accordingly.

\n

A patient with 0.5% of the normal DPD activity tolerated 0.8% of the standard dose (150 mg capecitabine every 5 days). A patient with undetectable DPD activity tolerated 0.43% of the standard dose (150 mg capecitabine every 5 days with every third dose skipped).

\n", - "version" : 0 - }, - "version" : 0 + "day" : -1, + "hasKeyword" : true, + "journal" : "European journal of human genetics : EJHG", + "meshDiseases" : [], + "meshTerms" : [], + "month" : 4, + "nonHuman" : false, + "objCls" : "Literature", + "pediatric" : false, + "pgkbPublication" : false, + "pubDate" : "2024-04-01T00:00:00-07:00", + "summary" : "By developing evidence-based pharmacogenetics guidelines to optimize pharmacotherapy, the Dutch Pharmacogenetics Working Group (DPWG) aims to advance the implementation of pharmacogenetics (PGx). This guideline outlines the gene-drug interaction of CYP2C9 and HLA-B with phenytoin, HLA-A and HLA-B with carbamazepine and HLA-B with oxcarbazepine and lamotrigine. A systematic review was performed and pharmacotherapeutic recommendations were developed. For CYP2C9 intermediate and poor metabolisers, the DPWG recommends lowering the daily dose of phenytoin and adjust based on effect and serum concentration after 7-10 days. For HLA-B*15:02 carriers, the risk of severe cutaneous adverse events associated with phenytoin, carbamazepine, oxcarbazepine, and lamotrigine is strongly increased. For carbamazepine, this risk is also increased in HLA-B*15:11 and HLA-A*31:01 carriers. For HLA-B*15:02, HLA-B*15:11 and HLA-A*31:01 positive patients, the DPWG recommends choosing an alternative anti-epileptic drug. If not possible, it is recommended to advise the patient to report any rash while using carbamazepine, lamotrigine, oxcarbazepine or phenytoin immediately. Carbamazepine should not be used in an HLA-B*15:02 positive patient. DPWG considers CYP2C9 genotyping before the start of phenytoin \"essential\" for toxicity prevention. For patients with an ancestry in which the abovementioned HLA-alleles are prevalent, the DPWG considers HLA-B*15:02 genotyping before the start of carbamazepine, phenytoin, oxcarbazepine, and lamotrigine \"beneficial\", as well as genotyping for HLA-B*15:11 and HLA-A*31:01 before initiating carbamazepine.", + "terms" : [ + {"id":1451577480,"resource":"PGx Paper Types","term":"Implementation","termId":"pgxPaperTypes:1451577480"} + ], + "type" : "Literature", + "version" : 4, + "year" : 2024 } ], - "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166104963" - }, - { - "citations" : [], "guideline" : { "objCls" : "Guideline Annotation", "id" : "PA166265161", @@ -109320,9 +110391,18 @@ "description" : "Added alternative drug tag.", "type" : "Update", "version" : 0 + }, + { + "id" : 1452439740, + "date" : "2024-04-11T06:26:19.969-07:00", + "description" : "Added 2024 publication.", + "type" : "Update", + "version" : 0 } ], - "literature" : [], + "literature" : [ + {"id":15156470,"title":"Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction of CYP2C9, HLA-A and HLA-B with anti-epileptic drugs.","_sameAs":"https://www.ncbi.nlm.nih.gov/pubmed/38570725","crossReferences":[{"id":1452435716,"resource":"PubMed","resourceId":"38570725","_url":"https://www.ncbi.nlm.nih.gov/pubmed/38570725"},{"id":1452435717,"resource":"DOI","resourceId":"10.1038/s41431-024-01572-4","_url":"http://dx.doi.org/10.1038%2Fs41431-024-01572-4"}],"objCls":"Literature","pubDate":"2024-04-01T00:00:00-07:00","terms":[{"id":1451577480,"resource":"PGx Paper Types","term":"Implementation","termId":"pgxPaperTypes:1451577480"}],"type":"Literature"} + ], "otherPrescribingGuidance" : false, "pediatric" : false, "recommendation" : true, @@ -109332,7 +110412,7 @@ "id" : "PA165954030", "symbol" : "HLA-A*31:01", "name" : "*31:01", - "version" : 5 + "version" : 9 } ], "relatedChemicals" : [ @@ -109340,7 +110420,7 @@ "objCls" : "Chemical", "id" : "PA448785", "name" : "carbamazepine", - "version" : 14 + "version" : 47 } ], "relatedGenes" : [ @@ -109349,7 +110429,7 @@ "id" : "PA35055", "symbol" : "HLA-A", "name" : "major histocompatibility complex, class I, A", - "version" : 42 + "version" : 1500 } ], "source" : "DPWG", @@ -109362,10 +110442,10 @@ "textMarkdown" : { "id" : 1451697741, "html" : "

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

\n

May 2021 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group (DPWG) has evaluated recommendations for carbamazepine based on the presence of the HLA-A*3101 allele.

\n

Wording in table taken from the Dutch guidelines May 2021 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
HLA-A*3101carbamazepinePatients with this genetic variation have an increased risk of experiencing the life-threatening cutaneous adverse events DRESS and Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). The risk of carbamazepine-induced DRESS in these patients is 0.89%.1. carefully weigh the risk of DRESS and SJS/TEN against the benefits 2. if an alternative is an option, choose an alternative
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for carbamazepine and HLAs:

\n
\n

The KNMP Pharmacogenetics Working Group considers HLA-B*1502 genotyping of patients of Asian, other than\nJapanese descent, HLA-A*3101 genotyping, and HLA-B*1511 genotyping of patients of Han Chinese, Korean, Thai\nor Japanese descent before starting carbamazepine to be beneficial for drug safety. It is advised to consider genotyping these patients before (or directly after) drug therapy has been initiated to guide drug selection.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n", - "version" : 5 + "version" : 6 }, "userId" : "cfthorn", - "version" : 11 + "version" : 31 }, "recommendations" : [ { @@ -109394,27 +110474,83 @@ "objCls" : "Chemical", "id" : "PA448785", "name" : "carbamazepine", - "version" : 14 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166265161", "name" : "Annotation of DPWG Guideline for carbamazepine and HLA-A", - "version" : 11 + "version" : 31 }, "text" : { "id" : 1452061474, "html" : "\n", "version" : 0 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166265161" }, { - "citations" : [], + "citations" : [ + { + "id" : 15156470, + "title" : "Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction of CYP2C9, HLA-A and HLA-B with anti-epileptic drugs.", + "_sameAs" : "https://www.ncbi.nlm.nih.gov/pubmed/38570725", + "authors" : [ + "Manson Lisanne E N", + "Nijenhuis Marga", + "Soree Bianca", + "de Boer-Veger Nienke J", + "Buunk Anne-Marie", + "Houwink Elisa J F", + "Risselada Arne", + "Rongen Gerard A P J M", + "van Schaik Ron H N", + "Swen Jesse J", + "Touw Daan J", + "van Westrhenen Roos", + "Deneer Vera H M", + "Guchelaar Henk-Jan" + ], + "crossReferences" : [ + { + "id" : 1452435716, + "resource" : "PubMed", + "resourceId" : "38570725", + "_url" : "https://www.ncbi.nlm.nih.gov/pubmed/38570725", + "version" : 0 + }, + { + "id" : 1452435717, + "resource" : "DOI", + "resourceId" : "10.1038/s41431-024-01572-4", + "_url" : "http://dx.doi.org/10.1038%2Fs41431-024-01572-4", + "version" : 0 + } + ], + "day" : -1, + "hasKeyword" : true, + "journal" : "European journal of human genetics : EJHG", + "meshDiseases" : [], + "meshTerms" : [], + "month" : 4, + "nonHuman" : false, + "objCls" : "Literature", + "pediatric" : false, + "pgkbPublication" : false, + "pubDate" : "2024-04-01T00:00:00-07:00", + "summary" : "By developing evidence-based pharmacogenetics guidelines to optimize pharmacotherapy, the Dutch Pharmacogenetics Working Group (DPWG) aims to advance the implementation of pharmacogenetics (PGx). This guideline outlines the gene-drug interaction of CYP2C9 and HLA-B with phenytoin, HLA-A and HLA-B with carbamazepine and HLA-B with oxcarbazepine and lamotrigine. A systematic review was performed and pharmacotherapeutic recommendations were developed. For CYP2C9 intermediate and poor metabolisers, the DPWG recommends lowering the daily dose of phenytoin and adjust based on effect and serum concentration after 7-10 days. For HLA-B*15:02 carriers, the risk of severe cutaneous adverse events associated with phenytoin, carbamazepine, oxcarbazepine, and lamotrigine is strongly increased. For carbamazepine, this risk is also increased in HLA-B*15:11 and HLA-A*31:01 carriers. For HLA-B*15:02, HLA-B*15:11 and HLA-A*31:01 positive patients, the DPWG recommends choosing an alternative anti-epileptic drug. If not possible, it is recommended to advise the patient to report any rash while using carbamazepine, lamotrigine, oxcarbazepine or phenytoin immediately. Carbamazepine should not be used in an HLA-B*15:02 positive patient. DPWG considers CYP2C9 genotyping before the start of phenytoin \"essential\" for toxicity prevention. For patients with an ancestry in which the abovementioned HLA-alleles are prevalent, the DPWG considers HLA-B*15:02 genotyping before the start of carbamazepine, phenytoin, oxcarbazepine, and lamotrigine \"beneficial\", as well as genotyping for HLA-B*15:11 and HLA-A*31:01 before initiating carbamazepine.", + "terms" : [ + {"id":1451577480,"resource":"PGx Paper Types","term":"Implementation","termId":"pgxPaperTypes:1451577480"} + ], + "type" : "Literature", + "version" : 4, + "year" : 2024 + } + ], "guideline" : { "objCls" : "Guideline Annotation", "id" : "PA166265162", @@ -109480,9 +110616,18 @@ "description" : "Added alternative drug tag.", "type" : "Update", "version" : 0 + }, + { + "id" : 1452439760, + "date" : "2024-04-11T06:30:02.288-07:00", + "description" : "Added 2024 publication.", + "type" : "Update", + "version" : 0 } ], - "literature" : [], + "literature" : [ + {"id":15156470,"title":"Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction of CYP2C9, HLA-A and HLA-B with anti-epileptic drugs.","_sameAs":"https://www.ncbi.nlm.nih.gov/pubmed/38570725","crossReferences":[{"id":1452435716,"resource":"PubMed","resourceId":"38570725","_url":"https://www.ncbi.nlm.nih.gov/pubmed/38570725"},{"id":1452435717,"resource":"DOI","resourceId":"10.1038/s41431-024-01572-4","_url":"http://dx.doi.org/10.1038%2Fs41431-024-01572-4"}],"objCls":"Literature","pubDate":"2024-04-01T00:00:00-07:00","terms":[{"id":1451577480,"resource":"PGx Paper Types","term":"Implementation","termId":"pgxPaperTypes:1451577480"}],"type":"Literature"} + ], "otherPrescribingGuidance" : false, "pediatric" : false, "recommendation" : true, @@ -109492,14 +110637,14 @@ "id" : "PA165954769", "symbol" : "HLA-B*15:02", "name" : "*15:02", - "version" : 5 + "version" : 21 }, { "objCls" : "Haplotype", "id" : "PA165954787", "symbol" : "HLA-B*15:11", "name" : "*15:11", - "version" : 6 + "version" : 21 } ], "relatedChemicals" : [ @@ -109507,7 +110652,7 @@ "objCls" : "Chemical", "id" : "PA448785", "name" : "carbamazepine", - "version" : 14 + "version" : 47 } ], "relatedGenes" : [ @@ -109516,30 +110661,30 @@ "id" : "PA35056", "symbol" : "HLA-B", "name" : "major histocompatibility complex, class I, B", - "version" : 40 + "version" : 2920 } ], "source" : "DPWG", "summaryMarkdown" : { "id" : 1451697780, "html" : "

Consider an alternative drug to carbamazepine in patients with the HLA-B*15:02 or HLA-B*15:11 alleles.

\n", - "version" : 1 + "version" : 2 }, "terms" : [], "textMarkdown" : { "id" : 1451697743, "html" : "

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

\n

May 2021 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group (DPWG) has evaluated recommendations for carbamazepine based on the presence of the HLA-B*15:02 or *15:11 alleles.

\n

Wording in table taken from the Dutch guidelines May 2021 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
HLA-B*1502carbamazepinePatients with this genetic variation (HLA-B*1502) have a severely increased risk of experiencing the life-threatening cutaneous adverse event Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). The risk of carbamazepine-induced SJS/TEN in these patients is 1.8-3.4%.1. choose an alternative if possible Phenytoin, lamotrigine and oxcarbazepine also pose an increased risk of SJS/TEN in these patients, but the final risk is 10-fold lower for these medicines than for carbamazepine. Furthermore, in the case of oxcarbazepine, the most severe forms (SJS/TEN overlap and TEN) have not been observed.
HLA-B*1511carbamazepinePatients with this genetic variation (HLA-B*1511) have an increased risk of experiencing the life-threatening cutaneous adverse event Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). The risk of carbamazepine-induced SJS/TEN in patients with the HLA-B*1502 allele, which carries a 4.6-6.6 times higher risk than the HLA-B*1511 allele, is 1.8- 3.4%. This would equate to a risk of carbamazepine-induced SJS/TEN in these patients of 0.27-0.73%.1. carefully weigh the risk of SJS/TEN against the benefits 2. if an alternative is an option, choose an alternative
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for carbamazepine and HLAs:

\n
\n

The KNMP Pharmacogenetics Working Group considers HLA-B*1502 genotyping of patients of Asian, other than\nJapanese descent, HLA-A*3101 genotyping, and HLA-B*1511 genotyping of patients of Han Chinese, Korean, Thai\nor Japanese descent before starting carbamazepine to be beneficial for drug safety. It is advised to consider genotyping these patients before (or directly after) drug therapy has been initiated to guide drug selection.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n", - "version" : 6 + "version" : 8 }, "userId" : "cfthorn", - "version" : 8 + "version" : 54 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166299115", - "name" : "Recommendation PA166299115", - "alternateDrugAvailable" : true, + "id" : "PA166299116", + "name" : "Recommendation PA166299116", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -109552,35 +110697,35 @@ }, "dosingInformation" : false, "implications" : [ - "Patients with this genetic variation have a severely increased risk of experiencing the life-threatening cutaneous adverse event Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). The risk of carbamazepine-induced SJS/TEN in these patients is 1.8-3.4%." + "The guideline does not provide a description of the impact of the presence of both HLA-B*15:02 and HLA-B*15:11 alleles on carbamazepine." ], - "lookupKey" : {"HLA-B": "*15:02 positive"}, + "lookupKey" : {"HLA-B": "1511 and 1502"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448785", "name" : "carbamazepine", - "version" : 14 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166265162", "name" : "Annotation of DPWG Guideline for carbamazepine and HLA-B", - "version" : 8 + "version" : 54 }, "text" : { - "id" : 1452061478, - "html" : "\n", + "id" : 1452061479, + "html" : "

The guideline does not provide a recommendation for carbamazepine in patients with both HLA-B*15:02 and HLA-B*15:11 alleles or positive for both HLA-B*15:02 and HLA-B*15:11 tests.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299113", - "name" : "Recommendation PA166299113", + "id" : "PA166299115", + "name" : "Recommendation PA166299115", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -109594,36 +110739,36 @@ }, "dosingInformation" : false, "implications" : [ - "Patients with this genetic variation have an increased risk of experiencing the life-threatening cutaneous adverse event Stevens-Johnson syndrome/toxic epidermal necrolysis\n(SJS/TEN). The risk of carbamazepine-induced SJS/TEN in patients with the HLA-B*1502 allele, which carries a 4.6-6.6 times higher risk than the HLA-B*1511 allele, is 1.8- 3.4%. This would equate to a risk of carbamazepine-induced SJS/TEN in these patients of 0.27-0.73%." + "Patients with this genetic variation have a severely increased risk of experiencing the life-threatening cutaneous adverse event Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). The risk of carbamazepine-induced SJS/TEN in these patients is 1.8-3.4%." ], - "lookupKey" : {"HLA-B": "*15:11 positive"}, + "lookupKey" : {"HLA-B": "*15:02 positive"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448785", "name" : "carbamazepine", - "version" : 14 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166265162", "name" : "Annotation of DPWG Guideline for carbamazepine and HLA-B", - "version" : 8 + "version" : 54 }, "text" : { - "id" : 1452061476, - "html" : "\n", + "id" : 1452061478, + "html" : "\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299116", - "name" : "Recommendation PA166299116", - "alternateDrugAvailable" : false, + "id" : "PA166299113", + "name" : "Recommendation PA166299113", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -109636,30 +110781,30 @@ }, "dosingInformation" : false, "implications" : [ - "The guideline does not provide a description of the impact of the presence of both HLA-B*15:02 and HLA-B*15:11 alleles on carbamazepine." + "Patients with this genetic variation have an increased risk of experiencing the life-threatening cutaneous adverse event Stevens-Johnson syndrome/toxic epidermal necrolysis\n(SJS/TEN). The risk of carbamazepine-induced SJS/TEN in patients with the HLA-B*1502 allele, which carries a 4.6-6.6 times higher risk than the HLA-B*1511 allele, is 1.8- 3.4%. This would equate to a risk of carbamazepine-induced SJS/TEN in these patients of 0.27-0.73%." ], - "lookupKey" : {"HLA-B": "1511 and 1502"}, + "lookupKey" : {"HLA-B": "*15:11 positive"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448785", "name" : "carbamazepine", - "version" : 14 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166265162", "name" : "Annotation of DPWG Guideline for carbamazepine and HLA-B", - "version" : 8 + "version" : 54 }, "text" : { - "id" : 1452061479, - "html" : "

The guideline does not provide a recommendation for carbamazepine in patients with both HLA-B*15:02 and HLA-B*15:11 alleles or positive for both HLA-B*15:02 and HLA-B*15:11 tests.

\n", + "id" : 1452061476, + "html" : "\n", "version" : 0 }, - "version" : 0 + "version" : 2 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166265162" @@ -109852,7 +110997,7 @@ "date" : "2021-04-22T00:00:00-07:00", "description" : "Added extended dosing", "type" : "Update", - "version" : 0 + "version" : 1 }, { "id" : 1451632780, @@ -109933,7 +111078,7 @@ "objCls" : "Chemical", "id" : "PA449015", "name" : "citalopram", - "version" : 21 + "version" : 49 } ], "relatedGenes" : [ @@ -109942,29 +111087,29 @@ "id" : "PA124", "symbol" : "CYP2C19", "name" : "cytochrome P450 family 2 subfamily C member 19", - "version" : 7210 + "version" : 7266 } ], "source" : "DPWG", "summaryMarkdown" : { "id" : 1447982039, "html" : "

The Dutch Pharmacogenetics Working Group Guideline for citalopram recommends for intermediate and poor metabolizers of CYP2C19 to not exceed the in the DPWG document specified daily doses.

\n", - "version" : 1 + "version" : 3 }, "terms" : [], "textMarkdown" : { "id" : 1447982038, "html" : "

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

\n

Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction between CYP2C19 and CYP2D6 and SSRIs. European journal of human genetics (2021)

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group published a paper with the guidelines as per the November 2018 update and further details on the assessed literature [Article:34782755].

\n

November 2018 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for citalopram based on CYP2C19 genotype. They recommend to not exceed the below mentioned daily doses for intermediate metabolizer and poor metabolizer (for PM = 50% of the standard maximum dose).

\n

Wording in table taken from Dutch guidelines November 2018 update

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
CYP2C19 UMcitalopram-NO action is needed for this gene-drug interaction. The gene variation increases conversion of citalopram to a weakly active metabolite. However, there is no significant effect on the plasma concentration of citalopram, the tolerance or the response.
CYP2C19 IMcitalopramThe risk of QT prolongation and torsades de pointes is theoretically increased because the gene variation leads to an increased citalopram plasma concentration. If you follow the dose recommendation below, the increased plasma concentration and the theoretically increased risk of QT prolongation will be offset.Do not exceed the following daily doses:
1. Adults up to 65 years: 30mg as tablets or 22mg as drops,
2. Adults 65 years or older: 15mg as tablets or 10mg as drops
CYP2C19 PMcitalopramThe risk of QT prolongation and therefore also the theoretical risk of torsades de pointes is increased as the gene variation leads to an increased citalopram plasma concentration. If you follow the dose recommendation below, the increased plasma concentration and the increased risk of QT prolongation will be offset.Do not exceed the following daily doses (50% of the standard maximum dose):
1. adults up to 65 years: 20mg as tablets or 16mg as drops,
2. Adults 65 years or older: 10mg as tablets or 8mg as drops
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for citalopram and CYP2C19:

\n
\n

The Dutch Pharmacogenetics Working Group considers genotyping before starting citalopram to be potentially beneficial. Genotyping can be considered on an individual patient basis. If, however, the genotype is available, the Dutch Pharmacogenetics Working Group recommends adhering to the gene-drug guideline.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n

2011 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for citalopram based on CYP2C19 genotype [Article:21412232]. They conclude to monitor plasma concentration and titrate dose to a maximum of 150% in response to efficacy and adverse drug event or select alternative drug (e.g. fluoxetine, paroxetine) for the CYP2C19 UM phenotype.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Phenotype (Genotype)Therapeutic Dose RecommendationLevel of EvidenceClinical Relevance
CYP2C19 PM (*2/*2, *2/*3, *3/*3)NonePublished controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpointsMinor clinical effect (statistically significant difference): QTc prolongation (<450 ms female, <470 ms male); international normalized ratio (INR) increase < 4.5. Kinetic effect (statistically significant difference)
CYP2C19 IM (*1/*2, *1/*3, *17/*2, *17/*3)NonePublished controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpointsMinor clinical effect (statistically significant difference): QTc prolongation (<450 ms female, <470 ms male); INR increase < 4.5. Kinetic effect (statistically significant difference)
CYP2C19 UM (*17/*17)Monitor plasma concentration and titrate dose to a maximum of 150% in response to efficacy and adverse drug event or select alternative drug (e.g. fluoxetine, paroxetine)Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpointsMinor clinical effect (statistically significant difference): QTc prolongation (<450 ms female, <470 ms male); INR increase < 4.5. Kinetic effect (statistically significant difference)
\n\n", - "version" : 20 + "version" : 22 }, "userId" : "matt", - "version" : 36 + "version" : 74 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166299296", - "name" : "Recommendation PA166299296", + "id" : "PA166299297", + "name" : "Recommendation PA166299297", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -109976,74 +111121,32 @@ "valid" : true, "version" : 1 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "The risk of QT prolongation and torsades de pointes is theoretically increased because the gene variation leads to an increased citalopram plasma concentration. If you follow the dose recommendation below, the increased plasma concentration and the theoretically increased risk of QT prolongation will be offset." + "The gene variation increases conversion of citalopram to a weakly active metabolite. However, there is no significant effect on the plasma concentration of citalopram, the tolerance or the response." ], - "lookupKey" : {"CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449015", "name" : "citalopram", - "version" : 21 + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104977", "name" : "Annotation of DPWG Guideline for citalopram and CYP2C19", - "version" : 36 + "version" : 74 }, "text" : { - "id" : 1452061659, - "html" : "

Do not exceed the following daily doses:

\n
    \n
  1. Adults up to 65 years: 30mg as tablets or 22mg as drops,
    2. \n
  2. Adults 65 years or older: 15mg as tablets or 10mg as drops
    3. \n
\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166299295", - "name" : "Recommendation PA166299295", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 981501929, - "description" : "Not Applicable", - "parents" : [], - "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", - "valid" : true, + "id" : 1452061660, + "html" : "

No action is needed for this gene-drug interaction.

\n", "version" : 1 }, - "dosingInformation" : true, - "implications" : [ - "The risk of QT prolongation and therefore also the theoretical risk of torsades de pointes is increased as the gene variation leads to an increased citalopram plasma concentration. If you follow the dose recommendation below, the increased plasma concentration and the increased risk of QT prolongation will be offset." - ], - "lookupKey" : {"CYP2C19": "Poor Metabolizer"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA449015", - "name" : "citalopram", - "version" : 21 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166104977", - "name" : "Annotation of DPWG Guideline for citalopram and CYP2C19", - "version" : 36 - }, - "text" : { - "id" : 1452061658, - "html" : "

Do not exceed the following daily doses (50% of the standard maximum dose):

\n
    \n
  1. adults up to 65 years: 20mg as tablets or 16mg as drops,
    2. \n
  2. Adults 65 years or older: 10mg as tablets or 8mg as drops
    3. \n
\n", - "version" : 0 - }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", @@ -110070,26 +111173,26 @@ "objCls" : "Chemical", "id" : "PA449015", "name" : "citalopram", - "version" : 21 + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104977", "name" : "Annotation of DPWG Guideline for citalopram and CYP2C19", - "version" : 36 + "version" : 74 }, "text" : { "id" : 1452061661, "html" : "

The guideline does not provide a recommendation for citalopram in normal metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 4 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299297", - "name" : "Recommendation PA166299297", + "id" : "PA166299296", + "name" : "Recommendation PA166299296", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -110101,32 +111204,74 @@ "valid" : true, "version" : 1 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "The gene variation increases conversion of citalopram to a weakly active metabolite. However, there is no significant effect on the plasma concentration of citalopram, the tolerance or the response." + "The risk of QT prolongation and torsades de pointes is theoretically increased because the gene variation leads to an increased citalopram plasma concentration. If you follow the dose recommendation below, the increased plasma concentration and the theoretically increased risk of QT prolongation will be offset." ], - "lookupKey" : {"CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449015", "name" : "citalopram", - "version" : 21 + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104977", "name" : "Annotation of DPWG Guideline for citalopram and CYP2C19", - "version" : 36 + "version" : 74 }, "text" : { - "id" : 1452061660, - "html" : "

No action is needed for this gene-drug interaction.

\n", + "id" : 1452061659, + "html" : "

Do not exceed the following daily doses:

\n
    \n
  1. Adults up to 65 years: 30mg as tablets or 22mg as drops,
    2. \n
  2. Adults 65 years or older: 15mg as tablets or 10mg as drops
    3. \n
\n", "version" : 0 }, - "version" : 0 + "version" : 2 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166299295", + "name" : "Recommendation PA166299295", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501929, + "description" : "Not Applicable", + "parents" : [], + "resource" : "Guideline Strength", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", + "valid" : true, + "version" : 1 + }, + "dosingInformation" : true, + "implications" : [ + "The risk of QT prolongation and therefore also the theoretical risk of torsades de pointes is increased as the gene variation leads to an increased citalopram plasma concentration. If you follow the dose recommendation below, the increased plasma concentration and the increased risk of QT prolongation will be offset." + ], + "lookupKey" : {"CYP2C19": "Poor Metabolizer"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA449015", + "name" : "citalopram", + "version" : 49 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104977", + "name" : "Annotation of DPWG Guideline for citalopram and CYP2C19", + "version" : 74 + }, + "text" : { + "id" : 1452061658, + "html" : "

Do not exceed the following daily doses (50% of the standard maximum dose):

\n
    \n
  1. adults up to 65 years: 20mg as tablets or 16mg as drops,
    2. \n
  2. Adults 65 years or older: 10mg as tablets or 8mg as drops
    3. \n
\n", + "version" : 0 + }, + "version" : 2 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166104977" @@ -110169,7 +111314,7 @@ "date" : "2021-04-22T00:00:00-07:00", "description" : "Added extended dosing", "type" : "Update", - "version" : 0 + "version" : 1 }, { "id" : 1451704244, @@ -110232,7 +111377,7 @@ "date" : "2024-03-28T00:00:00-07:00", "description" : "Tags updated: [Alt Drug added]", "type" : "Update", - "version" : 0 + "version" : 1 } ], "literature" : [ @@ -110247,7 +111392,7 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "relatedGenes" : [ @@ -110256,7 +111401,7 @@ "id" : "PA124", "symbol" : "CYP2C19", "name" : "cytochrome P450 family 2 subfamily C member 19", - "version" : 7210 + "version" : 7266 } ], "source" : "DPWG", @@ -110269,10 +111414,10 @@ "textMarkdown" : { "id" : 1450820781, "html" : "

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

\n

August 2019 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for clomipramine based on CYP2C19 genotype. They recommend to avoid clomipramine for CYP2C19 ultrarapid metabolizer (UM) with regards to Indication OBSESSIVE COMPULSIVE DISORDER or ANXIETY DISORDERS.

\n

Wording in table taken from the Dutch guidelines August 2019 update

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
CYP2C19 UMclomipramineThe gene variation increases the risk of ineffectiveness for obsessive compulsive disorder and anxiety disorders by reducing the plasma concentration of clomipramine. The gene variation has little to no effect on the plasma concentration of clomipramine+desmethylclomipramine, which determines the efficacy for depression and side effects.Indication OBSESSIVE COMPULSIVE DISORDER or ANXIETY DISORDERS: avoid clomipramine. Antidepressants that are not metabolised by CYP2C19 - or to a lesser extent - include, for example, fluoxetine, fluvoxamine and paroxetine. If it is not possible to avoid clomipramine: monitor the effect and side effects or the plasma concentrations of clomipramine and desmethylclomipramine. For obsessive compulsive disorder, the therapeutic plasma concentration of clomipramine is greater than 200 ng/mL in combination with a plasma concentration of desmethylclomipramine that is as low as possible. For anxiety disorders, the therapeutic plasma concentration of clomipramine is approximately 100 ng/mL in combination with a plasma concentration of desmethylclomipramine lower than 200 ng/mL. A sum of the plasma concentrations of clomipramine and desmethylclomipramine exceeding 600 ng/mL is considered toxic. Add a low dose of fluvoxamine if necessary, to inhibit CYP2C19 and CYP1A2 and thereby inhibit the conversion of clomipramine to desmethylclomipramine. Indication DEPRESSION: no action required
CYP2C19 IMclomipramine-NO action is required for this gene-drug interaction. The gene variation does increase clomipramine plasma concentrations, but not clomipramine+desmethylclomipramine plasma concentrations, which determines side effects and efficacy in depression. The increase in the plasma concentration of clomipramine is favourable for the efficacy in anxiety and obsessive compulsive disorder.
CYP2C19 PMclomipramine-NO action is required for this gene-drug interaction. The gene variation increases the plasma concentration of clomipramine. However, there is insufficient evidence to substantiate an increase of the plasma concentration of clomipramine+desmethylclomipramine to such an extent that it increases the risk of side effects. The increase in the plasma concentration of clomipramine is favourable for the efficacy in anxiety and obsessive compulsive disorder.
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for clomipramine and CYP2C19:

\n
\n

The KNMP Pharmacogenetics Working Group considers genotyping before starting clomipramine to be potentially beneficial in patients with anxiety disorders and obsessive compulsive disorder. Genotyping can be considered on an individual patient basis. If, however, the genotype is available, the KNMP Pharmacogenetics Working Group recommends adhering to the gene-drug guideline.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n", - "version" : 6 + "version" : 7 }, "userId" : "katrin", - "version" : 11 + "version" : 41 }, "recommendations" : [ { @@ -110301,21 +111446,21 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166184528", "name" : "Annotation of DPWG Guideline for clomipramine and CYP2C19", - "version" : 11 + "version" : 41 }, "text" : { "id" : 1452061492, "html" : "

Indication OBSESSIVE COMPULSIVE DISORDER or ANXIETY DISORDERS: avoid clomipramine. Antidepressants that are not metabolised by CYP2C19 - or to a lesser extent - include, for example, fluoxetine, fluvoxamine and paroxetine. If it is not possible to avoid clomipramine: monitor the effect and side effects or the plasma concentrations of clomipramine and desmethylclomipramine. For obsessive compulsive disorder, the therapeutic plasma concentration of clomipramine is greater than 200 ng/mL in combination with a plasma concentration of desmethylclomipramine that is as low as possible. For anxiety disorders, the therapeutic plasma concentration of clomipramine is approximately 100 ng/mL in combination with a plasma concentration of desmethylclomipramine lower than 200 ng/mL. A sum of the plasma concentrations of clomipramine and desmethylclomipramine exceeding 600 ng/mL is considered toxic. Add a low dose of fluvoxamine if necessary, to inhibit CYP2C19 and CYP1A2 and thereby inhibit the conversion of clomipramine to desmethylclomipramine. Indication DEPRESSION: no action required

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", @@ -110343,21 +111488,21 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166184528", "name" : "Annotation of DPWG Guideline for clomipramine and CYP2C19", - "version" : 11 + "version" : 41 }, "text" : { "id" : 1452061495, "html" : "

NO action is required for this gene-drug interaction.

\n", - "version" : 0 + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", @@ -110384,21 +111529,21 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166184528", "name" : "Annotation of DPWG Guideline for clomipramine and CYP2C19", - "version" : 11 + "version" : 41 }, "text" : { "id" : 1452061494, "html" : "

The guideline does not provide a recommendation for clomipramine in normal metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 4 }, { "objCls" : "Recommendation Annotation", @@ -110426,21 +111571,21 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166184528", "name" : "Annotation of DPWG Guideline for clomipramine and CYP2C19", - "version" : 11 + "version" : 41 }, "text" : { "id" : 1452061493, "html" : "

NO action is required for this gene-drug interaction.

\n", - "version" : 0 + "version" : 1 }, - "version" : 0 + "version" : 2 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166184528" @@ -110562,7 +111707,7 @@ "date" : "2020-04-14T00:00:00-07:00", "description" : "Corrected description and recommendation for CYP2D6 UMs", "type" : "Update", - "version" : 0 + "version" : 1 }, { "id" : 1451431304, @@ -110656,7 +111801,7 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "relatedGenes" : [ @@ -110665,29 +111810,29 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "DPWG", "summaryMarkdown" : { "id" : 1447981906, "html" : "

The Dutch Pharmacogenetics Working Group Guideline for clomipramine recommends dose changes and to monitor the effect and side effects and the plasma concentrations to set the maintenance dose for CYP2D6 poor (PM), and intermediate (IM) metabolizer or to avoid clomipramine in PM and ultrarapid (UM) metabolizer.

\n", - "version" : 2 + "version" : 4 }, "terms" : [], "textMarkdown" : { "id" : 1447981905, "html" : "

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

\n

August 2019 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for clomipramine based on CYP2D6 genotype. They recommend dose changes and to monitor the effect and side effects and the plasma concentrations to set the maintenance dose for CYP2D6 poor (PM), and intermediate (IM) metabolizer or to avoid clomipramine in PM and ultrarapid (UM) metabolizer.

\n

Wording in table taken from the Dutch guidelines August 2019 update

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
CYP2D6 UMclomipramineThe risk of ineffectiveness and cardiotoxic side effects may be increased. The gene variation leads to reduced plasma concentrations of clomipramine and the active metabolite desmethylclomipramine and to increased concentrations of the potentially cardiotoxic hydroxy metabolites.Use 1.5 times the standard dose and monitor the effect and side effects of the plasma concentrations of clomipramine and desmethylclomipramine to set the maintenance dose. For depression, the therapeutic range is 200-400 ng/mL for the sum of the plasma concentrations of clomipramine and desmethylclomipramine. For anxiety disorders, the therapeutic plasma concentration of clomipramine is approximately 100 ng/mL, in combination with a plasma concentration of desmethylclomipramine lower than 200 ng/mL. For obsessive compulsive disorder, the therapeutic plasma concentration of clomipramine is higher than 200 ng/mL, in combination with a plasma concentration of desmethylclomipramine that is as low as possible. If a dose increase is not wanted due to potential cardiotoxic hydroxy metabolites: avoid clomipramine. Antidepressants that are not metabolised by CYP2D6, or to a lesser extent, include citalopram and sertraline.
CYP2D6 IMclomipramineThe risk of side effects may be increased, because the gene variation leads to increased plasma concentrations of clomipramine and the active metabolite desmethylclomipramine.Use 70% of the standard dose and monitor the effect and side effects or the plasma concentrations of clomipramine and desmethylclomipramine. For depression, the therapeutic range is 200-400 ng/mL for the sum of the plasma concentrations of clomipramine and desmethylclomipramine. For anxiety disorders, the therapeutic plasma concentration of clomipramine is approximately 100 ng/mL, in combination with a plasma concentration of desmethylclomipramine lower than 200 ng/mLFor obsessive compulsive disorder, the therapeutic plasma concentration of clomipramine is higher than 200 ng/mL, in combination with a plasma concentration of desmethylclomipramine that is as low as possible. A sum of the plasma concentrations of clomipramine and desmethylclomipramine higher than 600 ng/mL is considered toxic.
CYP2D6 PMclomipramineThe risk of side effects may be increased, because the gene variation leads to increased plasma concentrations of clomipramine and the active metabolite desmethylclomipramine.Indication DEPRESSION: use 50% of the standard dose and monitor the effect and side effects or the plasma concentrations of clomipramine and desmethylclomipramine in order to set the maintenance dose. The therapeutic range is 200-400 ng/mL for the sum of the plasma concentrations of clomipramine and desmethylclomipramine. Values higher than 600 ng/mL are considered toxic. Indication ANXIETY DISORDERS or OBSESSIVE COMPULSIVE DISORDER: if side effects occur: use 50% of the standard dose and monitor the effect and side effects or the plasma concentrations of clomipramine and desmethylclomipramine in order to set the maintenance dose. It is not known whether it is possible to reduce the dose to such an extent that the side effects disappear while the effectiveness is retained. Clomipramine and desmethylclomipramine both contribute to the side effects. Only clomipramine contributes to the effectiveness. For anxiety disorders, the therapeutic plasma concentration of clomipramine is approximately 100 ng/mL, in combination with a plasma concentration of desmethylclomipramine lower than 200 ng/mL. For obsessive compulsive disorder, the therapeutic plasma concentration of clomipramine is higher than 200 ng/mL, in combination with a plasma concentration of desmethylclomipramine that is as low as possible. A sum of the plasma concentrations of clomipramine and desmethylclomipramine higher than 600 ng/mL is considered toxic, whilst the therapeutic upper limit for depression is 400 ng/mL. If dose reduction does not have the desired effect: avoid clomipramine. Antidepressants that are not metabolised by CYP2D6, or to a lesser extent, include citalopram and sertraline.
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for clomipramine and CYP2D6:

\n
\n

The Dutch Pharmacogenetics Working Group considers genotyping before starting clomipramine to be potentially beneficial for the prevention of side effects and for drug efficacy. Genotyping can be considered on an individual patient basis. If, however, the genotype is available, the Dutch Pharmacogenetics Working Group recommends adhering to the gene-drug guideline.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n

November 2018 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for clomipramine based on CYP2D6 genotype. They recommend dose changes and to monitor the effect and side effects and the plasma concentrations to set the maintenance dose for CYP2D6 poor (PM), intermediate (IM), and ultrarapid (UM) metabolizer or to avoid clomipramine in PM and UM.

\n

Wording in table taken from Dutch guidelines November 2018 update

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
CYP2D6 UMclomipramineThe risk of ineffectiveness and cardiotoxic side effects may be increased. The gene variation leads to reduced plasma concentrations of clomipramine and the active metabolite desmethylclomipramine and to increased concentrations of the potentially cardiotoxic hydroxy metabolites.Use 1.5 times the standard dose and monitor the effect and side effects of the plasma concentrations of clomipramine and desmethylclomipramine to set the maintenance dose. For depression, the therapeutic range is 200-400 ng/mL for the sum of the plasma concentrations of clomipramine and desmethylclomipramine. For anxiety disorders, the therapeutic plasma concentration of clomipramine is approximately 100 ng/mL, in combination with a plasma concentration of desmethylclomipramine lower than 200 ng/mL. For obsessive compulsive disorder, the therapeutic plasma concentration of clomipramine is higher than 200 ng/mL, in combination with a plasma concentration of desmethylclomipramine that is as low as possible. If a dose increase is not wanted due to potential cardiotoxic hydroxy metabolites: avoid clomipramine. Antidepressants that are not metabolised by CYP2D6, or to a lesser extent, include citalopram and sertraline.
CYP2D6 IMclomipramineThe risk of side effects may be increased, because the gene variation leads to increased plasma concentrations of clomipramine and the active metabolite desmethylclomipramine.Use 70% of the standard dose and monitor the effect and side effects or the plasma concentrations of clomipramine and desmethylclomipramine. For depression, the therapeutic range is 200-400 ng/mL for the sum of the plasma concentrations of clomipramine and desmethylclomipramine. For anxiety disorders, the therapeutic plasma concentration of clomipramine is approximately 100 ng/mL, in combination with a plasma concentration of desmethylclomipramine lower than 200 ng/mL. For obsessive compulsive disorder, the therapeutic plasma concentration of clomipramine is higher than 200 ng/mL, in combination with a plasma concentration of desmethylclomipramine that is as low as possible. A sum of the plasma concentrations of clomipramine and desmethylclomipramine higher than 600 ng/mL is considered toxic.
CYP2D6 PMclomipramineThe risk of side effects may be increased, because the gene variation leads to increased plasma concentrations of clomipramine and the active metabolite desmethylclomipramine.Indication DEPRESSION: use 50% of the standard dose and monitor the effect and side effects or the plasma concentrations of clomipramine and desmethylclomipramine in order to set the maintenance dose. The therapeutic range is 200-400 ng/mL for the sum of the plasma concentrations of clomipramine and desmethylclomipramine. Values higher than 600 ng/mL are considered toxic. Indication ANXIETY DISORDERS or OBSESSIVE COMPULSIVE DISORDER: if side effects occur: use 50% of the standard dose and monitor the effect and side effects or the plasma concentrations of clomipramine and desmethylclomipramine in order to set the maintenance dose. It is not known whether it is possible to reduce the dose to such an extent that the side effects disappear while the effectiveness is retained. Clomipramine and desmethylclomipramine both contribute to the side effects. Only clomipramine contributes to the effectiveness. For anxiety disorders, the therapeutic plasma concentration of clomipramine is approximately 100 ng/mL, in combination with a plasma concentration of desmethylclomipramine lower than 200 ng/mL. For obsessive compulsive disorder, the therapeutic plasma concentration of clomipramine is higher than 200 ng/mL, in combination with a plasma concentration of desmethylclomipramine that is as low as possible. A sum of the plasma concentrations of clomipramine and desmethylclomipramine higher than 600 ng/mL is considered toxic, whilst the therapeutic upper limit for depression is 400 ng/mL. If dose reduction does not have the desired effect: avoid clomipramine. Antidepressants that are not metabolised by CYP2D6, or to a lesser extent, include citalopram and sertraline.
\n

2011 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for clomipramine based on CYP2D6 genotypes [Article:21412232]. They recommend lower dose for patients carrying the poor metabolizer (PM) alleles and alternative drug for patients carrying the ultrarapid metabolizer (UM) allleles.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Phenotype (Genotype)Therapeutic Dose RecommendationLevel of EvidenceClinical Relevance
PM (two inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) alleles)Reduce dose by 50% and monitor (desmethyl) clomipramine plasma concentration.Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Clinical effect (S): long-standing discomfort (48-168 hr) without permanent injury e.g. failure of therapy with tricyclic antidepressants, atypical antipsychotic drugs; extrapyramidal side effects; parkinsonism; ADE resulting from increased bioavailability of tricyclic antidepressants, metoprolol, propafenone (central effects e.g. dizziness); INR 4.5-6.0; neutropenia 1.0-1.5x109/l; leucopenia 2.0-3.0x109/l; thrombocytopenia 50-75x109/l.
IM (two decreased-activity (*9, *10, *17, *29, *36, *41) alleles or carrying one active (*1, *2, *33, *35) and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele, or carrying one decreased-activity (*9, *10, *17, *29, *36, *41) allele and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele)Insufficient data to allow calculation of dose adjustment. Monitor (desmethyl)clomipramine plasma concentrationPublished controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Clinical effect (S): long-standing discomfort (48-168 hr) without permanent injury e.g. failure of therapy with tricyclic antidepressants, atypical antipsychotic drugs; extrapyramidal side effects; parkinsonism; ADE resulting from increased bioavailability of tricyclic antidepressants, metoprolol, propafenone (central effects e.g. dizziness); INR 4.5-6.0; neutropenia 1.0-1.5x109/l; leucopenia 2.0-3.0x109/l; thrombocytopenia 50-75x109/l.
UM (a gene duplication in absence of inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) or decreased-activity (*9, *10, *17, *29, *36, *41) alleles)Select alternative drug (e.g., citalopram, sertralin) or monitor (desmethyl)clomipramine plasma concentration.Published case reports, well documented, and having relevant pharmacokinetic or clinical endpoints. Well documented case series.Clinical effect (S): long-standing discomfort (48-168 hr) without permanent injury e.g. failure of therapy with tricyclic antidepressants, atypical antipsychotic drugs; extrapyramidal side effects; parkinsonism; ADE resulting from increased bioavailability of tricyclic antidepressants, metoprolol, propafenone (central effects e.g. dizziness); INR 4.5-6.0; neutropenia 1.0-1.5x109/l; leucopenia 2.0-3.0x109/l; thrombocytopenia 50-75x109/l.
\n\n", - "version" : 18 + "version" : 25 }, "userId" : "cfthorn", - "version" : 34 + "version" : 112 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166302150", - "name" : "Recommendation Annotation PA166302150", + "id" : "PA166302139", + "name" : "Recommendation Annotation PA166302139", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -110701,36 +111846,36 @@ }, "dosingInformation" : true, "implications" : [ - "The risk of ineffectiveness and cardiotoxic side effects may be increased. The gene variation leads to reduced plasma concentrations of clomipramine and the active metabolite desmethylclomipramine and to increased concentrations of the potentially cardiotoxic hydroxy metabolites." + "The risk of side effects may be increased, because the gene variation leads to increased plasma concentrations of clomipramine and the active metabolite desmethylclomipramine." ], - "lookupKey" : {"CYP2D6": "4.0"}, + "lookupKey" : {"CYP2D6": "0.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104964", "name" : "Annotation of DPWG Guideline for clomipramine and CYP2D6", - "version" : 34 + "version" : 112 }, "text" : { - "id" : 1452103689, - "html" : "

Use 1.5 times the standard dose and monitor the effect and side effects of the plasma concentrations of clomipramine and desmethylclomipramine to set the maintenance dose.

\n

For depression, the therapeutic range is 200-400 ng/mL for the sum of the plasma concentrations of clomipramine and desmethylclomipramine. For anxiety disorders, the therapeutic plasma concentration of clomipramine is approximately 100 ng/mL, in combination with a plasma concentration of desmethylclomipramine lower than 200 ng/mL. For obsessive compulsive disorder, the therapeutic plasma concentration of clomipramine is higher than 200 ng/mL, in combination with a plasma concentration of desmethylclomipramine that is as low as possible.

\n

If a dose increase is not wanted due to potential cardiotoxic hydroxy metabolites: avoid clomipramine. Antidepressants that are not metabolised by CYP2D6, or to a lesser extent, include citalopram and sertraline.

\n", + "id" : 1452103678, + "html" : "

Indication DEPRESSION: use 50% of the standard dose and monitor the effect and side effects or the plasma concentrations of clomipramine and desmethylclomipramine in order to set the maintenance dose. The therapeutic range is 200-400 ng/mL for the sum of the plasma concentrations of clomipramine and desmethylclomipramine. Values higher than 600 ng/mL are considered toxic.

\n

Indication ANXIETY DISORDERS or OBSESSIVE COMPULSIVE DISORDER: if side effects occur: use 50% of the standard dose and monitor the effect and side effects or the plasma concentrations of clomipramine and desmethylclomipramine in order to set the maintenance dose. It is not known whether it is possible to reduce the dose to such an extent that the side effects disappear while the effectiveness is retained. Clomipramine and desmethylclomipramine both contribute to the side effects. Only clomipramine contributes to the effectiveness.

\n

For anxiety disorders, the therapeutic plasma concentration of clomipramine is approximately 100 ng/mL, in combination with a plasma concentration of desmethylclomipramine lower than 200 ng/mL. For obsessive compulsive disorder, the therapeutic plasma concentration of clomipramine is higher than 200 ng/mL, in combination with a plasma concentration of desmethylclomipramine that is as low as possible. A sum of the plasma concentrations of clomipramine and desmethylclomipramine higher than 600 ng/mL is considered toxic, whilst the therapeutic upper limit for depression is 400 ng/mL.

\n

If dose reduction does not have the desired effect: avoid clomipramine. Antidepressants that are not metabolised by CYP2D6, or to a lesser extent, include citalopram and sertraline.

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Use 1.5 times the standard dose and monitor the effect and side effects of the plasma concentrations of clomipramine and desmethylclomipramine to set the maintenance dose.

\n

For depression, the therapeutic range is 200-400 ng/mL for the sum of the plasma concentrations of clomipramine and desmethylclomipramine. For anxiety disorders, the therapeutic plasma concentration of clomipramine is approximately 100 ng/mL, in combination with a plasma concentration of desmethylclomipramine lower than 200 ng/mL. For obsessive compulsive disorder, the therapeutic plasma concentration of clomipramine is higher than 200 ng/mL, in combination with a plasma concentration of desmethylclomipramine that is as low as possible.

\n

If a dose increase is not wanted due to potential cardiotoxic hydroxy metabolites: avoid clomipramine. Antidepressants that are not metabolised by CYP2D6, or to a lesser extent, include citalopram and sertraline.

\n", + "id" : 1452103679, + "html" : "

Use 70% of the standard dose and monitor the effect and side effects or the plasma concentrations of clomipramine and desmethylclomipramine.

\n

For depression, the therapeutic range is 200-400 ng/mL for the sum of the plasma concentrations of clomipramine and desmethylclomipramine. For anxiety disorders, the therapeutic plasma concentration of clomipramine is approximately 100 ng/mL, in combination with a plasma concentration of desmethylclomipramine lower than 200 ng/mL. For obsessive compulsive disorder, the therapeutic plasma concentration of clomipramine is higher than 200 ng/mL, in combination with a plasma concentration of desmethylclomipramine that is as low as possible. A sum of the plasma concentrations of clomipramine and desmethylclomipramine higher than 600 ng/mL is considered toxic.

\n", "version" : 0 }, "version" : 0 @@ -110794,14 +111939,14 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104964", "name" : "Annotation of DPWG Guideline for clomipramine and CYP2D6", - "version" : 34 + "version" : 112 }, "text" : { "id" : 1452103680, @@ -110812,50 +111957,9 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302145", - "name" : "Recommendation Annotation PA166302145", + "id" : "PA166302142", + "name" : "Recommendation Annotation PA166302142", "alternateDrugAvailable" : false, - "classification" : { - "id" : 1448526251, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on clomipramine." - ], - "lookupKey" : {"CYP2D6": "1.5"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA449048", - "name" : "clomipramine", - "version" : 7 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166104964", - "name" : "Annotation of DPWG Guideline for clomipramine and CYP2D6", - "version" : 34 - }, - "text" : { - "id" : 1452103684, - "html" : "

The guideline does not provide a recommendation for clomipramine in normal metabolizers.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166302149", - "name" : "Recommendation Annotation PA166302149", - "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -110868,35 +111972,35 @@ }, "dosingInformation" : true, "implications" : [ - "The risk of ineffectiveness and cardiotoxic side effects may be increased. The gene variation leads to reduced plasma concentrations of clomipramine and the active metabolite desmethylclomipramine and to increased concentrations of the potentially cardiotoxic hydroxy metabolites." + "The risk of side effects may be increased, because the gene variation leads to increased plasma concentrations of clomipramine and the active metabolite desmethylclomipramine." ], - "lookupKey" : {"CYP2D6": "3.0"}, + "lookupKey" : {"CYP2D6": "0.75"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104964", "name" : "Annotation of DPWG Guideline for clomipramine and CYP2D6", - "version" : 34 + "version" : 112 }, "text" : { - "id" : 1452103688, - "html" : "

Use 1.5 times the standard dose and monitor the effect and side effects of the plasma concentrations of clomipramine and desmethylclomipramine to set the maintenance dose.

\n

For depression, the therapeutic range is 200-400 ng/mL for the sum of the plasma concentrations of clomipramine and desmethylclomipramine. For anxiety disorders, the therapeutic plasma concentration of clomipramine is approximately 100 ng/mL, in combination with a plasma concentration of desmethylclomipramine lower than 200 ng/mL. For obsessive compulsive disorder, the therapeutic plasma concentration of clomipramine is higher than 200 ng/mL, in combination with a plasma concentration of desmethylclomipramine that is as low as possible.

\n

If a dose increase is not wanted due to potential cardiotoxic hydroxy metabolites: avoid clomipramine. Antidepressants that are not metabolised by CYP2D6, or to a lesser extent, include citalopram and sertraline.

\n", + "id" : 1452103681, + "html" : "

Use 70% of the standard dose and monitor the effect and side effects or the plasma concentrations of clomipramine and desmethylclomipramine.

\n

For depression, the therapeutic range is 200-400 ng/mL for the sum of the plasma concentrations of clomipramine and desmethylclomipramine. For anxiety disorders, the therapeutic plasma concentration of clomipramine is approximately 100 ng/mL, in combination with a plasma concentration of desmethylclomipramine lower than 200 ng/mL. For obsessive compulsive disorder, the therapeutic plasma concentration of clomipramine is higher than 200 ng/mL, in combination with a plasma concentration of desmethylclomipramine that is as low as possible. A sum of the plasma concentrations of clomipramine and desmethylclomipramine higher than 600 ng/mL is considered toxic.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302140", - "name" : "Recommendation Annotation PA166302140", + "id" : "PA166302143", + "name" : "Recommendation Annotation PA166302143", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -110912,24 +112016,24 @@ "implications" : [ "The risk of side effects may be increased, because the gene variation leads to increased plasma concentrations of clomipramine and the active metabolite desmethylclomipramine." ], - "lookupKey" : {"CYP2D6": "0.25"}, + "lookupKey" : {"CYP2D6": "1.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104964", "name" : "Annotation of DPWG Guideline for clomipramine and CYP2D6", - "version" : 34 + "version" : 112 }, "text" : { - "id" : 1452103679, + "id" : 1452103682, "html" : "

Use 70% of the standard dose and monitor the effect and side effects or the plasma concentrations of clomipramine and desmethylclomipramine.

\n

For depression, the therapeutic range is 200-400 ng/mL for the sum of the plasma concentrations of clomipramine and desmethylclomipramine. For anxiety disorders, the therapeutic plasma concentration of clomipramine is approximately 100 ng/mL, in combination with a plasma concentration of desmethylclomipramine lower than 200 ng/mL. For obsessive compulsive disorder, the therapeutic plasma concentration of clomipramine is higher than 200 ng/mL, in combination with a plasma concentration of desmethylclomipramine that is as low as possible. A sum of the plasma concentrations of clomipramine and desmethylclomipramine higher than 600 ng/mL is considered toxic.

\n", "version" : 0 }, @@ -110937,8 +112041,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302153", - "name" : "Recommendation Annotation PA166302153", + "id" : "PA166302149", + "name" : "Recommendation Annotation PA166302149", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -110954,24 +112058,24 @@ "implications" : [ "The risk of ineffectiveness and cardiotoxic side effects may be increased. The gene variation leads to reduced plasma concentrations of clomipramine and the active metabolite desmethylclomipramine and to increased concentrations of the potentially cardiotoxic hydroxy metabolites." ], - "lookupKey" : {"CYP2D6": "≥3.5"}, + "lookupKey" : {"CYP2D6": "3.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104964", "name" : "Annotation of DPWG Guideline for clomipramine and CYP2D6", - "version" : 34 + "version" : 112 }, "text" : { - "id" : 1452103692, + "id" : 1452103688, "html" : "

Use 1.5 times the standard dose and monitor the effect and side effects of the plasma concentrations of clomipramine and desmethylclomipramine to set the maintenance dose.

\n

For depression, the therapeutic range is 200-400 ng/mL for the sum of the plasma concentrations of clomipramine and desmethylclomipramine. For anxiety disorders, the therapeutic plasma concentration of clomipramine is approximately 100 ng/mL, in combination with a plasma concentration of desmethylclomipramine lower than 200 ng/mL. For obsessive compulsive disorder, the therapeutic plasma concentration of clomipramine is higher than 200 ng/mL, in combination with a plasma concentration of desmethylclomipramine that is as low as possible.

\n

If a dose increase is not wanted due to potential cardiotoxic hydroxy metabolites: avoid clomipramine. Antidepressants that are not metabolised by CYP2D6, or to a lesser extent, include citalopram and sertraline.

\n", "version" : 0 }, @@ -110979,90 +112083,50 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302144", - "name" : "Recommendation Annotation PA166302144", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 1448526251, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on clomipramine." - ], - "lookupKey" : {"CYP2D6": "1.25"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA449048", - "name" : "clomipramine", - "version" : 7 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166104964", - "name" : "Annotation of DPWG Guideline for clomipramine and CYP2D6", - "version" : 34 - }, - "text" : { - "id" : 1452103683, - "html" : "

The guideline does not provide a recommendation for clomipramine in normal metabolizers.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166302148", - "name" : "Recommendation Annotation PA166302148", - "alternateDrugAvailable" : false, + "id" : "PA166302150", + "name" : "Recommendation Annotation PA166302150", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on clomipramine." + "The risk of ineffectiveness and cardiotoxic side effects may be increased. The gene variation leads to reduced plasma concentrations of clomipramine and the active metabolite desmethylclomipramine and to increased concentrations of the potentially cardiotoxic hydroxy metabolites." ], - "lookupKey" : {"CYP2D6": "2.5"}, + "lookupKey" : {"CYP2D6": "4.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104964", "name" : "Annotation of DPWG Guideline for clomipramine and CYP2D6", - "version" : 34 + "version" : 112 }, "text" : { - "id" : 1452103687, - "html" : "

The guideline does not provide a recommendation for clomipramine in normal metabolizers.

\n", + "id" : 1452103689, + "html" : "

Use 1.5 times the standard dose and monitor the effect and side effects of the plasma concentrations of clomipramine and desmethylclomipramine to set the maintenance dose.

\n

For depression, the therapeutic range is 200-400 ng/mL for the sum of the plasma concentrations of clomipramine and desmethylclomipramine. For anxiety disorders, the therapeutic plasma concentration of clomipramine is approximately 100 ng/mL, in combination with a plasma concentration of desmethylclomipramine lower than 200 ng/mL. For obsessive compulsive disorder, the therapeutic plasma concentration of clomipramine is higher than 200 ng/mL, in combination with a plasma concentration of desmethylclomipramine that is as low as possible.

\n

If a dose increase is not wanted due to potential cardiotoxic hydroxy metabolites: avoid clomipramine. Antidepressants that are not metabolised by CYP2D6, or to a lesser extent, include citalopram and sertraline.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302139", - "name" : "Recommendation Annotation PA166302139", + "id" : "PA166302151", + "name" : "Recommendation Annotation PA166302151", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -111076,27 +112140,27 @@ }, "dosingInformation" : true, "implications" : [ - "The risk of side effects may be increased, because the gene variation leads to increased plasma concentrations of clomipramine and the active metabolite desmethylclomipramine." + "The risk of ineffectiveness and cardiotoxic side effects may be increased. The gene variation leads to reduced plasma concentrations of clomipramine and the active metabolite desmethylclomipramine and to increased concentrations of the potentially cardiotoxic hydroxy metabolites." ], - "lookupKey" : {"CYP2D6": "0.0"}, + "lookupKey" : {"CYP2D6": "≥3.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104964", "name" : "Annotation of DPWG Guideline for clomipramine and CYP2D6", - "version" : 34 + "version" : 112 }, "text" : { - "id" : 1452103678, - "html" : "

Indication DEPRESSION: use 50% of the standard dose and monitor the effect and side effects or the plasma concentrations of clomipramine and desmethylclomipramine in order to set the maintenance dose. The therapeutic range is 200-400 ng/mL for the sum of the plasma concentrations of clomipramine and desmethylclomipramine. Values higher than 600 ng/mL are considered toxic.

\n

Indication ANXIETY DISORDERS or OBSESSIVE COMPULSIVE DISORDER: if side effects occur: use 50% of the standard dose and monitor the effect and side effects or the plasma concentrations of clomipramine and desmethylclomipramine in order to set the maintenance dose. It is not known whether it is possible to reduce the dose to such an extent that the side effects disappear while the effectiveness is retained. Clomipramine and desmethylclomipramine both contribute to the side effects. Only clomipramine contributes to the effectiveness.

\n

For anxiety disorders, the therapeutic plasma concentration of clomipramine is approximately 100 ng/mL, in combination with a plasma concentration of desmethylclomipramine lower than 200 ng/mL. For obsessive compulsive disorder, the therapeutic plasma concentration of clomipramine is higher than 200 ng/mL, in combination with a plasma concentration of desmethylclomipramine that is as low as possible. A sum of the plasma concentrations of clomipramine and desmethylclomipramine higher than 600 ng/mL is considered toxic, whilst the therapeutic upper limit for depression is 400 ng/mL.

\n

If dose reduction does not have the desired effect: avoid clomipramine. Antidepressants that are not metabolised by CYP2D6, or to a lesser extent, include citalopram and sertraline.

\n", + "id" : 1452103690, + "html" : "

Use 1.5 times the standard dose and monitor the effect and side effects of the plasma concentrations of clomipramine and desmethylclomipramine to set the maintenance dose.

\n

For depression, the therapeutic range is 200-400 ng/mL for the sum of the plasma concentrations of clomipramine and desmethylclomipramine. For anxiety disorders, the therapeutic plasma concentration of clomipramine is approximately 100 ng/mL, in combination with a plasma concentration of desmethylclomipramine lower than 200 ng/mL. For obsessive compulsive disorder, the therapeutic plasma concentration of clomipramine is higher than 200 ng/mL, in combination with a plasma concentration of desmethylclomipramine that is as low as possible.

\n

If a dose increase is not wanted due to potential cardiotoxic hydroxy metabolites: avoid clomipramine. Antidepressants that are not metabolised by CYP2D6, or to a lesser extent, include citalopram and sertraline.

\n", "version" : 0 }, "version" : 0 @@ -111127,14 +112191,14 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104964", "name" : "Annotation of DPWG Guideline for clomipramine and CYP2D6", - "version" : 34 + "version" : 112 }, "text" : { "id" : 1452103691, @@ -111145,8 +112209,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302156", - "name" : "Recommendation Annotation PA166302156", + "id" : "PA166302153", + "name" : "Recommendation Annotation PA166302153", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -111162,24 +112226,24 @@ "implications" : [ "The risk of ineffectiveness and cardiotoxic side effects may be increased. The gene variation leads to reduced plasma concentrations of clomipramine and the active metabolite desmethylclomipramine and to increased concentrations of the potentially cardiotoxic hydroxy metabolites." ], - "lookupKey" : {"CYP2D6": "≥6.0"}, + "lookupKey" : {"CYP2D6": "≥3.5"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104964", "name" : "Annotation of DPWG Guideline for clomipramine and CYP2D6", - "version" : 34 + "version" : 112 }, "text" : { - "id" : 1452103695, + "id" : 1452103692, "html" : "

Use 1.5 times the standard dose and monitor the effect and side effects of the plasma concentrations of clomipramine and desmethylclomipramine to set the maintenance dose.

\n

For depression, the therapeutic range is 200-400 ng/mL for the sum of the plasma concentrations of clomipramine and desmethylclomipramine. For anxiety disorders, the therapeutic plasma concentration of clomipramine is approximately 100 ng/mL, in combination with a plasma concentration of desmethylclomipramine lower than 200 ng/mL. For obsessive compulsive disorder, the therapeutic plasma concentration of clomipramine is higher than 200 ng/mL, in combination with a plasma concentration of desmethylclomipramine that is as low as possible.

\n

If a dose increase is not wanted due to potential cardiotoxic hydroxy metabolites: avoid clomipramine. Antidepressants that are not metabolised by CYP2D6, or to a lesser extent, include citalopram and sertraline.

\n", "version" : 0 }, @@ -111187,9 +112251,9 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302143", - "name" : "Recommendation Annotation PA166302143", - "alternateDrugAvailable" : false, + "id" : "PA166302154", + "name" : "Recommendation Annotation PA166302154", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -111202,76 +112266,77 @@ }, "dosingInformation" : true, "implications" : [ - "The risk of side effects may be increased, because the gene variation leads to increased plasma concentrations of clomipramine and the active metabolite desmethylclomipramine." + "The risk of ineffectiveness and cardiotoxic side effects may be increased. The gene variation leads to reduced plasma concentrations of clomipramine and the active metabolite desmethylclomipramine and to increased concentrations of the potentially cardiotoxic hydroxy metabolites." ], - "lookupKey" : {"CYP2D6": "1.0"}, + "lookupKey" : {"CYP2D6": "≥4.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104964", "name" : "Annotation of DPWG Guideline for clomipramine and CYP2D6", - "version" : 34 + "version" : 112 }, "text" : { - "id" : 1452103682, - "html" : "

Use 70% of the standard dose and monitor the effect and side effects or the plasma concentrations of clomipramine and desmethylclomipramine.

\n

For depression, the therapeutic range is 200-400 ng/mL for the sum of the plasma concentrations of clomipramine and desmethylclomipramine. For anxiety disorders, the therapeutic plasma concentration of clomipramine is approximately 100 ng/mL, in combination with a plasma concentration of desmethylclomipramine lower than 200 ng/mL. For obsessive compulsive disorder, the therapeutic plasma concentration of clomipramine is higher than 200 ng/mL, in combination with a plasma concentration of desmethylclomipramine that is as low as possible. A sum of the plasma concentrations of clomipramine and desmethylclomipramine higher than 600 ng/mL is considered toxic.

\n", + "id" : 1452103693, + "html" : "

Use 1.5 times the standard dose and monitor the effect and side effects of the plasma concentrations of clomipramine and desmethylclomipramine to set the maintenance dose.

\n

For depression, the therapeutic range is 200-400 ng/mL for the sum of the plasma concentrations of clomipramine and desmethylclomipramine. For anxiety disorders, the therapeutic plasma concentration of clomipramine is approximately 100 ng/mL, in combination with a plasma concentration of desmethylclomipramine lower than 200 ng/mL. For obsessive compulsive disorder, the therapeutic plasma concentration of clomipramine is higher than 200 ng/mL, in combination with a plasma concentration of desmethylclomipramine that is as low as possible.

\n

If a dose increase is not wanted due to potential cardiotoxic hydroxy metabolites: avoid clomipramine. Antidepressants that are not metabolised by CYP2D6, or to a lesser extent, include citalopram and sertraline.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302147", - "name" : "Recommendation Annotation PA166302147", - "alternateDrugAvailable" : false, + "id" : "PA166302155", + "name" : "Recommendation Annotation PA166302155", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on clomipramine." + "The risk of ineffectiveness and cardiotoxic side effects may be increased. The gene variation leads to reduced plasma concentrations of clomipramine and the active metabolite desmethylclomipramine and to increased concentrations of the potentially cardiotoxic hydroxy metabolites." ], - "lookupKey" : {"CYP2D6": "2.25"}, + "lookupKey" : {"CYP2D6": "≥5.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104964", "name" : "Annotation of DPWG Guideline for clomipramine and CYP2D6", - "version" : 34 + "version" : 112 }, "text" : { - "id" : 1452103686, - "html" : "

The guideline does not provide a recommendation for clomipramine in normal metabolizers.

\n", + "id" : 1452103694, + "html" : "

Use 1.5 times the standard dose and monitor the effect and side effects of the plasma concentrations of clomipramine and desmethylclomipramine to set the maintenance dose.

\n

For depression, the therapeutic range is 200-400 ng/mL for the sum of the plasma concentrations of clomipramine and desmethylclomipramine. For anxiety disorders, the therapeutic plasma concentration of clomipramine is approximately 100 ng/mL, in combination with a plasma concentration of desmethylclomipramine lower than 200 ng/mL. For obsessive compulsive disorder, the therapeutic plasma concentration of clomipramine is higher than 200 ng/mL, in combination with a plasma concentration of desmethylclomipramine that is as low as possible.

\n

If a dose increase is not wanted due to potential cardiotoxic hydroxy metabolites: avoid clomipramine. Antidepressants that are not metabolised by CYP2D6, or to a lesser extent, include citalopram and sertraline.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302151", - "name" : "Recommendation Annotation PA166302151", + "id" : "PA166302156", + "name" : "Recommendation Annotation PA166302156", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -111287,24 +112352,24 @@ "implications" : [ "The risk of ineffectiveness and cardiotoxic side effects may be increased. The gene variation leads to reduced plasma concentrations of clomipramine and the active metabolite desmethylclomipramine and to increased concentrations of the potentially cardiotoxic hydroxy metabolites." ], - "lookupKey" : {"CYP2D6": "≥3.0"}, + "lookupKey" : {"CYP2D6": "≥6.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104964", "name" : "Annotation of DPWG Guideline for clomipramine and CYP2D6", - "version" : 34 + "version" : 112 }, "text" : { - "id" : 1452103690, + "id" : 1452103695, "html" : "

Use 1.5 times the standard dose and monitor the effect and side effects of the plasma concentrations of clomipramine and desmethylclomipramine to set the maintenance dose.

\n

For depression, the therapeutic range is 200-400 ng/mL for the sum of the plasma concentrations of clomipramine and desmethylclomipramine. For anxiety disorders, the therapeutic plasma concentration of clomipramine is approximately 100 ng/mL, in combination with a plasma concentration of desmethylclomipramine lower than 200 ng/mL. For obsessive compulsive disorder, the therapeutic plasma concentration of clomipramine is higher than 200 ng/mL, in combination with a plasma concentration of desmethylclomipramine that is as low as possible.

\n

If a dose increase is not wanted due to potential cardiotoxic hydroxy metabolites: avoid clomipramine. Antidepressants that are not metabolised by CYP2D6, or to a lesser extent, include citalopram and sertraline.

\n", "version" : 0 }, @@ -111312,87 +112377,85 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302142", - "name" : "Recommendation Annotation PA166302142", + "id" : "PA166302148", + "name" : "Recommendation Annotation PA166302148", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "The risk of side effects may be increased, because the gene variation leads to increased plasma concentrations of clomipramine and the active metabolite desmethylclomipramine." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on clomipramine." ], - "lookupKey" : {"CYP2D6": "0.75"}, + "lookupKey" : {"CYP2D6": "2.5"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104964", "name" : "Annotation of DPWG Guideline for clomipramine and CYP2D6", - "version" : 34 + "version" : 112 }, "text" : { - "id" : 1452103681, - "html" : "

Use 70% of the standard dose and monitor the effect and side effects or the plasma concentrations of clomipramine and desmethylclomipramine.

\n

For depression, the therapeutic range is 200-400 ng/mL for the sum of the plasma concentrations of clomipramine and desmethylclomipramine. For anxiety disorders, the therapeutic plasma concentration of clomipramine is approximately 100 ng/mL, in combination with a plasma concentration of desmethylclomipramine lower than 200 ng/mL. For obsessive compulsive disorder, the therapeutic plasma concentration of clomipramine is higher than 200 ng/mL, in combination with a plasma concentration of desmethylclomipramine that is as low as possible. A sum of the plasma concentrations of clomipramine and desmethylclomipramine higher than 600 ng/mL is considered toxic.

\n", + "id" : 1452103687, + "html" : "

The guideline does not provide a recommendation for clomipramine in normal metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302155", - "name" : "Recommendation Annotation PA166302155", - "alternateDrugAvailable" : true, + "id" : "PA166302147", + "name" : "Recommendation Annotation PA166302147", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "The risk of ineffectiveness and cardiotoxic side effects may be increased. The gene variation leads to reduced plasma concentrations of clomipramine and the active metabolite desmethylclomipramine and to increased concentrations of the potentially cardiotoxic hydroxy metabolites." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on clomipramine." ], - "lookupKey" : {"CYP2D6": "≥5.0"}, + "lookupKey" : {"CYP2D6": "2.25"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104964", "name" : "Annotation of DPWG Guideline for clomipramine and CYP2D6", - "version" : 34 + "version" : 112 }, "text" : { - "id" : 1452103694, - "html" : "

Use 1.5 times the standard dose and monitor the effect and side effects of the plasma concentrations of clomipramine and desmethylclomipramine to set the maintenance dose.

\n

For depression, the therapeutic range is 200-400 ng/mL for the sum of the plasma concentrations of clomipramine and desmethylclomipramine. For anxiety disorders, the therapeutic plasma concentration of clomipramine is approximately 100 ng/mL, in combination with a plasma concentration of desmethylclomipramine lower than 200 ng/mL. For obsessive compulsive disorder, the therapeutic plasma concentration of clomipramine is higher than 200 ng/mL, in combination with a plasma concentration of desmethylclomipramine that is as low as possible.

\n

If a dose increase is not wanted due to potential cardiotoxic hydroxy metabolites: avoid clomipramine. Antidepressants that are not metabolised by CYP2D6, or to a lesser extent, include citalopram and sertraline.

\n", + "id" : 1452103686, + "html" : "

The guideline does not provide a recommendation for clomipramine in normal metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", @@ -111419,21 +112482,103 @@ "objCls" : "Chemical", "id" : "PA449048", "name" : "clomipramine", - "version" : 7 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104964", "name" : "Annotation of DPWG Guideline for clomipramine and CYP2D6", - "version" : 34 + "version" : 112 }, "text" : { "id" : 1452103685, "html" : "

The guideline does not provide a recommendation for clomipramine in normal metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166302145", + "name" : "Recommendation Annotation PA166302145", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 1448526251, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : false, + "implications" : [ + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on clomipramine." + ], + "lookupKey" : {"CYP2D6": "1.5"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA449048", + "name" : "clomipramine", + "version" : 41 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104964", + "name" : "Annotation of DPWG Guideline for clomipramine and CYP2D6", + "version" : 112 + }, + "text" : { + "id" : 1452103684, + "html" : "

The guideline does not provide a recommendation for clomipramine in normal metabolizers.

\n", + "version" : 0 + }, + "version" : 2 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166302144", + "name" : "Recommendation Annotation PA166302144", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 1448526251, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : false, + "implications" : [ + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on clomipramine." + ], + "lookupKey" : {"CYP2D6": "1.25"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA449048", + "name" : "clomipramine", + "version" : 41 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104964", + "name" : "Annotation of DPWG Guideline for clomipramine and CYP2D6", + "version" : 112 + }, + "text" : { + "id" : 1452103683, + "html" : "

The guideline does not provide a recommendation for clomipramine in normal metabolizers.

\n", + "version" : 0 + }, + "version" : 2 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166104964" @@ -111657,7 +112802,7 @@ "objCls" : "Chemical", "id" : "PA449053", "name" : "clopidogrel", - "version" : 20 + "version" : 58 } ], "relatedGenes" : [ @@ -111666,29 +112811,29 @@ "id" : "PA124", "symbol" : "CYP2C19", "name" : "cytochrome P450 family 2 subfamily C member 19", - "version" : 7210 + "version" : 7266 } ], "source" : "DPWG", "summaryMarkdown" : { "id" : 1447981900, "html" : "

Avoid clopidogrel use in patients who are CYP2C19 poor metabolizers and are undergoing percutaneous coronary intervention, stroke or TIA. For CYP2C19 intermediate metabolizers who are undergoing percutaneous coronary intervention, stroke, or TIA, choose an alternative drug or double the dose to 150 mg/day (600 mg loading dose). No action is required for patients who are CYP2C19 ultra-rapid metabolizers.

\n", - "version" : 1 + "version" : 2 }, "terms" : [], "textMarkdown" : { "id" : 1447981899, "html" : "

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

\n

November 2018 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for clopidogrel based on CYP2C19 genotype. In patients who are undergoing percutaneous coronary intervention, stroke, or TIA, they recommend avoiding clopidogrel use in CYP2C19 poor metabolizers, and choosing an alternative drug or doubling the dose to 150 mg/day (600 mg loading dose) in CYP2C19 intermediate metabolizers. No action is required for CYP2C19 ultrarapid metabolizers.

\n

Wording in table taken from the Dutch guidelines November 2018 update

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
CYP2C19 PMclopidogrelThe risk of serious cardiovascular and cerebrovascular events is increased in patients undergoing balloon angioplasty or stent placement (percutaneous coronary intervention) and in patients with a stroke or TIA, because the genetic variation reduces the activation of clopidogrel. No negative clinical consequences have been proved in other patients.PERCUTANEOUS CORONARY INTERVENTION, STROKE or TIA: avoid clopidogrel. Prasugrel, ticagrelor and acetylsalicylic acid/dipyridamole are not metabolised by CYP2C19 (or to a lesser extent).
OTHER INDICATIONS: determine the level of inhibition of platelet aggregation by clopidogrel. Consider an alternative in poor responders. Prasugrel and ticagrelor are not metabolised by CYP2C19 (or to a lesser extent).
CYP2C19 IMclopidogrelThe risk of serious cardiovascular and cerebrovascular events is increased in patients undergoing balloon angioplasty or stent placement (percutaneous coronary intervention) and in patients with a stroke or TIA, as the genetic variation reduces the activation of clopidogrel. No negative clinical consequences have been observed in other patients.PERCUTANEOUS CORONARY INTERVENTION, STROKE or TIA: choose an alternative or double the dose to 150 mg/day (600 mg loading dose). Prasugrel, ticagrelor and acetylsalicylic acid/dipyridamole are not metabolised by CYP2C19 (or to a lesser extent).
OTHER INDICATIONS: no action required
CYP2C19 UMclopidogrelThe genetic variation results in increased conversion of clopidogrel to the active metabolite. However, this can result in both positive effects (reduction in the risk of serious cardiovascular and cerebrovascular events) and negative effects (increase in the risk of bleeding).NO action is required for this gene-drug interaction
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for clopidogrel and CYP2C19:

\n
\n

The Dutch Pharmacogenetics Working Group considers genotyping before starting clopidogrel in percutaneous coronary intervention or stroke patients to be essential for drug efficacy. Genotyping must be performed before drug therapy has been initiated to guide drug and dose selection.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n

2011 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for clopidogrel based on the CYP2C19 genotype [Article:21412232]. For the CYP2C19 PM and IM phenotype they conclude an increased risk for reduced response to clopidogrel and recommend to consider an alternative drug. Prasugrel is not or to a much smaller extent metabolized by CYP2C19 but is associated with an increased bleeding risk compared to clopidogrel.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Phenotype (Genotype)Therapeutic Dose RecommendationLevel of EvidenceClinical Relevance
CYP2C19 PM (*2/*2, *2/*3, *3/*3)Increased risk for reduced response to clopidogrel. Consider alternative drug. Prasugrel is not or to a much smaller extent metabolized by CYP2C19 but is associated with an increased bleeding risk compared to clopidogrelPublished controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpointsClinical effect (statistically significant difference): death; arrhythmia; unanticipated myelosuppression
CYP2C19 IM (*1/*2, *1/*3, *17/*2, *17/*3)Increased risk for reduced response to clopidogrel. Consider alternative drug. Prasugrel is not or to a much smaller extent metabolized by CYP2C19 but is associated with an increased bleeding risk compared to clopidogrelPublished controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpointsClinical effect (statistically significant difference): death; arrhythmia; unanticipated myelosuppression
CYP2C19 UM (*17/*17)NonePublished controlled studies of moderate quality# relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpointsMinor clinical effect (statistically significant difference): QTc prolongation (<450 ms female, <470 ms male); international normalized ratio increase < 4.5 Kinetic effect (statistically significant difference)
\n\n", - "version" : 18 + "version" : 29 }, "userId" : "katrin", - "version" : 34 + "version" : 81 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166299208", - "name" : "Recommendation PA166299208", + "id" : "PA166299211", + "name" : "Recommendation PA166299211", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -111702,36 +112847,36 @@ }, "dosingInformation" : false, "implications" : [ - "The risk of serious cardiovascular and cerebrovascular events is increased in patients undergoing balloon angioplasty or stent placement (percutaneous coronary intervention) and in patients with a stroke or TIA, as the genetic variation reduces the activation of clopidogrel. No negative clinical consequences have been observed in other patients." + "The risk of serious cardiovascular and cerebrovascular events is increased in patients undergoing balloon angioplasty or stent placement (percutaneous coronary intervention) and in patients with a stroke or TIA, because the genetic variation reduces the activation of clopidogrel. No negative clinical consequences have been proved in other patients." ], - "lookupKey" : {"CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449053", "name" : "clopidogrel", - "version" : 20 + "version" : 58 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104956", "name" : "Annotation of DPWG Guideline for clopidogrel and CYP2C19", - "version" : 34 + "version" : 81 }, "text" : { - "id" : 1452061571, - "html" : "

PERCUTANEOUS CORONARY INTERVENTION, STROKE or TIA: choose an alternative or double the dose to 150 mg/day (600 mg loading dose). Prasugrel, ticagrelor and acetylsalicylic acid/dipyridamole are not metabolised by CYP2C19 (or to a lesser extent).\nOTHER INDICATIONS: no action required

\n", + "id" : 1452061574, + "html" : "

PERCUTANEOUS CORONARY INTERVENTION, STROKE or TIA: avoid clopidogrel. Prasugrel, ticagrelor and acetylsalicylic acid/dipyridamole are not metabolised by CYP2C19 (or to a lesser extent).\nOTHER INDICATIONS: determine the level of inhibition of platelet aggregation by clopidogrel. Consider an alternative in poor responders. Prasugrel and ticagrelor are not metabolised by CYP2C19 (or to a lesser extent).

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299211", - "name" : "Recommendation PA166299211", - "alternateDrugAvailable" : true, + "id" : "PA166299209", + "name" : "Recommendation PA166299209", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -111744,30 +112889,30 @@ }, "dosingInformation" : false, "implications" : [ - "The risk of serious cardiovascular and cerebrovascular events is increased in patients undergoing balloon angioplasty or stent placement (percutaneous coronary intervention) and in patients with a stroke or TIA, because the genetic variation reduces the activation of clopidogrel. No negative clinical consequences have been proved in other patients." + "The genetic variation results in increased conversion of clopidogrel to the active metabolite. However, this can result in both positive effects (reduction in the risk of serious cardiovascular and cerebrovascular events) and negative effects (increase in the risk of bleeding)." ], - "lookupKey" : {"CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449053", "name" : "clopidogrel", - "version" : 20 + "version" : 58 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104956", "name" : "Annotation of DPWG Guideline for clopidogrel and CYP2C19", - "version" : 34 + "version" : 81 }, "text" : { - "id" : 1452061574, - "html" : "

PERCUTANEOUS CORONARY INTERVENTION, STROKE or TIA: avoid clopidogrel. Prasugrel, ticagrelor and acetylsalicylic acid/dipyridamole are not metabolised by CYP2C19 (or to a lesser extent).\nOTHER INDICATIONS: determine the level of inhibition of platelet aggregation by clopidogrel. Consider an alternative in poor responders. Prasugrel and ticagrelor are not metabolised by CYP2C19 (or to a lesser extent).

\n", - "version" : 0 + "id" : 1452061572, + "html" : "

NO action is required for this gene-drug interaction

\n", + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", @@ -111794,27 +112939,27 @@ "objCls" : "Chemical", "id" : "PA449053", "name" : "clopidogrel", - "version" : 20 + "version" : 58 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104956", "name" : "Annotation of DPWG Guideline for clopidogrel and CYP2C19", - "version" : 34 + "version" : 81 }, "text" : { "id" : 1452061573, "html" : "

The guideline does not provide a recommendation for clopidogrel in normal metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 4 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299209", - "name" : "Recommendation PA166299209", - "alternateDrugAvailable" : false, + "id" : "PA166299208", + "name" : "Recommendation PA166299208", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -111827,30 +112972,30 @@ }, "dosingInformation" : false, "implications" : [ - "The genetic variation results in increased conversion of clopidogrel to the active metabolite. However, this can result in both positive effects (reduction in the risk of serious cardiovascular and cerebrovascular events) and negative effects (increase in the risk of bleeding)." + "The risk of serious cardiovascular and cerebrovascular events is increased in patients undergoing balloon angioplasty or stent placement (percutaneous coronary intervention) and in patients with a stroke or TIA, as the genetic variation reduces the activation of clopidogrel. No negative clinical consequences have been observed in other patients." ], - "lookupKey" : {"CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449053", "name" : "clopidogrel", - "version" : 20 + "version" : 58 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104956", "name" : "Annotation of DPWG Guideline for clopidogrel and CYP2C19", - "version" : 34 + "version" : 81 }, "text" : { - "id" : 1452061572, - "html" : "

NO action is required for this gene-drug interaction

\n", + "id" : 1452061571, + "html" : "

PERCUTANEOUS CORONARY INTERVENTION, STROKE or TIA: choose an alternative or double the dose to 150 mg/day (600 mg loading dose). Prasugrel, ticagrelor and acetylsalicylic acid/dipyridamole are not metabolised by CYP2C19 (or to a lesser extent).\nOTHER INDICATIONS: no action required

\n", "version" : 0 }, - "version" : 0 + "version" : 2 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166104956" @@ -112150,7 +113295,7 @@ "objCls" : "Chemical", "id" : "PA449088", "name" : "codeine", - "version" : 14 + "version" : 48 } ], "relatedGenes" : [ @@ -112159,29 +113304,29 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "DPWG", "summaryMarkdown" : { "id" : 1447981992, "html" : "

The Pharmacogenetics Working Group Guideline for codeine includes individual recommendations for cough or pain for CYP2D6 poor, intermediate, and ultrarapid metabolizer. In addition, for ultrarapid metabolizer, higher or lower doses and additional risk factors are taken into consideration.

\n", - "version" : 1 + "version" : 2 }, "terms" : [], "textMarkdown" : { "id" : 1447981991, "html" : "

Note that the FDA released a safety announcement on 4/20/2017 stating that codeine and tramadol should not be used in children under 12 years.

\n

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

\n

Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction of CYP2D6 and opioids (codeine, tramadol and oxycodone). European journal of human genetics (2021)

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group published a paper with the guidelines as per the November 2018 update including more details and scoring the clinical implementation [Article:34267337]

\n

November 2018 update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for codeine based on CYP2D6 genotype. The guideline includes individual recommendations for cough or pain for CYP2D6 poor, intermediate, and ultrarapid metabolizer. In addition, for ultrarapid metabolizer the recommendations consider higher or lower doses and additional risk factors.

\n

Wording in table taken from the Dutch guidelines November 2018 update

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
CYP2D6 UMcodeineThe genetic variation increases the conversion of codeine to morphine. This can result in an increase in side effects. Death has occurred in children who received analgesic doses. One adult with reduced kidney function and co-medication with two CYP3A4 inhibitors became comatose after use of codeine for a cough.DOSES HIGHER THAN 20 mg every 6 hours for adults and 10 mg every 6 hours for children aged 12 years or older AND/OR ADDITIONAL RISK FACTORS, such as co-medication with CYP3A4 inhibitors and/or reduced kidney function:
Codeine is contra-indicated.
if possible, select an alternative
- For PAIN: do not select tramadol, as this is also metabolised by CYP2D6. Morphine is not metabolised by CYP2D6. Oxycodone is metabolised by CYP2D6 to a limited extent, but this does not result in differences in side effects in patients.
- For COUGH: noscapine is not metabolised by CYP2D6.
 
DOSES LOWER THAN OR EQUAL TO 20 mg every 6 hours for adults and 10 mg every 6 hours for children aged 12 years or older AND NO ADDITIONAL RISK FACTORS, such as co-medication with CYP3A4 inhibitors and/or reduced kidney function:
No action required.
CYP2D6 IMcodeineThe genetic variation reduces the conversion of codeine to morphine. This can result in reduced analgesia.For COUGH:
1. No action required.
 
For PAIN:
It is not possible to offer adequately substantiated advice for dose adjustment based on the limited available literature for this phenotype.
1. Be alert to a reduced effectiveness.
2. In the case of inadequate effectiveness: 1. Try a dose increase., 2. If this does not work: choose an alternative.
Do not select tramadol, as this is also metabolised by CYP2D6. Morphine is not metabolised by CYP2D6. Oxycodone is metabolised by CYP2D6 to a limited extent, but this does not result in differences in analgesia in patients.
3. If no alternative is selected: advise the patient to report inadequate analgesia.
CYP2D6 PMcodeineThe genetic variation reduces the conversion of codeine to morphine. This can result in reduced analgesia.For COUGH:
1. No action required.
 
For PAIN:
It is not possible to offer adequately substantiated advice for dose adjustment based on the limited available literature for this phenotype.
1. Choose an alternative.
Do not select tramadol, as this is also metabolised by CYP2D6. Morphine is not metabolised by CYP2D6. Oxycodone is metabolised by CYP2D6 to a limited extent, but this does not result in differences in analgesia in patients.
2. If an alternative is not an option: advise the patient to report inadequate analgesia.
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for codeine and CYP2D6:

\n
\n

The Dutch Pharmacogenetics Working Group considers genotyping before starting codeine in doses higher than 20 mg every 6 hours for adults and 10 mg every 6 hours for children aged 12 years or older, and in patients with additional risk factors, such as co-medication with CYP3A4 inhibitors and/or impaired renal function, to be beneficial for drug safety. It is advised to genotype these patients before (or directly after) drug therapy has been initiated to guide drug and dose selection.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n

2011 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for codeine based on CYP2D6 genotypes [Article:21412232]. They recommend alternative analgesics for patients carrying the poor metabolizer (PM) alleles, intermediate metabolizer (IM) alleles or ultrarapid metabolizer (UM) allleles.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Phenotype (Genotype)Therapeutic Dose RecommendationLevel of EvidenceClinical Relevance
PM (two inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) alleles)Analgesia: select alternative drug (e.g., acetaminophen, NSAID, morphine-not tramadol or oxycodone) or be alert to symptoms of insufficient pain relief. Cough: no.Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Clinical effect (S): short-lived discomfort (< 48 hr) without permanent injury: e.g. reduced decrease in resting heart rate; reduction in exercise tachycardia; decreased pain relief from oxycodone; ADE resulting from increased bioavailability of atomoxetine (decreased appetite, insomnia, sleep disturbance etc); neutropenia > 1.5x109/l; leucopenia > 3.0x109/l; thrombocytopenia > 75x109/l; moderate diarrhea not affecting daily activities; reduced glucose increase following oral glucose tolerance test.
IM (two decreased-activity (*9, *10, *17, *29, *36, *41) alleles or carrying one active (*1, *2, *33, *35) and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele, or carrying one decreased-activity (*9, *10, *17, *29, *36, *41) allele and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele)Analgesia: select alternative drug (e.g., acetaminophen, NSAID, morphine-not tramadol or oxycodone) or be alert to symptoms of insufficient pain relief. Cough: noPublished controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Minor clinical effect (S): QTc prolongation (<450 ms female, <470 ms male); INR increase < 4.5; Kinetic effect (S).
UM (a gene duplication in absence of inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) or decreased-activity (*9, *10, *17, *29, *36, *41) alleles)Analgesia: select alternative drug (e.g., acetaminophen, NSAID, morphine-not tramadol or oxycodone) or be alert to ADE. Cough: be extra alert to ADEs due to increased morphine plasma concentration.Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Clinical effect (S): death; arrhythmia; unanticipated myelosuppression.
\n\n", - "version" : 21 + "version" : 26 }, "userId" : "carrillo", - "version" : 37 + "version" : 138 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166302264", - "name" : "Recommendation Annotation PA166302264", + "id" : "PA166302161", + "name" : "Recommendation Annotation PA166302161", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -112195,76 +113340,77 @@ }, "dosingInformation" : false, "implications" : [ - "The genetic variation increases the conversion of codeine to morphine. This can result in an increase in side effects. Death has occurred in children who received analgesic doses. One adult with reduced kidney function and co-medication with two CYP3A4 inhibitors became comatose after use of codeine for a cough." + "The genetic variation reduces the conversion of codeine to morphine. This can result in reduced analgesia." ], - "lookupKey" : {"CYP2D6": "≥3.0"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"CYP2D6": "0.0"}, + "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449088", "name" : "codeine", - "version" : 14 + "version" : 48 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104970", "name" : "Annotation of DPWG Guideline for codeine and CYP2D6", - "version" : 37 + "version" : 138 }, "text" : { - "id" : 1452103823, - "html" : "

DOSES HIGHER THAN 20 mg every 6 hours for adults and 10 mg every 6 hours for children aged 12 years or older AND/OR ADDITIONAL RISK FACTORS, such as co-medication with CYP3A4 inhibitors and/or reduced kidney function:

\n

Codeine is contra-indicated. If possible, select an alternative.

\n\n

DOSES LOWER THAN OR EQUAL TO 20 mg every 6 hours for adults and 10 mg every 6 hours for children aged 12 years or older AND NO ADDITIONAL RISK FACTORS, such as co-medication with CYP3A4 inhibitors and/or reduced kidney function:\nNo action required.

\n", - "version" : 0 + "id" : 1452103700, + "html" : "

For PAIN:\nIt is not possible to offer adequately substantiated advice for dose adjustment based on the limited available literature for this phenotype.

\n
    \n
  1. Choose an alternative.\nDo not select tramadol, as this is also metabolised by CYP2D6. Morphine is not metabolised by CYP2D6. Oxycodone is metabolised by CYP2D6 to a limited extent, but this does not result in differences in analgesia in patients.
    2. \n
  2. If an alternative is not an option: advise the patient to report inadequate analgesia.
    3. \n
\n

For COUGH:\nNo action required.

\n", + "version" : 1 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302242", - "name" : "Recommendation Annotation PA166302242", - "alternateDrugAvailable" : false, + "id" : "PA166302181", + "name" : "Recommendation Annotation PA166302181", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on codeine." + "The genetic variation reduces the conversion of codeine to morphine. This can result in reduced analgesia." ], - "lookupKey" : {"CYP2D6": "1.5"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"CYP2D6": "0.25"}, + "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449088", "name" : "codeine", - "version" : 14 + "version" : 48 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104970", "name" : "Annotation of DPWG Guideline for codeine and CYP2D6", - "version" : 37 + "version" : 138 }, "text" : { - "id" : 1452103801, - "html" : "

The guideline does not provide a recommendation for codeine in normal metabolizers.

\n", - "version" : 0 + "id" : 1452103740, + "html" : "

For PAIN:\nIt is not possible to offer adequately substantiated advice for dose adjustment based on the limited available literature for this phenotype.

\n
    \n
  1. Be alert to a reduced effectiveness.
    2. \n
  2. In the case of inadequate effectiveness: 1. Try a dose increase. 2. If this does not work: choose an alternative.\nDo not select tramadol, as this is also metabolised by CYP2D6. Morphine is not metabolised by CYP2D6. Oxycodone is metabolised by CYP2D6 to a limited extent, but this does not result in differences in analgesia in patients.
    3. \n
  3. If no alternative is selected: advise the patient to report inadequate analgesia.
    4. \n
\n

For COUGH:\nNo action required.

\n", + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302268", - "name" : "Recommendation Annotation PA166302268", + "id" : "PA166302202", + "name" : "Recommendation Annotation PA166302202", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -112276,37 +113422,37 @@ "valid" : true, "version" : 1 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "The genetic variation increases the conversion of codeine to morphine. This can result in an increase in side effects. Death has occurred in children who received analgesic doses. One adult with reduced kidney function and co-medication with two CYP3A4 inhibitors became comatose after use of codeine for a cough." + "The genetic variation reduces the conversion of codeine to morphine. This can result in reduced analgesia." ], - "lookupKey" : {"CYP2D6": "≥5.0"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"CYP2D6": "0.75"}, + "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449088", "name" : "codeine", - "version" : 14 + "version" : 48 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104970", "name" : "Annotation of DPWG Guideline for codeine and CYP2D6", - "version" : 37 + "version" : 138 }, "text" : { - "id" : 1452103827, - "html" : "

DOSES HIGHER THAN 20 mg every 6 hours for adults and 10 mg every 6 hours for children aged 12 years or older AND/OR ADDITIONAL RISK FACTORS, such as co-medication with CYP3A4 inhibitors and/or reduced kidney function:

\n

Codeine is contra-indicated. If possible, select an alternative.

\n\n

DOSES LOWER THAN OR EQUAL TO 20 mg every 6 hours for adults and 10 mg every 6 hours for children aged 12 years or older AND NO ADDITIONAL RISK FACTORS, such as co-medication with CYP3A4 inhibitors and/or reduced kidney function:\nNo action required.

\n", - "version" : 0 + "id" : 1452103761, + "html" : "

For PAIN:\nIt is not possible to offer adequately substantiated advice for dose adjustment based on the limited available literature for this phenotype.

\n
    \n
  1. Be alert to a reduced effectiveness.
    2. \n
  2. In the case of inadequate effectiveness: 1. Try a dose increase. 2. If this does not work: choose an alternative.\nDo not select tramadol, as this is also metabolised by CYP2D6. Morphine is not metabolised by CYP2D6. Oxycodone is metabolised by CYP2D6 to a limited extent, but this does not result in differences in analgesia in patients.
    3. \n
  3. If no alternative is selected: advise the patient to report inadequate analgesia.
    4. \n
\n

For COUGH:\nNo action required.

\n", + "version" : 1 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302202", - "name" : "Recommendation Annotation PA166302202", + "id" : "PA166302201", + "name" : "Recommendation Annotation PA166302201", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -112322,33 +113468,33 @@ "implications" : [ "The genetic variation reduces the conversion of codeine to morphine. This can result in reduced analgesia." ], - "lookupKey" : {"CYP2D6": "0.75"}, + "lookupKey" : {"CYP2D6": "0.5"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449088", "name" : "codeine", - "version" : 14 + "version" : 48 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104970", "name" : "Annotation of DPWG Guideline for codeine and CYP2D6", - "version" : 37 + "version" : 138 }, "text" : { - "id" : 1452103761, + "id" : 1452103760, "html" : "

For PAIN:\nIt is not possible to offer adequately substantiated advice for dose adjustment based on the limited available literature for this phenotype.

\n
    \n
  1. Be alert to a reduced effectiveness.
    2. \n
  2. In the case of inadequate effectiveness: 1. Try a dose increase. 2. If this does not work: choose an alternative.\nDo not select tramadol, as this is also metabolised by CYP2D6. Morphine is not metabolised by CYP2D6. Oxycodone is metabolised by CYP2D6 to a limited extent, but this does not result in differences in analgesia in patients.
    3. \n
  3. If no alternative is selected: advise the patient to report inadequate analgesia.
    4. \n
\n

For COUGH:\nNo action required.

\n", - "version" : 0 + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302263", - "name" : "Recommendation Annotation PA166302263", + "id" : "PA166302221", + "name" : "Recommendation Annotation PA166302221", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -112360,37 +113506,37 @@ "valid" : true, "version" : 1 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "The genetic variation increases the conversion of codeine to morphine. This can result in an increase in side effects. Death has occurred in children who received analgesic doses. One adult with reduced kidney function and co-medication with two CYP3A4 inhibitors became comatose after use of codeine for a cough." + "The genetic variation reduces the conversion of codeine to morphine. This can result in reduced analgesia." ], - "lookupKey" : {"CYP2D6": "4.0"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"CYP2D6": "1.0"}, + "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449088", "name" : "codeine", - "version" : 14 + "version" : 48 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104970", "name" : "Annotation of DPWG Guideline for codeine and CYP2D6", - "version" : 37 + "version" : 138 }, "text" : { - "id" : 1452103822, - "html" : "

DOSES HIGHER THAN 20 mg every 6 hours for adults and 10 mg every 6 hours for children aged 12 years or older AND/OR ADDITIONAL RISK FACTORS, such as co-medication with CYP3A4 inhibitors and/or reduced kidney function:

\n

Codeine is contra-indicated. If possible, select an alternative.

\n\n

DOSES LOWER THAN OR EQUAL TO 20 mg every 6 hours for adults and 10 mg every 6 hours for children aged 12 years or older AND NO ADDITIONAL RISK FACTORS, such as co-medication with CYP3A4 inhibitors and/or reduced kidney function:\nNo action required.

\n", - "version" : 0 + "id" : 1452103780, + "html" : "

For PAIN:\nIt is not possible to offer adequately substantiated advice for dose adjustment based on the limited available literature for this phenotype.

\n
    \n
  1. Be alert to a reduced effectiveness.
    2. \n
  2. In the case of inadequate effectiveness: 1. Try a dose increase. 2. If this does not work: choose an alternative.\nDo not select tramadol, as this is also metabolised by CYP2D6. Morphine is not metabolised by CYP2D6. Oxycodone is metabolised by CYP2D6 to a limited extent, but this does not result in differences in analgesia in patients.
    3. \n
  3. If no alternative is selected: advise the patient to report inadequate analgesia.
    4. \n
\n

For COUGH:\nNo action required.

\n", + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302241", - "name" : "Recommendation Annotation PA166302241", + "id" : "PA166302242", + "name" : "Recommendation Annotation PA166302242", "alternateDrugAvailable" : false, "classification" : { "id" : 1448526251, @@ -112405,24 +113551,24 @@ "implications" : [ "The guideline does not provide a description of the impact of a normal metabolizer phenotype on codeine." ], - "lookupKey" : {"CYP2D6": "1.25"}, + "lookupKey" : {"CYP2D6": "1.5"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449088", "name" : "codeine", - "version" : 14 + "version" : 48 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104970", "name" : "Annotation of DPWG Guideline for codeine and CYP2D6", - "version" : 37 + "version" : 138 }, "text" : { - "id" : 1452103800, + "id" : 1452103801, "html" : "

The guideline does not provide a recommendation for codeine in normal metabolizers.

\n", "version" : 0 }, @@ -112430,176 +113576,172 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302267", - "name" : "Recommendation Annotation PA166302267", - "alternateDrugAvailable" : true, + "id" : "PA166302241", + "name" : "Recommendation Annotation PA166302241", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, "dosingInformation" : false, "implications" : [ - "The genetic variation increases the conversion of codeine to morphine. This can result in an increase in side effects. Death has occurred in children who received analgesic doses. One adult with reduced kidney function and co-medication with two CYP3A4 inhibitors became comatose after use of codeine for a cough." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on codeine." ], - "lookupKey" : {"CYP2D6": "≥4.0"}, + "lookupKey" : {"CYP2D6": "1.25"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449088", "name" : "codeine", - "version" : 14 + "version" : 48 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104970", "name" : "Annotation of DPWG Guideline for codeine and CYP2D6", - "version" : 37 + "version" : 138 }, "text" : { - "id" : 1452103826, - "html" : "

DOSES HIGHER THAN 20 mg every 6 hours for adults and 10 mg every 6 hours for children aged 12 years or older AND/OR ADDITIONAL RISK FACTORS, such as co-medication with CYP3A4 inhibitors and/or reduced kidney function:

\n

Codeine is contra-indicated. If possible, select an alternative.

\n\n

DOSES LOWER THAN OR EQUAL TO 20 mg every 6 hours for adults and 10 mg every 6 hours for children aged 12 years or older AND NO ADDITIONAL RISK FACTORS, such as co-medication with CYP3A4 inhibitors and/or reduced kidney function:\nNo action required.

\n", + "id" : 1452103800, + "html" : "

The guideline does not provide a recommendation for codeine in normal metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302201", - "name" : "Recommendation Annotation PA166302201", - "alternateDrugAvailable" : true, + "id" : "PA166302244", + "name" : "Recommendation Annotation PA166302244", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "The genetic variation reduces the conversion of codeine to morphine. This can result in reduced analgesia." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on codeine." ], - "lookupKey" : {"CYP2D6": "0.5"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"CYP2D6": "2.25"}, + "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449088", "name" : "codeine", - "version" : 14 + "version" : 48 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104970", "name" : "Annotation of DPWG Guideline for codeine and CYP2D6", - "version" : 37 + "version" : 138 }, "text" : { - "id" : 1452103760, - "html" : "

For PAIN:\nIt is not possible to offer adequately substantiated advice for dose adjustment based on the limited available literature for this phenotype.

\n
    \n
  1. Be alert to a reduced effectiveness.
    2. \n
  2. In the case of inadequate effectiveness: 1. Try a dose increase. 2. If this does not work: choose an alternative.\nDo not select tramadol, as this is also metabolised by CYP2D6. Morphine is not metabolised by CYP2D6. Oxycodone is metabolised by CYP2D6 to a limited extent, but this does not result in differences in analgesia in patients.
    3. \n
  3. If no alternative is selected: advise the patient to report inadequate analgesia.
    4. \n
\n

For COUGH:\nNo action required.

\n", + "id" : 1452103803, + "html" : "

The guideline does not provide a recommendation for codeine in normal metabolizers.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302161", - "name" : "Recommendation Annotation PA166302161", - "alternateDrugAvailable" : true, + "id" : "PA166302243", + "name" : "Recommendation Annotation PA166302243", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, "dosingInformation" : false, "implications" : [ - "The genetic variation reduces the conversion of codeine to morphine. This can result in reduced analgesia." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on codeine." ], - "lookupKey" : {"CYP2D6": "0.0"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"CYP2D6": "2.0"}, + "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449088", "name" : "codeine", - "version" : 14 + "version" : 48 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104970", "name" : "Annotation of DPWG Guideline for codeine and CYP2D6", - "version" : 37 + "version" : 138 }, "text" : { - "id" : 1452103700, - "html" : "

For PAIN:\nIt is not possible to offer adequately substantiated advice for dose adjustment based on the limited available literature for this phenotype.

\n
    \n
  1. Choose an alternative.\nDo not select tramadol, as this is also metabolised by CYP2D6. Morphine is not metabolised by CYP2D6. Oxycodone is metabolised by CYP2D6 to a limited extent, but this does not result in differences in analgesia in patients.
    2. \n
  2. If an alternative is not an option: advise the patient to report inadequate analgesia.
    3. \n
\n

For COUGH:\nNo action required.

\n", + "id" : 1452103802, + "html" : "

The guideline does not provide a recommendation for codeine in normal metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302262", - "name" : "Recommendation Annotation PA166302262", - "alternateDrugAvailable" : true, + "id" : "PA166302261", + "name" : "Recommendation Annotation PA166302261", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, "dosingInformation" : false, "implications" : [ - "The genetic variation increases the conversion of codeine to morphine. This can result in an increase in side effects. Death has occurred in children who received analgesic doses. One adult with reduced kidney function and co-medication with two CYP3A4 inhibitors became comatose after use of codeine for a cough." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on codeine." ], - "lookupKey" : {"CYP2D6": "3.0"}, + "lookupKey" : {"CYP2D6": "2.5"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449088", "name" : "codeine", - "version" : 14 + "version" : 48 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104970", "name" : "Annotation of DPWG Guideline for codeine and CYP2D6", - "version" : 37 + "version" : 138 }, "text" : { - "id" : 1452103821, - "html" : "

DOSES HIGHER THAN 20 mg every 6 hours for adults and 10 mg every 6 hours for children aged 12 years or older AND/OR ADDITIONAL RISK FACTORS, such as co-medication with CYP3A4 inhibitors and/or reduced kidney function:

\n

Codeine is contra-indicated. If possible, select an alternative.

\n\n

DOSES LOWER THAN OR EQUAL TO 20 mg every 6 hours for adults and 10 mg every 6 hours for children aged 12 years or older AND NO ADDITIONAL RISK FACTORS, such as co-medication with CYP3A4 inhibitors and/or reduced kidney function:\nNo action required.

\n", + "id" : 1452103820, + "html" : "

The guideline does not provide a recommendation for codeine in normal metabolizers.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302266", - "name" : "Recommendation Annotation PA166302266", + "id" : "PA166302269", + "name" : "Recommendation Annotation PA166302269", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -112615,115 +113757,117 @@ "implications" : [ "The genetic variation increases the conversion of codeine to morphine. This can result in an increase in side effects. Death has occurred in children who received analgesic doses. One adult with reduced kidney function and co-medication with two CYP3A4 inhibitors became comatose after use of codeine for a cough." ], - "lookupKey" : {"CYP2D6": "≥3.5"}, + "lookupKey" : {"CYP2D6": "≥6.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449088", "name" : "codeine", - "version" : 14 + "version" : 48 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104970", "name" : "Annotation of DPWG Guideline for codeine and CYP2D6", - "version" : 37 + "version" : 138 }, "text" : { - "id" : 1452103825, - "html" : "

DOSES HIGHER THAN 20 mg every 6 hours for adults and 10 mg every 6 hours for children aged 12 years or older AND/OR ADDITIONAL RISK FACTORS, such as co-medication with CYP3A4 inhibitors and/or reduced kidney function:\nCodeine is contra-indicated. If possible, select an alternative.

\n\n

DOSES LOWER THAN OR EQUAL TO 20 mg every 6 hours for adults and 10 mg every 6 hours for children aged 12 years or older AND NO ADDITIONAL RISK FACTORS, such as co-medication with CYP3A4 inhibitors and/or reduced kidney function:\nNo action required.

\n", - "version" : 0 + "id" : 1452103828, + "html" : "

DOSES HIGHER THAN 20 mg every 6 hours for adults and 10 mg every 6 hours for children aged 12 years or older AND/OR ADDITIONAL RISK FACTORS, such as co-medication with CYP3A4 inhibitors and/or reduced kidney function:

\n

Codeine is contra-indicated. If possible, select an alternative.

\n\n

DOSES LOWER THAN OR EQUAL TO 20 mg every 6 hours for adults and 10 mg every 6 hours for children aged 12 years or older AND NO ADDITIONAL RISK FACTORS, such as co-medication with CYP3A4 inhibitors and/or reduced kidney function:\nNo action required.

\n", + "version" : 1 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302244", - "name" : "Recommendation Annotation PA166302244", - "alternateDrugAvailable" : false, + "id" : "PA166302268", + "name" : "Recommendation Annotation PA166302268", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, "dosingInformation" : false, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on codeine." + "The genetic variation increases the conversion of codeine to morphine. This can result in an increase in side effects. Death has occurred in children who received analgesic doses. One adult with reduced kidney function and co-medication with two CYP3A4 inhibitors became comatose after use of codeine for a cough." ], - "lookupKey" : {"CYP2D6": "2.25"}, + "lookupKey" : {"CYP2D6": "≥5.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449088", "name" : "codeine", - "version" : 14 + "version" : 48 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104970", "name" : "Annotation of DPWG Guideline for codeine and CYP2D6", - "version" : 37 + "version" : 138 }, "text" : { - "id" : 1452103803, - "html" : "

The guideline does not provide a recommendation for codeine in normal metabolizers.

\n", - "version" : 0 + "id" : 1452103827, + "html" : "

DOSES HIGHER THAN 20 mg every 6 hours for adults and 10 mg every 6 hours for children aged 12 years or older AND/OR ADDITIONAL RISK FACTORS, such as co-medication with CYP3A4 inhibitors and/or reduced kidney function:

\n

Codeine is contra-indicated. If possible, select an alternative.

\n\n

DOSES LOWER THAN OR EQUAL TO 20 mg every 6 hours for adults and 10 mg every 6 hours for children aged 12 years or older AND NO ADDITIONAL RISK FACTORS, such as co-medication with CYP3A4 inhibitors and/or reduced kidney function:\nNo action required.

\n", + "version" : 1 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302261", - "name" : "Recommendation Annotation PA166302261", - "alternateDrugAvailable" : false, + "id" : "PA166302267", + "name" : "Recommendation Annotation PA166302267", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, "dosingInformation" : false, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on codeine." + "The genetic variation increases the conversion of codeine to morphine. This can result in an increase in side effects. Death has occurred in children who received analgesic doses. One adult with reduced kidney function and co-medication with two CYP3A4 inhibitors became comatose after use of codeine for a cough." ], - "lookupKey" : {"CYP2D6": "2.5"}, + "lookupKey" : {"CYP2D6": "≥4.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449088", "name" : "codeine", - "version" : 14 + "version" : 48 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104970", "name" : "Annotation of DPWG Guideline for codeine and CYP2D6", - "version" : 37 + "version" : 138 }, "text" : { - "id" : 1452103820, - "html" : "

The guideline does not provide a recommendation for codeine in normal metabolizers.

\n", - "version" : 0 + "id" : 1452103826, + "html" : "

DOSES HIGHER THAN 20 mg every 6 hours for adults and 10 mg every 6 hours for children aged 12 years or older AND/OR ADDITIONAL RISK FACTORS, such as co-medication with CYP3A4 inhibitors and/or reduced kidney function:

\n

Codeine is contra-indicated. If possible, select an alternative.

\n\n

DOSES LOWER THAN OR EQUAL TO 20 mg every 6 hours for adults and 10 mg every 6 hours for children aged 12 years or older AND NO ADDITIONAL RISK FACTORS, such as co-medication with CYP3A4 inhibitors and/or reduced kidney function:\nNo action required.

\n", + "version" : 1 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302265", - "name" : "Recommendation Annotation PA166302265", + "id" : "PA166302266", + "name" : "Recommendation Annotation PA166302266", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -112739,74 +113883,75 @@ "implications" : [ "The genetic variation increases the conversion of codeine to morphine. This can result in an increase in side effects. Death has occurred in children who received analgesic doses. One adult with reduced kidney function and co-medication with two CYP3A4 inhibitors became comatose after use of codeine for a cough." ], - "lookupKey" : {"CYP2D6": "≥3.25"}, + "lookupKey" : {"CYP2D6": "≥3.5"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449088", "name" : "codeine", - "version" : 14 + "version" : 48 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104970", "name" : "Annotation of DPWG Guideline for codeine and CYP2D6", - "version" : 37 + "version" : 138 }, "text" : { - "id" : 1452103824, - "html" : "

DOSES HIGHER THAN 20 mg every 6 hours for adults and 10 mg every 6 hours for children aged 12 years or older AND/OR ADDITIONAL RISK FACTORS, such as co-medication with CYP3A4 inhibitors and/or reduced kidney function:

\n

Codeine is contra-indicated. If possible, select an alternative.

\n\n

DOSES LOWER THAN OR EQUAL TO 20 mg every 6 hours for adults and 10 mg every 6 hours for children aged 12 years or older AND NO ADDITIONAL RISK FACTORS, such as co-medication with CYP3A4 inhibitors and/or reduced kidney function:\nNo action required.

\n", - "version" : 0 + "id" : 1452103825, + "html" : "

DOSES HIGHER THAN 20 mg every 6 hours for adults and 10 mg every 6 hours for children aged 12 years or older AND/OR ADDITIONAL RISK FACTORS, such as co-medication with CYP3A4 inhibitors and/or reduced kidney function:\nCodeine is contra-indicated. If possible, select an alternative.

\n\n

DOSES LOWER THAN OR EQUAL TO 20 mg every 6 hours for adults and 10 mg every 6 hours for children aged 12 years or older AND NO ADDITIONAL RISK FACTORS, such as co-medication with CYP3A4 inhibitors and/or reduced kidney function:\nNo action required.

\n", + "version" : 1 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302243", - "name" : "Recommendation Annotation PA166302243", - "alternateDrugAvailable" : false, + "id" : "PA166302265", + "name" : "Recommendation Annotation PA166302265", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, "dosingInformation" : false, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on codeine." + "The genetic variation increases the conversion of codeine to morphine. This can result in an increase in side effects. Death has occurred in children who received analgesic doses. One adult with reduced kidney function and co-medication with two CYP3A4 inhibitors became comatose after use of codeine for a cough." ], - "lookupKey" : {"CYP2D6": "2.0"}, + "lookupKey" : {"CYP2D6": "≥3.25"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449088", "name" : "codeine", - "version" : 14 + "version" : 48 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104970", "name" : "Annotation of DPWG Guideline for codeine and CYP2D6", - "version" : 37 + "version" : 138 }, "text" : { - "id" : 1452103802, - "html" : "

The guideline does not provide a recommendation for codeine in normal metabolizers.

\n", - "version" : 0 + "id" : 1452103824, + "html" : "

DOSES HIGHER THAN 20 mg every 6 hours for adults and 10 mg every 6 hours for children aged 12 years or older AND/OR ADDITIONAL RISK FACTORS, such as co-medication with CYP3A4 inhibitors and/or reduced kidney function:

\n

Codeine is contra-indicated. If possible, select an alternative.

\n\n

DOSES LOWER THAN OR EQUAL TO 20 mg every 6 hours for adults and 10 mg every 6 hours for children aged 12 years or older AND NO ADDITIONAL RISK FACTORS, such as co-medication with CYP3A4 inhibitors and/or reduced kidney function:\nNo action required.

\n", + "version" : 1 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302221", - "name" : "Recommendation Annotation PA166302221", + "id" : "PA166302264", + "name" : "Recommendation Annotation PA166302264", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -112818,37 +113963,37 @@ "valid" : true, "version" : 1 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "The genetic variation reduces the conversion of codeine to morphine. This can result in reduced analgesia." + "The genetic variation increases the conversion of codeine to morphine. This can result in an increase in side effects. Death has occurred in children who received analgesic doses. One adult with reduced kidney function and co-medication with two CYP3A4 inhibitors became comatose after use of codeine for a cough." ], - "lookupKey" : {"CYP2D6": "1.0"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"CYP2D6": "≥3.0"}, + "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449088", "name" : "codeine", - "version" : 14 + "version" : 48 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104970", "name" : "Annotation of DPWG Guideline for codeine and CYP2D6", - "version" : 37 + "version" : 138 }, "text" : { - "id" : 1452103780, - "html" : "

For PAIN:\nIt is not possible to offer adequately substantiated advice for dose adjustment based on the limited available literature for this phenotype.

\n
    \n
  1. Be alert to a reduced effectiveness.
    2. \n
  2. In the case of inadequate effectiveness: 1. Try a dose increase. 2. If this does not work: choose an alternative.\nDo not select tramadol, as this is also metabolised by CYP2D6. Morphine is not metabolised by CYP2D6. Oxycodone is metabolised by CYP2D6 to a limited extent, but this does not result in differences in analgesia in patients.
    3. \n
  3. If no alternative is selected: advise the patient to report inadequate analgesia.
    4. \n
\n

For COUGH:\nNo action required.

\n", - "version" : 0 + "id" : 1452103823, + "html" : "

DOSES HIGHER THAN 20 mg every 6 hours for adults and 10 mg every 6 hours for children aged 12 years or older AND/OR ADDITIONAL RISK FACTORS, such as co-medication with CYP3A4 inhibitors and/or reduced kidney function:

\n

Codeine is contra-indicated. If possible, select an alternative.

\n\n

DOSES LOWER THAN OR EQUAL TO 20 mg every 6 hours for adults and 10 mg every 6 hours for children aged 12 years or older AND NO ADDITIONAL RISK FACTORS, such as co-medication with CYP3A4 inhibitors and/or reduced kidney function:\nNo action required.

\n", + "version" : 1 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302269", - "name" : "Recommendation Annotation PA166302269", + "id" : "PA166302263", + "name" : "Recommendation Annotation PA166302263", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -112864,33 +114009,33 @@ "implications" : [ "The genetic variation increases the conversion of codeine to morphine. This can result in an increase in side effects. Death has occurred in children who received analgesic doses. One adult with reduced kidney function and co-medication with two CYP3A4 inhibitors became comatose after use of codeine for a cough." ], - "lookupKey" : {"CYP2D6": "≥6.0"}, + "lookupKey" : {"CYP2D6": "4.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449088", "name" : "codeine", - "version" : 14 + "version" : 48 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104970", "name" : "Annotation of DPWG Guideline for codeine and CYP2D6", - "version" : 37 + "version" : 138 }, "text" : { - "id" : 1452103828, + "id" : 1452103822, "html" : "

DOSES HIGHER THAN 20 mg every 6 hours for adults and 10 mg every 6 hours for children aged 12 years or older AND/OR ADDITIONAL RISK FACTORS, such as co-medication with CYP3A4 inhibitors and/or reduced kidney function:

\n

Codeine is contra-indicated. If possible, select an alternative.

\n\n

DOSES LOWER THAN OR EQUAL TO 20 mg every 6 hours for adults and 10 mg every 6 hours for children aged 12 years or older AND NO ADDITIONAL RISK FACTORS, such as co-medication with CYP3A4 inhibitors and/or reduced kidney function:\nNo action required.

\n", - "version" : 0 + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302181", - "name" : "Recommendation Annotation PA166302181", + "id" : "PA166302262", + "name" : "Recommendation Annotation PA166302262", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -112902,32 +114047,32 @@ "valid" : true, "version" : 1 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "The genetic variation reduces the conversion of codeine to morphine. This can result in reduced analgesia." + "The genetic variation increases the conversion of codeine to morphine. This can result in an increase in side effects. Death has occurred in children who received analgesic doses. One adult with reduced kidney function and co-medication with two CYP3A4 inhibitors became comatose after use of codeine for a cough." ], - "lookupKey" : {"CYP2D6": "0.25"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"CYP2D6": "3.0"}, + "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449088", "name" : "codeine", - "version" : 14 + "version" : 48 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104970", "name" : "Annotation of DPWG Guideline for codeine and CYP2D6", - "version" : 37 + "version" : 138 }, "text" : { - "id" : 1452103740, - "html" : "

For PAIN:\nIt is not possible to offer adequately substantiated advice for dose adjustment based on the limited available literature for this phenotype.

\n
    \n
  1. Be alert to a reduced effectiveness.
    2. \n
  2. In the case of inadequate effectiveness: 1. Try a dose increase. 2. If this does not work: choose an alternative.\nDo not select tramadol, as this is also metabolised by CYP2D6. Morphine is not metabolised by CYP2D6. Oxycodone is metabolised by CYP2D6 to a limited extent, but this does not result in differences in analgesia in patients.
    3. \n
  3. If no alternative is selected: advise the patient to report inadequate analgesia.
    4. \n
\n

For COUGH:\nNo action required.

\n", - "version" : 0 + "id" : 1452103821, + "html" : "

DOSES HIGHER THAN 20 mg every 6 hours for adults and 10 mg every 6 hours for children aged 12 years or older AND/OR ADDITIONAL RISK FACTORS, such as co-medication with CYP3A4 inhibitors and/or reduced kidney function:

\n

Codeine is contra-indicated. If possible, select an alternative.

\n\n

DOSES LOWER THAN OR EQUAL TO 20 mg every 6 hours for adults and 10 mg every 6 hours for children aged 12 years or older AND NO ADDITIONAL RISK FACTORS, such as co-medication with CYP3A4 inhibitors and/or reduced kidney function:\nNo action required.

\n", + "version" : 2 }, - "version" : 0 + "version" : 2 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166104970" @@ -113143,7 +114288,7 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "relatedGenes" : [ @@ -113152,192 +114297,25 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "DPWG", "summaryMarkdown" : { "id" : 1447982020, "html" : "

The Dutch Pharmacogenetics Working Group Guideline for doxepin recommends dose changes and to monitor the effect and side effects or the plasma concentrations to set the maintenance dose for CYP2D6 poor (PM), intermediate (IM), and ultrarapid (UM) metabolizer or to avoid doxepin in UM.

\n", - "version" : 1 + "version" : 2 }, "terms" : [], "textMarkdown" : { "id" : 1447982019, "html" : "

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

\n

November 2018 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for doxepin based on CYP2D6 genotype. They recommend dose changes and to monitor the effect and side effects or the plasma concentrations to set the maintenance dose for CYP2D6 poor (PM), intermediate (IM), and ultrarapid (UM) metabolizer or to avoid doxepin in UM.

\n

Wording in table taken from the Dutch guidelines November 2018 update

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
CYP2D6 UMdoxepinThe risk of ineffectiveness and cardiotoxic side effects may be increased. The gene variation leads to reduced plasma concentrations of doxepin and the active metabolite nordoxepin and an increase in the plasma concentrations of the potentially cardiotoxic hydroxy metabolites.Double the standard dose and monitor the effect and side effects or the plasma concentrations of doxepin and nordoxepin in order to set the maintenance dose. The therapeutic range is 100-250 ng/mL for the sum of doxepin and nordoxepin plasma concentrations. Values higher than 400 ng/mL are considered toxic. If a dose increase is not wanted due to the potentially cardiotoxic hydroxy metabolites: avoid doxepin. Antidepressants that are not metabolised by CYP2D6, or to a lesser extent, include citalopram and sertraline.
CYP2D6 IMdoxepinThe risk of side effects may be increased, because the gene variation leads to increased plasma concentrations of doxepin and the active metabolite nordoxepin.Use 80% of the standard dose and monitor the effect and side effects or the plasma concentrations of doxepin and nordoxepin in order to set the maintenance dose. The therapeutic range is 100-250 ng/mL for the sum of doxepin and nordoxepin plasma concentrations. Values higher than 400 ng/mL are considered toxic.
CYP2D6 PMdoxepinThe risk of side effects may be increased, because the gene variation leads to increased plasma concentrations of doxepin and the active metabolite nordoxepin.Use 40% of the standard dose and monitor the effect and side effects or the plasma concentrations of doxepin and nordoxepin in order to set the maintenance dose. The therapeutic range is 100-250 ng/mL for the sum of doxepin and nordoxepin plasma concentrations. Values higher than 400 ng/mL are considered toxic.
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for doxepin and CYP2D6:

\n
\n

The Dutch Pharmacogenetics Working Group considers genotyping before starting doxepin to be potentially beneficial for the prevention of side effects. Genotyping can be considered on an individual patient basis. If, however, the genotype is available, the Dutch Pharmacogenetics Working Group recommends adhering to the gene-drug guideline.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n

2011 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for doxepin based on CYP2D6 genotypes [Article:21412232]. They recommend lower dose for patients carrying the poor metabolizer (PM) alleles and intermediate metabolizer alleles and alternative drug for patients carrying the ultrarapid metabolizer (UM) allleles.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Phenotype (Genotype)Therapeutic Dose RecommendationLevel of EvidenceClinical Relevance
PM (two inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) alleles)Reduce dose by 60%. Adjust maintenance dose in response to (nor)doxepin plasma concentrationPublished controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Clinical effect (S): death; arrhythmia; unanticipated myelosuppression.
IM (two decreased-activity (*9, *10, *17, *29, *36, *41) alleles or carrying one active (*1, *2, *33, *35) and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele, or carrying one decreased-activity (*9, *10, *17, *29, *36, *41) allele and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele)Reduce dose by 20%. Adjust maintenance dose in response to (nor)doxepin plasma concentration.Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Minor clinical effect (S): QTc prolongation (<450 ms female, <470 ms male); INR increase < 4.5 Kinetic effect (S)
UM (a gene duplication in absence of inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) or decreased-activity (*9, *10, *17, *29, *36, *41) alleles)Select alternative drug (citalopram, sertraline) or increase dose by 100%. Adjust maintenance dose in response to (nor)doxepin plasma concentration.Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Minor clinical effect (S): QTc prolongation (<450 ms female, <470 ms male); INR increase < 4.5 Kinetic effect (S).
\n\n", - "version" : 16 + "version" : 21 }, "userId" : "lester", - "version" : 31 + "version" : 102 }, "recommendations" : [ - { - "objCls" : "Recommendation Annotation", - "id" : "PA166302273", - "name" : "Recommendation Annotation PA166302273", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 981501929, - "description" : "Not Applicable", - "parents" : [], - "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", - "valid" : true, - "version" : 1 - }, - "dosingInformation" : true, - "implications" : [ - "The risk of side effects may be increased, because the gene variation leads to increased plasma concentrations of doxepin and the active metabolite nordoxepin." - ], - "lookupKey" : {"CYP2D6": "0.75"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA449409", - "name" : "doxepin", - "version" : 9 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166104994", - "name" : "Annotation of DPWG Guideline for doxepin and CYP2D6", - "version" : 31 - }, - "text" : { - "id" : 1452103832, - "html" : "

Use 80% of the standard dose and monitor the effect and side effects or the plasma concentrations of doxepin and nordoxepin in order to set the maintenance dose. The therapeutic range is 100-250 ng/mL for the sum of doxepin and nordoxepin plasma concentrations. Values higher than 400 ng/mL are considered toxic.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166302286", - "name" : "Recommendation Annotation PA166302286", - "alternateDrugAvailable" : true, - "classification" : { - "id" : 981501929, - "description" : "Not Applicable", - "parents" : [], - "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", - "valid" : true, - "version" : 1 - }, - "dosingInformation" : true, - "implications" : [ - "The risk of ineffectiveness and cardiotoxic side effects may be increased. The gene variation leads to reduced plasma concentrations of doxepin and the active metabolite nordoxepin and an increase in the plasma concentrations of the potentially cardiotoxic hydroxy metabolites." - ], - "lookupKey" : {"CYP2D6": "≥5.0"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA449409", - "name" : "doxepin", - "version" : 9 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166104994", - "name" : "Annotation of DPWG Guideline for doxepin and CYP2D6", - "version" : 31 - }, - "text" : { - "id" : 1452103865, - "html" : "

Double the standard dose and monitor the effect and side effects or the plasma concentrations of doxepin and nordoxepin in order to set the maintenance dose. The therapeutic range is 100-250 ng/mL for the sum of doxepin and nordoxepin plasma concentrations. Values higher than 400 ng/mL are considered toxic.

\n

If a dose increase is not wanted due to the potentially cardiotoxic hydroxy metabolites: avoid doxepin. Antidepressants that are not metabolised by CYP2D6, or to a lesser extent, include citalopram and sertraline.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166302277", - "name" : "Recommendation Annotation PA166302277", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 1448526251, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on doxepin." - ], - "lookupKey" : {"CYP2D6": "2.0"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA449409", - "name" : "doxepin", - "version" : 9 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166104994", - "name" : "Annotation of DPWG Guideline for doxepin and CYP2D6", - "version" : 31 - }, - "text" : { - "id" : 1452103836, - "html" : "

The guideline does not provide a recommendation for doxepin in normal metabolizers.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166302281", - "name" : "Recommendation Annotation PA166302281", - "alternateDrugAvailable" : true, - "classification" : { - "id" : 981501929, - "description" : "Not Applicable", - "parents" : [], - "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", - "valid" : true, - "version" : 1 - }, - "dosingInformation" : true, - "implications" : [ - "The risk of ineffectiveness and cardiotoxic side effects may be increased. The gene variation leads to reduced plasma concentrations of doxepin and the active metabolite nordoxepin and an increase in the plasma concentrations of the potentially cardiotoxic hydroxy metabolites." - ], - "lookupKey" : {"CYP2D6": "4.0"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA449409", - "name" : "doxepin", - "version" : 9 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166104994", - "name" : "Annotation of DPWG Guideline for doxepin and CYP2D6", - "version" : 31 - }, - "text" : { - "id" : 1452103860, - "html" : "

Double the standard dose and monitor the effect and side effects or the plasma concentrations of doxepin and nordoxepin in order to set the maintenance dose. The therapeutic range is 100-250 ng/mL for the sum of doxepin and nordoxepin plasma concentrations. Values higher than 400 ng/mL are considered toxic.

\n

If a dose increase is not wanted due to the potentially cardiotoxic hydroxy metabolites: avoid doxepin. Antidepressants that are not metabolised by CYP2D6, or to a lesser extent, include citalopram and sertraline.

\n", - "version" : 0 - }, - "version" : 0 - }, { "objCls" : "Recommendation Annotation", "id" : "PA166302272", @@ -113364,14 +114342,14 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104994", "name" : "Annotation of DPWG Guideline for doxepin and CYP2D6", - "version" : 31 + "version" : 102 }, "text" : { "id" : 1452103831, @@ -113382,9 +114360,9 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302285", - "name" : "Recommendation Annotation PA166302285", - "alternateDrugAvailable" : true, + "id" : "PA166302270", + "name" : "Recommendation Annotation PA166302270", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -113397,77 +114375,36 @@ }, "dosingInformation" : true, "implications" : [ - "The risk of ineffectiveness and cardiotoxic side effects may be increased. The gene variation leads to reduced plasma concentrations of doxepin and the active metabolite nordoxepin and an increase in the plasma concentrations of the potentially cardiotoxic hydroxy metabolites." + "The risk of side effects may be increased, because the gene variation leads to increased plasma concentrations of doxepin and the active metabolite nordoxepin." ], - "lookupKey" : {"CYP2D6": "≥4.0"}, + "lookupKey" : {"CYP2D6": "0.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104994", "name" : "Annotation of DPWG Guideline for doxepin and CYP2D6", - "version" : 31 + "version" : 102 }, "text" : { - "id" : 1452103864, - "html" : "

Double the standard dose and monitor the effect and side effects or the plasma concentrations of doxepin and nordoxepin in order to set the maintenance dose. The therapeutic range is 100-250 ng/mL for the sum of doxepin and nordoxepin plasma concentrations. Values higher than 400 ng/mL are considered toxic.

\n

If a dose increase is not wanted due to the potentially cardiotoxic hydroxy metabolites: avoid doxepin. Antidepressants that are not metabolised by CYP2D6, or to a lesser extent, include citalopram and sertraline.

\n", + "id" : 1452103829, + "html" : "

Use 40% of the standard dose and monitor the effect and side effects or the plasma concentrations of doxepin and nordoxepin in order to set the maintenance dose. The therapeutic range is 100-250 ng/mL for the sum of doxepin and nordoxepin plasma concentrations. Values higher than 400 ng/mL are considered toxic.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302276", - "name" : "Recommendation Annotation PA166302276", + "id" : "PA166302271", + "name" : "Recommendation Annotation PA166302271", "alternateDrugAvailable" : false, - "classification" : { - "id" : 1448526251, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on doxepin." - ], - "lookupKey" : {"CYP2D6": "1.5"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA449409", - "name" : "doxepin", - "version" : 9 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166104994", - "name" : "Annotation of DPWG Guideline for doxepin and CYP2D6", - "version" : 31 - }, - "text" : { - "id" : 1452103835, - "html" : "

The guideline does not provide a recommendation for doxepin in normal metabolizers.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166302280", - "name" : "Recommendation Annotation PA166302280", - "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -113480,35 +114417,35 @@ }, "dosingInformation" : true, "implications" : [ - "The risk of ineffectiveness and cardiotoxic side effects may be increased. The gene variation leads to reduced plasma concentrations of doxepin and the active metabolite nordoxepin and an increase in the plasma concentrations of the potentially cardiotoxic hydroxy metabolites." + "The risk of side effects may be increased, because the gene variation leads to increased plasma concentrations of doxepin and the active metabolite nordoxepin." ], - "lookupKey" : {"CYP2D6": "3.0"}, + "lookupKey" : {"CYP2D6": "0.25"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104994", "name" : "Annotation of DPWG Guideline for doxepin and CYP2D6", - "version" : 31 + "version" : 102 }, "text" : { - "id" : 1452103839, - "html" : "

Double the standard dose and monitor the effect and side effects or the plasma concentrations of doxepin and nordoxepin in order to set the maintenance dose. The therapeutic range is 100-250 ng/mL for the sum of doxepin and nordoxepin plasma concentrations. Values higher than 400 ng/mL are considered toxic.

\n

If a dose increase is not wanted due to the potentially cardiotoxic hydroxy metabolites: avoid doxepin. Antidepressants that are not metabolised by CYP2D6, or to a lesser extent, include citalopram and sertraline.

\n", + "id" : 1452103830, + "html" : "

Use 80% of the standard dose and monitor the effect and side effects or the plasma concentrations of doxepin and nordoxepin in order to set the maintenance dose. The therapeutic range is 100-250 ng/mL for the sum of doxepin and nordoxepin plasma concentrations. Values higher than 400 ng/mL are considered toxic.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302271", - "name" : "Recommendation Annotation PA166302271", + "id" : "PA166302273", + "name" : "Recommendation Annotation PA166302273", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -113524,24 +114461,24 @@ "implications" : [ "The risk of side effects may be increased, because the gene variation leads to increased plasma concentrations of doxepin and the active metabolite nordoxepin." ], - "lookupKey" : {"CYP2D6": "0.25"}, + "lookupKey" : {"CYP2D6": "0.75"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104994", "name" : "Annotation of DPWG Guideline for doxepin and CYP2D6", - "version" : 31 + "version" : 102 }, "text" : { - "id" : 1452103830, + "id" : 1452103832, "html" : "

Use 80% of the standard dose and monitor the effect and side effects or the plasma concentrations of doxepin and nordoxepin in order to set the maintenance dose. The therapeutic range is 100-250 ng/mL for the sum of doxepin and nordoxepin plasma concentrations. Values higher than 400 ng/mL are considered toxic.

\n", "version" : 0 }, @@ -113549,9 +114486,9 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302284", - "name" : "Recommendation Annotation PA166302284", - "alternateDrugAvailable" : true, + "id" : "PA166302274", + "name" : "Recommendation Annotation PA166302274", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -113564,27 +114501,27 @@ }, "dosingInformation" : true, "implications" : [ - "The risk of ineffectiveness and cardiotoxic side effects may be increased. The gene variation leads to reduced plasma concentrations of doxepin and the active metabolite nordoxepin and an increase in the plasma concentrations of the potentially cardiotoxic hydroxy metabolites." + "The risk of side effects may be increased, because the gene variation leads to increased plasma concentrations of doxepin and the active metabolite nordoxepin." ], - "lookupKey" : {"CYP2D6": "≥3.5"}, + "lookupKey" : {"CYP2D6": "1.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104994", "name" : "Annotation of DPWG Guideline for doxepin and CYP2D6", - "version" : 31 + "version" : 102 }, "text" : { - "id" : 1452103863, - "html" : "

Double the standard dose and monitor the effect and side effects or the plasma concentrations of doxepin and nordoxepin in order to set the maintenance dose. The therapeutic range is 100-250 ng/mL for the sum of doxepin and nordoxepin plasma concentrations. Values higher than 400 ng/mL are considered toxic.

\n

If a dose increase is not wanted due to the potentially cardiotoxic hydroxy metabolites: avoid doxepin. Antidepressants that are not metabolised by CYP2D6, or to a lesser extent, include citalopram and sertraline.

\n", + "id" : 1452103833, + "html" : "

Use 80% of the standard dose and monitor the effect and side effects or the plasma concentrations of doxepin and nordoxepin in order to set the maintenance dose. The therapeutic range is 100-250 ng/mL for the sum of doxepin and nordoxepin plasma concentrations. Values higher than 400 ng/mL are considered toxic.

\n", "version" : 0 }, "version" : 0 @@ -113614,14 +114551,14 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104994", "name" : "Annotation of DPWG Guideline for doxepin and CYP2D6", - "version" : 31 + "version" : 102 }, "text" : { "id" : 1452103834, @@ -113630,6 +114567,129 @@ }, "version" : 0 }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166302276", + "name" : "Recommendation Annotation PA166302276", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 1448526251, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : false, + "implications" : [ + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on doxepin." + ], + "lookupKey" : {"CYP2D6": "1.5"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA449409", + "name" : "doxepin", + "version" : 38 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104994", + "name" : "Annotation of DPWG Guideline for doxepin and CYP2D6", + "version" : 102 + }, + "text" : { + "id" : 1452103835, + "html" : "

The guideline does not provide a recommendation for doxepin in normal metabolizers.

\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166302277", + "name" : "Recommendation Annotation PA166302277", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 1448526251, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : false, + "implications" : [ + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on doxepin." + ], + "lookupKey" : {"CYP2D6": "2.0"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA449409", + "name" : "doxepin", + "version" : 38 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104994", + "name" : "Annotation of DPWG Guideline for doxepin and CYP2D6", + "version" : 102 + }, + "text" : { + "id" : 1452103836, + "html" : "

The guideline does not provide a recommendation for doxepin in normal metabolizers.

\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166302278", + "name" : "Recommendation Annotation PA166302278", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 1448526251, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : false, + "implications" : [ + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on doxepin." + ], + "lookupKey" : {"CYP2D6": "2.25"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA449409", + "name" : "doxepin", + "version" : 38 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104994", + "name" : "Annotation of DPWG Guideline for doxepin and CYP2D6", + "version" : 102 + }, + "text" : { + "id" : 1452103837, + "html" : "

The guideline does not provide a recommendation for doxepin in normal metabolizers.

\n", + "version" : 0 + }, + "version" : 0 + }, { "objCls" : "Recommendation Annotation", "id" : "PA166302279", @@ -113655,14 +114715,14 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104994", "name" : "Annotation of DPWG Guideline for doxepin and CYP2D6", - "version" : 31 + "version" : 102 }, "text" : { "id" : 1452103838, @@ -113673,9 +114733,9 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302270", - "name" : "Recommendation Annotation PA166302270", - "alternateDrugAvailable" : false, + "id" : "PA166302280", + "name" : "Recommendation Annotation PA166302280", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -113688,27 +114748,111 @@ }, "dosingInformation" : true, "implications" : [ - "The risk of side effects may be increased, because the gene variation leads to increased plasma concentrations of doxepin and the active metabolite nordoxepin." + "The risk of ineffectiveness and cardiotoxic side effects may be increased. The gene variation leads to reduced plasma concentrations of doxepin and the active metabolite nordoxepin and an increase in the plasma concentrations of the potentially cardiotoxic hydroxy metabolites." ], - "lookupKey" : {"CYP2D6": "0.0"}, + "lookupKey" : {"CYP2D6": "3.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104994", "name" : "Annotation of DPWG Guideline for doxepin and CYP2D6", - "version" : 31 + "version" : 102 }, "text" : { - "id" : 1452103829, - "html" : "

Use 40% of the standard dose and monitor the effect and side effects or the plasma concentrations of doxepin and nordoxepin in order to set the maintenance dose. The therapeutic range is 100-250 ng/mL for the sum of doxepin and nordoxepin plasma concentrations. Values higher than 400 ng/mL are considered toxic.

\n", + "id" : 1452103839, + "html" : "

Double the standard dose and monitor the effect and side effects or the plasma concentrations of doxepin and nordoxepin in order to set the maintenance dose. The therapeutic range is 100-250 ng/mL for the sum of doxepin and nordoxepin plasma concentrations. Values higher than 400 ng/mL are considered toxic.

\n

If a dose increase is not wanted due to the potentially cardiotoxic hydroxy metabolites: avoid doxepin. Antidepressants that are not metabolised by CYP2D6, or to a lesser extent, include citalopram and sertraline.

\n", + "version" : 0 + }, + "version" : 1 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166302281", + "name" : "Recommendation Annotation PA166302281", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981501929, + "description" : "Not Applicable", + "parents" : [], + "resource" : "Guideline Strength", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", + "valid" : true, + "version" : 1 + }, + "dosingInformation" : true, + "implications" : [ + "The risk of ineffectiveness and cardiotoxic side effects may be increased. The gene variation leads to reduced plasma concentrations of doxepin and the active metabolite nordoxepin and an increase in the plasma concentrations of the potentially cardiotoxic hydroxy metabolites." + ], + "lookupKey" : {"CYP2D6": "4.0"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA449409", + "name" : "doxepin", + "version" : 38 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104994", + "name" : "Annotation of DPWG Guideline for doxepin and CYP2D6", + "version" : 102 + }, + "text" : { + "id" : 1452103860, + "html" : "

Double the standard dose and monitor the effect and side effects or the plasma concentrations of doxepin and nordoxepin in order to set the maintenance dose. The therapeutic range is 100-250 ng/mL for the sum of doxepin and nordoxepin plasma concentrations. Values higher than 400 ng/mL are considered toxic.

\n

If a dose increase is not wanted due to the potentially cardiotoxic hydroxy metabolites: avoid doxepin. Antidepressants that are not metabolised by CYP2D6, or to a lesser extent, include citalopram and sertraline.

\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166302282", + "name" : "Recommendation Annotation PA166302282", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981501929, + "description" : "Not Applicable", + "parents" : [], + "resource" : "Guideline Strength", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", + "valid" : true, + "version" : 1 + }, + "dosingInformation" : true, + "implications" : [ + "The risk of ineffectiveness and cardiotoxic side effects may be increased. The gene variation leads to reduced plasma concentrations of doxepin and the active metabolite nordoxepin and an increase in the plasma concentrations of the potentially cardiotoxic hydroxy metabolites." + ], + "lookupKey" : {"CYP2D6": "≥3.0"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA449409", + "name" : "doxepin", + "version" : 38 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104994", + "name" : "Annotation of DPWG Guideline for doxepin and CYP2D6", + "version" : 102 + }, + "text" : { + "id" : 1452103861, + "html" : "

Double the standard dose and monitor the effect and side effects or the plasma concentrations of doxepin and nordoxepin in order to set the maintenance dose. The therapeutic range is 100-250 ng/mL for the sum of doxepin and nordoxepin plasma concentrations. Values higher than 400 ng/mL are considered toxic.

\n

If a dose increase is not wanted due to the potentially cardiotoxic hydroxy metabolites: avoid doxepin. Antidepressants that are not metabolised by CYP2D6, or to a lesser extent, include citalopram and sertraline.

\n", "version" : 0 }, "version" : 0 @@ -113739,14 +114883,14 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104994", "name" : "Annotation of DPWG Guideline for doxepin and CYP2D6", - "version" : 31 + "version" : 102 }, "text" : { "id" : 1452103862, @@ -113757,8 +114901,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302287", - "name" : "Recommendation Annotation PA166302287", + "id" : "PA166302284", + "name" : "Recommendation Annotation PA166302284", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -113774,24 +114918,24 @@ "implications" : [ "The risk of ineffectiveness and cardiotoxic side effects may be increased. The gene variation leads to reduced plasma concentrations of doxepin and the active metabolite nordoxepin and an increase in the plasma concentrations of the potentially cardiotoxic hydroxy metabolites." ], - "lookupKey" : {"CYP2D6": "≥6.0"}, + "lookupKey" : {"CYP2D6": "≥3.5"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104994", "name" : "Annotation of DPWG Guideline for doxepin and CYP2D6", - "version" : 31 + "version" : 102 }, "text" : { - "id" : 1452103866, + "id" : 1452103863, "html" : "

Double the standard dose and monitor the effect and side effects or the plasma concentrations of doxepin and nordoxepin in order to set the maintenance dose. The therapeutic range is 100-250 ng/mL for the sum of doxepin and nordoxepin plasma concentrations. Values higher than 400 ng/mL are considered toxic.

\n

If a dose increase is not wanted due to the potentially cardiotoxic hydroxy metabolites: avoid doxepin. Antidepressants that are not metabolised by CYP2D6, or to a lesser extent, include citalopram and sertraline.

\n", "version" : 0 }, @@ -113799,9 +114943,9 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302274", - "name" : "Recommendation Annotation PA166302274", - "alternateDrugAvailable" : false, + "id" : "PA166302285", + "name" : "Recommendation Annotation PA166302285", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -113814,76 +114958,77 @@ }, "dosingInformation" : true, "implications" : [ - "The risk of side effects may be increased, because the gene variation leads to increased plasma concentrations of doxepin and the active metabolite nordoxepin." + "The risk of ineffectiveness and cardiotoxic side effects may be increased. The gene variation leads to reduced plasma concentrations of doxepin and the active metabolite nordoxepin and an increase in the plasma concentrations of the potentially cardiotoxic hydroxy metabolites." ], - "lookupKey" : {"CYP2D6": "1.0"}, + "lookupKey" : {"CYP2D6": "≥4.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104994", "name" : "Annotation of DPWG Guideline for doxepin and CYP2D6", - "version" : 31 + "version" : 102 }, "text" : { - "id" : 1452103833, - "html" : "

Use 80% of the standard dose and monitor the effect and side effects or the plasma concentrations of doxepin and nordoxepin in order to set the maintenance dose. The therapeutic range is 100-250 ng/mL for the sum of doxepin and nordoxepin plasma concentrations. Values higher than 400 ng/mL are considered toxic.

\n", + "id" : 1452103864, + "html" : "

Double the standard dose and monitor the effect and side effects or the plasma concentrations of doxepin and nordoxepin in order to set the maintenance dose. The therapeutic range is 100-250 ng/mL for the sum of doxepin and nordoxepin plasma concentrations. Values higher than 400 ng/mL are considered toxic.

\n

If a dose increase is not wanted due to the potentially cardiotoxic hydroxy metabolites: avoid doxepin. Antidepressants that are not metabolised by CYP2D6, or to a lesser extent, include citalopram and sertraline.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302278", - "name" : "Recommendation Annotation PA166302278", - "alternateDrugAvailable" : false, + "id" : "PA166302286", + "name" : "Recommendation Annotation PA166302286", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on doxepin." + "The risk of ineffectiveness and cardiotoxic side effects may be increased. The gene variation leads to reduced plasma concentrations of doxepin and the active metabolite nordoxepin and an increase in the plasma concentrations of the potentially cardiotoxic hydroxy metabolites." ], - "lookupKey" : {"CYP2D6": "2.25"}, + "lookupKey" : {"CYP2D6": "≥5.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104994", "name" : "Annotation of DPWG Guideline for doxepin and CYP2D6", - "version" : 31 + "version" : 102 }, "text" : { - "id" : 1452103837, - "html" : "

The guideline does not provide a recommendation for doxepin in normal metabolizers.

\n", + "id" : 1452103865, + "html" : "

Double the standard dose and monitor the effect and side effects or the plasma concentrations of doxepin and nordoxepin in order to set the maintenance dose. The therapeutic range is 100-250 ng/mL for the sum of doxepin and nordoxepin plasma concentrations. Values higher than 400 ng/mL are considered toxic.

\n

If a dose increase is not wanted due to the potentially cardiotoxic hydroxy metabolites: avoid doxepin. Antidepressants that are not metabolised by CYP2D6, or to a lesser extent, include citalopram and sertraline.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302282", - "name" : "Recommendation Annotation PA166302282", + "id" : "PA166302287", + "name" : "Recommendation Annotation PA166302287", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -113899,24 +115044,24 @@ "implications" : [ "The risk of ineffectiveness and cardiotoxic side effects may be increased. The gene variation leads to reduced plasma concentrations of doxepin and the active metabolite nordoxepin and an increase in the plasma concentrations of the potentially cardiotoxic hydroxy metabolites." ], - "lookupKey" : {"CYP2D6": "≥3.0"}, + "lookupKey" : {"CYP2D6": "≥6.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104994", "name" : "Annotation of DPWG Guideline for doxepin and CYP2D6", - "version" : 31 + "version" : 102 }, "text" : { - "id" : 1452103861, + "id" : 1452103866, "html" : "

Double the standard dose and monitor the effect and side effects or the plasma concentrations of doxepin and nordoxepin in order to set the maintenance dose. The therapeutic range is 100-250 ng/mL for the sum of doxepin and nordoxepin plasma concentrations. Values higher than 400 ng/mL are considered toxic.

\n

If a dose increase is not wanted due to the potentially cardiotoxic hydroxy metabolites: avoid doxepin. Antidepressants that are not metabolised by CYP2D6, or to a lesser extent, include citalopram and sertraline.

\n", "version" : 0 }, @@ -113942,7 +115087,7 @@ "date" : "2019-05-27T00:00:00-07:00", "description" : "Annotation current with November 2018 DPWG Guideline release", "type" : "Create", - "version" : 0 + "version" : 1 }, { "id" : 1450820791, @@ -114047,21 +115192,21 @@ "id" : "PA165818808", "symbol" : "CYP2B6*18", "name" : "*18", - "version" : 19 + "version" : 45 }, { "objCls" : "Haplotype", "id" : "PA165818760", "symbol" : "CYP2B6*5", "name" : "*5", - "version" : 19 + "version" : 45 }, { "objCls" : "Haplotype", "id" : "PA165818762", "symbol" : "CYP2B6*6", "name" : "*6", - "version" : 18 + "version" : 43 } ], "relatedChemicals" : [ @@ -114069,7 +115214,7 @@ "objCls" : "Chemical", "id" : "PA449441", "name" : "efavirenz", - "version" : 9 + "version" : 40 } ], "relatedGenes" : [ @@ -114078,7 +115223,7 @@ "id" : "PA123", "symbol" : "CYP2B6", "name" : "cytochrome P450 family 2 subfamily B member 6", - "version" : 6788 + "version" : 6829 } ], "source" : "DPWG", @@ -114091,10 +115236,10 @@ "textMarkdown" : { "id" : 1450415252, "html" : "

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

\n

June 2023 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group posted updates for CYP2B6, see Farmacogenetica-Update - juni 2023. The posted content translates to the following:\n"For CYP2B6, there were also separate contraindications for patients with one or two *5 alleles. This is because *5 was reported to be reduced or fully functional depending on the drug. However, more recent data indicate full functionality of *5 for all drugs. It has therefore been decided to abolish the separate contraindications for patients with *5 in six months’ time. Healthcare providers should therefore match patients currently linked to CYP2B6 *1/*5 or CYP2B6 *5/*5 to CYP2B6 NORMAL METABOLISER (NM) and patients currently linked to CYP2B6 *5/*6 OR *5/*18 have been linked to CYP2B6 INTERMEDIATE METABOLISER (IM)."

\n

May 2021 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has updated their therapeutic dose recommendations for efavirenz based on CYP2B6 genotype. There are now specific recommendations for the *5/*6 and *5/*18 genotypes and advice that no action is required in patients with the *1/*5 or *5/*5 genotypes.

\n

Wording in table taken from the Dutch guidelines May 2021 update

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
CYP2B6 IM otheraefavirenzGenetic variations increase the efavirenz plasma concentration and therefore the risk of side effects. However, the efavirenz plasma concentration remains within the therapeutic range for the majority of patients.1. Determine the efavirenz plasma concentration if side effects occur and reduce the dose if needed. In 14 IM adults, a dose reduction to 400 mg/day (2/3rd of the standard dose) was sufficient to achieve therapeutic plasma concentrations and to reduce or resolve side effects. The therapeutic range established for efavirenz is 1000-4000 ng/ml.
CYP2B6 PM othera,befavirenzGenetic variations increase the risk of side effects. The standard dose leads to an efavirenz concentration in the toxic range in the majority of patients with this genotype.* Efavirenz in MONOpreparation, adults and children FROM 40 KG: Body mass index LESS THAN or EQUAL to 25: 1. The recommended initial dose is 400 mg/day and this dose should be titrated to plasma concentration if needed (further reduction to 200 mg/day or in rare cases an increase to 600 mg/day). The therapeutic range established for efavirenz is 1000-4000 ng/ml. Body mass index GREATER than 25: 1. The recommended initial dose is 600 mg/day and this dose should be titrated to plasma concentration if needed (reduction to 400 or 200 mg/day). The therapeutic range established for efavirenz is 1000-4000 ng/ml.
*Efavirenz in MONOpreparation, children LIGHTER THAN 40 KG: 1. Start with the standard dose and titrate this dose to plasma concentration if needed. In adults, therapeutic plasma concentrations were achieved at either 2/3rd of the standard dose (1/3rd of the patients) or 1/3rd of the standard dose (2/3rd of the patients). In children younger than 3 years, therapeutic plasma concentrations were achieved at doses of approximately 10 mg/kg per day (as capsules) (100 mg/day for 7-14 kg and 150 mg/day for 14-17 kg; 50-75% of the standard dose). The therapeutic range established for efavirenz is 1000-4000 ng/ml.
*Efavirenz in COMBINATION preparation: 1. Initiate the combination preparation and titrate the efavirenz dose to plasma concentration if needed (reduction to 400 or 200 mg/day) The therapeutic range established for efavirenz is 1000-4000 ng/ml.
CYP2B6 *1/*5efavirenzGene variant *5 has no effect on the metabolism and consequently on the efficacy and side effects of efavirenz.NO action is required for this gene-drug interaction
CYP2B6 *5/*5efavirenzGene variant *5 has no effect on the metabolism and consequently on the efficacy and side effects of efavirenz.NO action is required for this gene-drug interaction
CYP2B6 *5/*6 or *5/*18efavirenzThe genetic variation increases the plasma concentration of efavirenz and thereby the risk of side effects. However, the efavirenz plasma concentration remains within the therapeutic range for the majority of patients.Determine the efavirenz plasma concentration if side effects occur and reduce the dose if needed. In 14 adults with a genotype with the same effect, a reduction of the dose to 400 mg/day (2/3 of the standard dose) was sufficient to achieve therapeutic plasma concentrations and for the side effects to reduce or disappear. The therapeutic range established for efavirenz is 1000-4000 ng/mL.
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for efavirenz and CYP2B6:

\n
\n

The KNMP Pharmacogenetics Working Group considers genotyping of patients with body mass index ≤ 25 and scheduled to receive efavirenz in a single drug preparation before starting efavirenz to be potentially beneficial for avoiding\ntherapy discontinuation due to adverse events. Genotyping can be considered on an individual patient basis. If, however, the genotype is available, the KNMP Pharmacogenetics Working Group recommends adhering to the gene-drug\nguideline.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n

a These groups are referred to in the DPWG recommendation PDF as 'IM ANDERS' and 'PM ANDERS', which use the Dutch word 'anders'. PharmGKB has translated these as 'IM other' and PM other', respectively.

\n

b Footnote from the guideline:

\n
\n

Note: the dosing recommendations above are based on PM patients with the *6/*6 genotype. There is evidence that the *18/*18 genotype in PM patients (only present in negroid patients) may require greater dose reductions.
\nConsiderations:\nDetailed justification for the recommendation is contained in the risk analysis. The considerations used for adults are also given below. The median or mean plasma concentrations or AUC in PM patients are above the therapeutic range, except in 3 studies with low efavirenz plasma concentrations in EM patients (2 of the 3 studies performed in Africa and 1 study in the United States and Italy). A recent study showed a similar virological response for efavirenz 400 and 600 mg/day in patients not selected on genotype. The risk of underdose is therefore very small if the initial dose is reduced to 400 mg/day. Two small studies showed that dose reductions did not reduce the efficacy (HIV remained undetectable), but side effects did reduce in 24 PM patients. Compliance improves with administration of a combination preparation and the absence of unnecessary side effects due to excessive plasma concentrations.\nConsideration to CYP2B6 inducers such as rifampicin is not needed in PM patients. The significantly low or absent metabolic capacity of CYP2B6 makes induction of little to no relevance. Moreover, the effects of enzyme induction by rifampicin and enzyme inhibition by isoniazid on efavirenz plasma concentrations seem to largely cancel each other out, independent of the CYP2B6 phenotype of the patient."

\n
\n

November 2018 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for efavirenz based on CYP2B6 genotype. They recommend adjusting the initial efavirenz dose for patients with the CYP2B6 PM phenotype and titrate the dose to plasma concentration if needed. For patients with CYP2B6 IM phenotype, they recommend determining the efavirenz plasma concentration if side effects occur and reducing the dose if needed.

\n

Wording in table taken from the Dutch guidelines November 2018 update

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
CYP2B6 IMefavirenzGenetic variations increase the efavirenz plasma concentration and therefore the risk of side effects. However, the efavirenz plasma concentration remains within the therapeutic range for the majority of patients.1. Determine the efavirenz plasma concentration if side effects occur and reduce the dose if needed. In 14 IM adults, a dose reduction to 400 mg/day (2/3rd of the standard dose) was sufficient to achieve therapeutic plasma concentrations and to reduce or resolve side effects. The therapeutic range established for efavirenz is 1000-4000 ng/ml.
CYP2B6 PMefavirenzGenetic variations increase the risk of side effects. The standard dose leads to an efavirenz concentration in the toxic range in the majority of patients with this genotype.* Efavirenz in MONOpreparation, adults and children FROM 40 KG: Body mass index LESS THAN or EQUAL to 25: 1. The recommended initial dose is 400 mg/day and this dose should be titrated to plasma concentration if needed (further reduction to 200 mg/day or in rare cases an increase to 600 mg/day). The therapeutic range established for efavirenz is 1000-4000 ng/ml. Body mass index GREATER than 25: 1. The recommended initial dose is 600 mg/day and this dose should be titrated to plasma concentration if needed (reduction to 400 or 200 mg/day). The therapeutic range established for efavirenz is 1000-4000 ng/ml.
*Efavirenz in MONOpreparation, children LIGHTER THAN 40 KG: 1. Start with the standard dose and titrate this dose to plasma concentration if needed. In adults, therapeutic plasma concentrations were achieved at either 2/3rd of the standard dose (1/3rd of the patients) or 1/3rd of the standard dose (2/3rd of the patients). In children younger than 3 years, therapeutic plasma concentrations were achieved at doses of approximately 10 mg/kg per day (as capsules) (100 mg/day for 7-14 kg and 150 mg/day for 14-17 kg; 50-75% of the standard dose). The therapeutic range established for efavirenz is 1000-4000 ng/ml.
*Efavirenz in COMBINATION preparation: 1. Initiate the combination preparation and titrate the efavirenz dose to plasma concentration if needed (reduction to 400 or 200 mg/day) The therapeutic range established for efavirenz is 1000-4000 ng/ml.
\n

"Note: the dosing recommendations above are based on PM patients with the *6/*6 genotype. There is evidence that the *18/*18\ngenotype in PM patients (only present in negroid patients) may require greater dose reductions.\nConsiderations:\nDetailed justification for the recommendation is contained in the risk analysis. The considerations used for adults are also given below. The median or mean plasma concentrations or AUC in PM patients are above the therapeutic range, except in 3 studies with low efavirenz plasma concentrations in EM patients (2 of the 3 studies performed in Africa and 1 study in the United States and Italy). A recent study showed a similar virological response for efavirenz 400 and 600 mg/day in patients not selected on genotype. The risk of underdose is therefore very small if the initial dose is reduced to 400 mg/day. Two small studies showed that dose reductions did not reduce the efficacy (HIV remained undetectable), but side effects did reduce in 24 PM patients. Compliance improves with administration of a combination preparation and the absence of unnecessary side effects due to excessive plasma concentrations.\nConsideration to CYP2B6 inducers such as rifampicin is not needed in PM patients. The significantly low or absent metabolic capacity of CYP2B6 makes induction of little to no relevance. Moreover, the effects of enzyme induction by rifampicin and enzyme inhibition by isoniazid on efavirenz plasma concentrations seem to largely cancel each other out, independent of the CYP2B6 phenotype of the patient."

\n", - "version" : 7 + "version" : 10 }, "userId" : "lgong", - "version" : 16 + "version" : 83 }, "recommendations" : [ { @@ -114123,21 +115268,21 @@ "objCls" : "Chemical", "id" : "PA449441", "name" : "efavirenz", - "version" : 9 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182846", "name" : "Annotation of DPWG Guideline for efavirenz and CYP2B6", - "version" : 16 + "version" : 83 }, "text" : { "id" : 1452061465, "html" : "

Efavirenz in MONOpreparation, adults and children FROM 40 KG: Body mass index LESS THAN or EQUAL to 25: 1. The recommended initial dose is 400 mg/day and this dose should be titrated to plasma concentration if needed (further reduction to 200 mg/day or in rare cases an increase to 600 mg/day). The therapeutic range established for efavirenz is 1000-4000 ng/ml. Body mass index GREATER than 25: 1. The recommended initial dose is 600 mg/day and this dose should be titrated to plasma concentration if needed (reduction to 400 or 200 mg/day). The therapeutic range established for efavirenz is 1000-4000 ng/ml.\n*Efavirenz in MONOpreparation, children LIGHTER THAN 40 KG: 1. Start with the standard dose and titrate this dose to plasma concentration if needed. In adults, therapeutic plasma concentrations were achieved at either 2/3rd of the standard dose (1/3rd of the patients) or 1/3rd of the standard dose (2/3rd of the patients). In children younger than 3 years, therapeutic plasma concentrations were achieved at doses of approximately 10 mg/kg per day (as capsules) (100 mg/day for 7-14 kg and 150 mg/day for 14-17 kg; 50-75% of the standard dose). The therapeutic range established for efavirenz is 1000-4000 ng/ml.\n*Efavirenz in COMBINATION preparation: 1. Initiate the combination preparation and titrate the efavirenz dose to plasma concentration if needed (reduction to 400 or 200 mg/day) The therapeutic range established for efavirenz is 1000-4000 ng/ml.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", @@ -114165,21 +115310,21 @@ "objCls" : "Chemical", "id" : "PA449441", "name" : "efavirenz", - "version" : 9 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182846", "name" : "Annotation of DPWG Guideline for efavirenz and CYP2B6", - "version" : 16 + "version" : 83 }, "text" : { "id" : 1452061464, "html" : "

Determine the efavirenz plasma concentration if side effects occur and reduce the dose if needed. In 14 IM adults, a dose reduction to 400 mg/day (2/3rd of the standard dose) was sufficient to achieve therapeutic plasma concentrations and to reduce or resolve side effects. The therapeutic range established for efavirenz is 1000-4000 ng/ml.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", @@ -114206,21 +115351,21 @@ "objCls" : "Chemical", "id" : "PA449441", "name" : "efavirenz", - "version" : 9 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182846", "name" : "Annotation of DPWG Guideline for efavirenz and CYP2B6", - "version" : 16 + "version" : 83 }, "text" : { "id" : 1452061466, "html" : "

The guideline does not provide a recommendation for efavirenz in normal metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166182846" @@ -114391,7 +115536,7 @@ "objCls" : "Chemical", "id" : "PA166123486", "name" : "eliglustat", - "version" : 5 + "version" : 6 } ], "relatedGenes" : [ @@ -114400,29 +115545,29 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "DPWG", "summaryMarkdown" : { "id" : 1450415099, "html" : "

The Dutch Pharmacogenetics Working Group Guideline for eliglustat recommends to use an alternative in CYP2D6 ultrarapid metabolizer. For CYP2D6 poor metabolizer in combination with CYP3A inhibitors and strong inducers, the guideline recommends to choose an alternative if possible. For intermediate metabolizers recommendations are provided for co-medication with CYP2D6 and/or CYP3A inhibitors and CYP3A inducers.

\n", - "version" : 1 + "version" : 3 }, "terms" : [], "textMarkdown" : { "id" : 1450415097, "html" : "

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

\n

November 2018 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for eliglustat based on CYP2D6 genotype. They recommend to use an alternative in CYP2D6 ultrarapid metabolizer. For CYP2D6 poor metabolizer in combination with CYP3A inhibitors and strong inducers, the guideline recommends to choose an alternative if possible. For intermediate metabolizers, recommendations are provided for co-medication with CYP2D6 and/or CYP3A inhibitors and CPY3A inducers.

\n

Wording in table taken from the Dutch guidelines November 2018 update

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
CYP2D6 UMeliglustatThis gene variation increases the conversion of eliglustat to inactive metabolites. As a result, a normal dose is not effective. There is not enough scientific substantiation to suggest an effective dose for all UM.Eliglustat is contra-indicated. Choose an alternative if possible.
CYP2D6 IMeliglustatThis gene variation reduces the conversion of eliglustat to inactive metabolites. However, in the absence of CYP2D6 and CYP3A inhibitors, this does not result in a clinically significant increased risk of side effects.- Co-medication with BOTH a MODERATE to STRONG CYP2D6 INHIBITOR AND a MODERATE to STRONG CYP3A INHIBITOR: Eliglustat is contra-indicated.
1. Choose an alternative if possible.
Strong CYP2D6 inhibitor: for example paroxetine, fluoxetine, quinidine, bupropione. Moderate CYP2D6 inhibitor: for example duloxetine, terbinafine, moclobemide, mirabegron, cinacalcet, dronedarone. Strong CYP3A inhibitor: for example ketoconazole, clarithromycin, itraconazole, cobicistat, indinavir, lopinavir, ritonavir, saquinavir, telaprevir, tipranavir, posaconazole, voriconazole, telithromycin, conivaptan, boceprevir. Moderate CYP3A inhibitor: for example erythromycin, ciprofloxacin, fluconazole, diltiazem, verapamil, aprepitant, atazanavir, darunavir, fosamprenavir, imatinib, cimetidine.
 
- Co-medication with a STRONG CYP2D6 INHIBITOR (e.g. paroxetine, fluoxetine, quinidine, bupropione):
1. Use a dose of 84mg eliglustat 1x daily.
 
- Co-medication with a MODERATE CYP2D6 INHIBITOR (for example duloxetine, terbinafine, moclobemide, mirabegron, cinacalcet, dronedarone):
1. Consider a dose of 84mg eliglustat 1x daily.
2. Be alert to side effects.
 
- Co-medication with a STRONG CYP3A INHIBITOR (for example ketoconazole, clarithromycin, itraconazole, cobicistat, indinavir, lopinavir, ritonavir, saquinavir, telaprevir, tipranavir, posaconazole, voriconazole, telithromycin, conivaptan, boceprevir):
1. Choose an alternative if possible.
2. If an alternative is not an option: consider a dose of 84 mg eliglustat 1x daily and be alert to side effects.
 
- Co-medication with a MODERATE CYP3A INHIBITOR (for example erythromycin, ciprofloxacin, fluconazole, diltiazem, verapamil, aprepitant, atazanavir, darunavir, fosamprenavir, imatinib, cimetidine):
1. Choose an alternative.
2. If an alternative is not an option: consider a dose of 84mg eliglustat 1x daily and be alert to side effects.
 
- Co-medication with a STRONG CYP3A INDUCER (for example rifampicin, carbamazepine, phenobarbital, phenytoin, rifabutine, hypericum): Eliglustat is not recommended. The plasma concentration may decrease so sharply that a therapeutic effect cannot be achieved.
1. Choose an alternative if possible.
 
- NO co-medication with a moderate or strong CYP2D6 or CYP3A inhibitor or strong CYP3A inducer:
1. Use the standard dose of 84mg 2x daily.
CYP2D6 PMeliglustatThis gene variation reduces the conversion of eliglustat to inactive metabolites. This increases the risk of side effects, such as a (small, dose-dependent) elongation of the QT interval. CYP3A inhibitors increase this risk even further.- Co-medication with a STRONG CYP3A INHIBITOR (for example ketoconazole, clarithromycin, itraconazole, cobicistat, indinavir, lopinavir, ritonavir, saquinavir, telaprevir, tipranavir, posaconazole, voriconazole, telithromycin, conivaptan, boceprevir): Eliglustat is contra-indicated.
1. Choose an alternative if possible.
 
- Co-medication with a MODERATE CYP3A INHIBITOR (for example erythromycin, ciprofloxacin, fluconazole, diltiazem, verapamil, aprepitant, atazanavir, darunavir, fosamprenavir, imatinib, cimetidine): Eliglustat is not recommended.
1. Choose an alternative if possible.
 
- Co-medication with a WEAK CYP3A INHIBITOR (for example amlopidine, cilostazole, fluvoxamine, goldenseal, isoniazide, ranitidine, ranolazine):
1. Choose an alternative for the weak CYP3A inhibitor if possible.
2. If an alternative is not an option: Use a dose of 84mg eliglustat 1x daily and be alert to side effects.
 
- Co-medication with a STRONG CYP3A INDUCER (for example rifampicin, carbamazepine, phenobarbital, phenytoin, rifabutine, hypericum): Eliglustat is not recommended. The plasma concentration may decrease so sharply that a therapeutic effect cannot be achieved.
1. Choose an alternative if possible.
 
- NO co-medication with a CYP3A inhibitor or strong CYP3A inducer:
1. Use a dose of 84mg 1x daily.
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for eliglustat and CYP2D6:

\n
\n

Due to the absence of publications of new clinical studies or case reports with patients with a CYP2D6 genotype\nleading to reduced or increased CYP2D6 activity in medical journals, and thus the absence of evidence of an\nincrease in adverse events code ≥ D (grade ≥ 3) in these patients, the clinical implication of the gene-drug interaction\nscores only 2 out of the maximum of 10 points (with pre-emptive genotyping considered to be potentially beneficial for\nscores ranging from 0 to 2 points) (see also the Clinical Implication Score tables at the end of this risk analysis).\nHowever, there is not enough evidence to reject the warnings and recommendations in the SmPC. In addition, the\nClinical Implication Score is mainly (for 80%) based on studies published in medical journals and therefore not suited\nto determine the clinical implication for gene-drug interactions for which data are only provided by pre-registration\nstudies. For these reasons, the KNMP Pharmacogenetics Working Group decided to ignore the Clinical Implication\nScore and adopt the genotyping recommendation in the SmPC. The SmPC indicates that genotyping must be performed before starting eliglustat to guide drug and dose selection. This would amount to genotyping being essential for\ndrug safety according to the nomenclature of the KNMP Pharmacogenetics Working Group.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n", - "version" : 5 + "version" : 11 }, "userId" : "katrin", - "version" : 13 + "version" : 71 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166302370", - "name" : "Recommendation Annotation PA166302370", + "id" : "PA166302288", + "name" : "Recommendation Annotation PA166302288", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -114434,114 +115579,74 @@ "valid" : true, "version" : 1 }, - "dosingInformation" : false, - "implications" : [ - "This gene variation increases the conversion of eliglustat to inactive metabolites. As a result, a normal dose is not effective. There is not enough scientific substantiation to suggest an effective dose for all UM." - ], - "lookupKey" : {"CYP2D6": "≥3.5"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA166123486", - "name" : "eliglustat", - "version" : 5 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166182823", - "name" : "Annotation of DPWG Guideline for eliglustat and CYP2D6", - "version" : 13 - }, - "text" : { - "id" : 1452103949, - "html" : "

Eliglustat is contra-indicated. Choose an alternative if possible.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166302361", - "name" : "Recommendation Annotation PA166302361", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 1448526251, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on eliglustat." + "This gene variation reduces the conversion of eliglustat to inactive metabolites. This increases the risk of side effects, such as a (small, dose-dependent) elongation of the QT interval. CYP3A inhibitors increase this risk even further." ], - "lookupKey" : {"CYP2D6": "1.25"}, + "lookupKey" : {"CYP2D6": "0.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166123486", "name" : "eliglustat", - "version" : 5 + "version" : 6 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182823", "name" : "Annotation of DPWG Guideline for eliglustat and CYP2D6", - "version" : 13 + "version" : 71 }, "text" : { - "id" : 1452103940, - "html" : "

The guideline does not provide a recommendation for eliglustat in normal metabolizers.

\n", - "version" : 0 + "id" : 1452103867, + "html" : "

Co-medication with a STRONG CYP3A INHIBITOR (for example ketoconazole, clarithromycin, itraconazole, cobicistat, indinavir, lopinavir, ritonavir, saquinavir, telaprevir, tipranavir, posaconazole, voriconazole, telithromycin, conivaptan, boceprevir):

\n\n

Co-medication with a MODERATE CYP3A INHIBITOR (for example erythromycin, ciprofloxacin, fluconazole, diltiazem, verapamil, aprepitant, atazanavir, darunavir, fosamprenavir, imatinib, cimetidine):

\n\n

Co-medication with a WEAK CYP3A INHIBITOR (for example amlopidine, cilostazole, fluvoxamine, goldenseal, isoniazide, ranitidine, ranolazine):

\n\n

Co-medication with a STRONG CYP3A INDUCER (for example rifampicin, carbamazepine, phenobarbital, phenytoin, rifabutine, hypericum):

\n\n

NO co-medication with a CYP3A inhibitor or strong CYP3A inducer:

\n\n", + "version" : 1 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302365", - "name" : "Recommendation Annotation PA166302365", - "alternateDrugAvailable" : false, + "id" : "PA166302301", + "name" : "Recommendation Annotation PA166302301", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on eliglustat." + "This gene variation reduces the conversion of eliglustat to inactive metabolites. However, in the absence of CYP2D6 and CYP3A inhibitors, this does not result in a clinically significant increased risk of side effects." ], - "lookupKey" : {"CYP2D6": "2.5"}, + "lookupKey" : {"CYP2D6": "0.25"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166123486", "name" : "eliglustat", - "version" : 5 + "version" : 6 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182823", "name" : "Annotation of DPWG Guideline for eliglustat and CYP2D6", - "version" : 13 + "version" : 71 }, "text" : { - "id" : 1452103944, - "html" : "

The guideline does not provide a recommendation for eliglustat in normal metabolizers.

\n", - "version" : 0 + "id" : 1452103880, + "html" : "

Co-medication with BOTH a MODERATE to STRONG CYP2D6 INHIBITOR AND a MODERATE to STRONG CYP3A INHIBITOR:

\n\n

Strong CYP2D6 inhibitor: for example paroxetine, fluoxetine, quinidine, bupropione. Moderate CYP2D6 inhibitor: for example duloxetine, terbinafine, moclobemide, mirabegron, cinacalcet, dronedarone. Strong CYP3A inhibitor: for example ketoconazole, clarithromycin, itraconazole, cobicistat, indinavir, lopinavir, ritonavir, saquinavir, telaprevir, tipranavir, posaconazole, voriconazole, telithromycin, conivaptan, boceprevir. Moderate CYP3A inhibitor: for example erythromycin, ciprofloxacin, fluconazole, diltiazem, verapamil, aprepitant, atazanavir, darunavir, fosamprenavir, imatinib, cimetidine.

\n

Co-medication with a STRONG CYP2D6 INHIBITOR (e.g. paroxetine, fluoxetine, quinidine, bupropione):

\n\n

Co-medication with a MODERATE CYP2D6 INHIBITOR (for example duloxetine, terbinafine, moclobemide, mirabegron, cinacalcet, dronedarone):

\n\n

Co-medication with a STRONG CYP3A INHIBITOR (for example ketoconazole, clarithromycin, itraconazole, cobicistat, indinavir, lopinavir, ritonavir, saquinavir, telaprevir, tipranavir, posaconazole, voriconazole, telithromycin, conivaptan, boceprevir):

\n\n

Co-medication with a MODERATE CYP3A INHIBITOR (for example erythromycin, ciprofloxacin, fluconazole, diltiazem, verapamil, aprepitant, atazanavir, darunavir, fosamprenavir, imatinib, cimetidine):

\n\n

Co-medication with a STRONG CYP3A INDUCER (for example rifampicin, carbamazepine, phenobarbital, phenytoin, rifabutine, hypericum): Eliglustat is not recommended. The plasma concentration may decrease so sharply that a therapeutic effect cannot be achieved.

\n\n

NO co-medication with a moderate or strong CYP2D6 or CYP3A inhibitor or strong CYP3A inducer:

\n\n", + "version" : 1 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -114569,14 +115674,14 @@ "objCls" : "Chemical", "id" : "PA166123486", "name" : "eliglustat", - "version" : 5 + "version" : 6 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182823", "name" : "Annotation of DPWG Guideline for eliglustat and CYP2D6", - "version" : 13 + "version" : 71 }, "text" : { "id" : 1452103900, @@ -114587,8 +115692,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302369", - "name" : "Recommendation Annotation PA166302369", + "id" : "PA166302322", + "name" : "Recommendation Annotation PA166302322", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -114600,69 +115705,79 @@ "valid" : true, "version" : 1 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "This gene variation increases the conversion of eliglustat to inactive metabolites. As a result, a normal dose is not effective. There is not enough scientific substantiation to suggest an effective dose for all UM." + "This gene variation reduces the conversion of eliglustat to inactive metabolites. However, in the absence of CYP2D6 and CYP3A inhibitors, this does not result in a clinically significant increased risk of side effects." ], - "lookupKey" : {"CYP2D6": "≥3.25"}, + "lookupKey" : {"CYP2D6": "0.75"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166123486", "name" : "eliglustat", - "version" : 5 + "version" : 6 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182823", "name" : "Annotation of DPWG Guideline for eliglustat and CYP2D6", - "version" : 13 + "version" : 71 }, "text" : { - "id" : 1452103948, - "html" : "

Eliglustat is contra-indicated. Choose an alternative if possible.

\n", + "id" : 1452103901, + "html" : "

Co-medication with BOTH a MODERATE to STRONG CYP2D6 INHIBITOR AND a MODERATE to STRONG CYP3A INHIBITOR:

\n\n

Strong CYP2D6 inhibitor: for example paroxetine, fluoxetine, quinidine, bupropione. Moderate CYP2D6 inhibitor: for example duloxetine, terbinafine, moclobemide, mirabegron, cinacalcet, dronedarone. Strong CYP3A inhibitor: for example ketoconazole, clarithromycin, itraconazole, cobicistat, indinavir, lopinavir, ritonavir, saquinavir, telaprevir, tipranavir, posaconazole, voriconazole, telithromycin, conivaptan, boceprevir. Moderate CYP3A inhibitor: for example erythromycin, ciprofloxacin, fluconazole, diltiazem, verapamil, aprepitant, atazanavir, darunavir, fosamprenavir, imatinib, cimetidine.

\n

Co-medication with a STRONG CYP2D6 INHIBITOR (e.g. paroxetine, fluoxetine, quinidine, bupropione):

\n\n

Co-medication with a MODERATE CYP2D6 INHIBITOR (for example duloxetine, terbinafine, moclobemide, mirabegron, cinacalcet, dronedarone):

\n\n

Co-medication with a STRONG CYP3A INHIBITOR (for example ketoconazole, clarithromycin, itraconazole, cobicistat, indinavir, lopinavir, ritonavir, saquinavir, telaprevir, tipranavir, posaconazole, voriconazole, telithromycin, conivaptan, boceprevir):

\n\n

Co-medication with a MODERATE CYP3A INHIBITOR (for example erythromycin, ciprofloxacin, fluconazole, diltiazem, verapamil, aprepitant, atazanavir, darunavir, fosamprenavir, imatinib, cimetidine):

\n\n

Co-medication with a STRONG CYP3A INDUCER (for example rifampicin, carbamazepine, phenobarbital, phenytoin, rifabutine, hypericum): Eliglustat is not recommended. The plasma concentration may decrease so sharply that a therapeutic effect cannot be achieved.

\n\n

NO co-medication with a moderate or strong CYP2D6 or CYP3A inhibitor or strong CYP3A inducer:

\n\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302373", - "name" : "Recommendation Annotation PA166302373", + "id" : "PA166302341", + "name" : "Recommendation Annotation PA166302341", "alternateDrugAvailable" : true, - "dosingInformation" : false, + "classification" : { + "id" : 981501929, + "description" : "Not Applicable", + "parents" : [], + "resource" : "Guideline Strength", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", + "valid" : true, + "version" : 1 + }, + "dosingInformation" : true, "implications" : [ - "This gene variation increases the conversion of eliglustat to inactive metabolites. As a result, a normal dose is not effective. There is not enough scientific substantiation to suggest an effective dose for all UM." + "This gene variation reduces the conversion of eliglustat to inactive metabolites. However, in the absence of CYP2D6 and CYP3A inhibitors, this does not result in a clinically significant increased risk of side effects." ], - "lookupKey" : {"CYP2D6": "≥6.0"}, + "lookupKey" : {"CYP2D6": "1.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166123486", "name" : "eliglustat", - "version" : 5 + "version" : 6 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182823", "name" : "Annotation of DPWG Guideline for eliglustat and CYP2D6", - "version" : 13 + "version" : 71 }, "text" : { - "id" : 1452103952, - "html" : "

Eliglustat is contra-indicated. Choose an alternative if possible.

\n", + "id" : 1452103920, + "html" : "

Co-medication with BOTH a MODERATE to STRONG CYP2D6 INHIBITOR AND a MODERATE to STRONG CYP3A INHIBITOR:

\n\n

Strong CYP2D6 inhibitor: for example paroxetine, fluoxetine, quinidine, bupropione. Moderate CYP2D6 inhibitor: for example duloxetine, terbinafine, moclobemide, mirabegron, cinacalcet, dronedarone. Strong CYP3A inhibitor: for example ketoconazole, clarithromycin, itraconazole, cobicistat, indinavir, lopinavir, ritonavir, saquinavir, telaprevir, tipranavir, posaconazole, voriconazole, telithromycin, conivaptan, boceprevir. Moderate CYP3A inhibitor: for example erythromycin, ciprofloxacin, fluconazole, diltiazem, verapamil, aprepitant, atazanavir, darunavir, fosamprenavir, imatinib, cimetidine.

\n

Co-medication with a STRONG CYP2D6 INHIBITOR (e.g. paroxetine, fluoxetine, quinidine, bupropione):

\n\n

Co-medication with a MODERATE CYP2D6 INHIBITOR (for example duloxetine, terbinafine, moclobemide, mirabegron, cinacalcet, dronedarone):

\n\n

Co-medication with a STRONG CYP3A INHIBITOR (for example ketoconazole, clarithromycin, itraconazole, cobicistat, indinavir, lopinavir, ritonavir, saquinavir, telaprevir, tipranavir, posaconazole, voriconazole, telithromycin, conivaptan, boceprevir):

\n\n

Co-medication with a MODERATE CYP3A INHIBITOR (for example erythromycin, ciprofloxacin, fluconazole, diltiazem, verapamil, aprepitant, atazanavir, darunavir, fosamprenavir, imatinib, cimetidine):

\n\n

Co-medication with a STRONG CYP3A INDUCER (for example rifampicin, carbamazepine, phenobarbital, phenytoin, rifabutine, hypericum): Eliglustat is not recommended. The plasma concentration may decrease so sharply that a therapeutic effect cannot be achieved.

\n\n

NO co-medication with a moderate or strong CYP2D6 or CYP3A inhibitor or strong CYP3A inducer:

\n\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302364", - "name" : "Recommendation Annotation PA166302364", + "id" : "PA166302361", + "name" : "Recommendation Annotation PA166302361", "alternateDrugAvailable" : false, "classification" : { "id" : 1448526251, @@ -114677,24 +115792,24 @@ "implications" : [ "The guideline does not provide a description of the impact of a normal metabolizer phenotype on eliglustat." ], - "lookupKey" : {"CYP2D6": "2.25"}, + "lookupKey" : {"CYP2D6": "1.25"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166123486", "name" : "eliglustat", - "version" : 5 + "version" : 6 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182823", "name" : "Annotation of DPWG Guideline for eliglustat and CYP2D6", - "version" : 13 + "version" : 71 }, "text" : { - "id" : 1452103943, + "id" : 1452103940, "html" : "

The guideline does not provide a recommendation for eliglustat in normal metabolizers.

\n", "version" : 0 }, @@ -114702,134 +115817,131 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302368", - "name" : "Recommendation Annotation PA166302368", - "alternateDrugAvailable" : true, + "id" : "PA166302362", + "name" : "Recommendation Annotation PA166302362", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, "dosingInformation" : false, "implications" : [ - "This gene variation increases the conversion of eliglustat to inactive metabolites. As a result, a normal dose is not effective. There is not enough scientific substantiation to suggest an effective dose for all UM." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on eliglustat." ], - "lookupKey" : {"CYP2D6": "≥3.0"}, + "lookupKey" : {"CYP2D6": "1.5"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166123486", "name" : "eliglustat", - "version" : 5 + "version" : 6 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182823", "name" : "Annotation of DPWG Guideline for eliglustat and CYP2D6", - "version" : 13 + "version" : 71 }, "text" : { - "id" : 1452103947, - "html" : "

Eliglustat is contra-indicated. Choose an alternative if possible.

\n", + "id" : 1452103941, + "html" : "

The guideline does not provide a recommendation for eliglustat in normal metabolizers.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302372", - "name" : "Recommendation Annotation PA166302372", - "alternateDrugAvailable" : true, + "id" : "PA166302363", + "name" : "Recommendation Annotation PA166302363", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, "dosingInformation" : false, "implications" : [ - "This gene variation increases the conversion of eliglustat to inactive metabolites. As a result, a normal dose is not effective. There is not enough scientific substantiation to suggest an effective dose for all UM." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on eliglustat." ], - "lookupKey" : {"CYP2D6": "≥5.0"}, + "lookupKey" : {"CYP2D6": "2.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166123486", "name" : "eliglustat", - "version" : 5 + "version" : 6 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182823", "name" : "Annotation of DPWG Guideline for eliglustat and CYP2D6", - "version" : 13 + "version" : 71 }, "text" : { - "id" : 1452103951, - "html" : "

Eliglustat is contra-indicated. Choose an alternative if possible.

\n", + "id" : 1452103942, + "html" : "

The guideline does not provide a recommendation for eliglustat in normal metabolizers.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302288", - "name" : "Recommendation Annotation PA166302288", - "alternateDrugAvailable" : true, + "id" : "PA166302364", + "name" : "Recommendation Annotation PA166302364", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "This gene variation reduces the conversion of eliglustat to inactive metabolites. This increases the risk of side effects, such as a (small, dose-dependent) elongation of the QT interval. CYP3A inhibitors increase this risk even further." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on eliglustat." ], - "lookupKey" : {"CYP2D6": "0.0"}, + "lookupKey" : {"CYP2D6": "2.25"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166123486", "name" : "eliglustat", - "version" : 5 + "version" : 6 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182823", "name" : "Annotation of DPWG Guideline for eliglustat and CYP2D6", - "version" : 13 + "version" : 71 }, "text" : { - "id" : 1452103867, - "html" : "

Co-medication with a STRONG CYP3A INHIBITOR (for example ketoconazole, clarithromycin, itraconazole, cobicistat, indinavir, lopinavir, ritonavir, saquinavir, telaprevir, tipranavir, posaconazole, voriconazole, telithromycin, conivaptan, boceprevir):

\n\n

Co-medication with a MODERATE CYP3A INHIBITOR (for example erythromycin, ciprofloxacin, fluconazole, diltiazem, verapamil, aprepitant, atazanavir, darunavir, fosamprenavir, imatinib, cimetidine):

\n\n

Co-medication with a WEAK CYP3A INHIBITOR (for example amlopidine, cilostazole, fluvoxamine, goldenseal, isoniazide, ranitidine, ranolazine):

\n\n

Co-medication with a STRONG CYP3A INDUCER (for example rifampicin, carbamazepine, phenobarbital, phenytoin, rifabutine, hypericum):

\n\n

NO co-medication with a CYP3A inhibitor or strong CYP3A inducer:

\n\n", + "id" : 1452103943, + "html" : "

The guideline does not provide a recommendation for eliglustat in normal metabolizers.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302363", - "name" : "Recommendation Annotation PA166302363", + "id" : "PA166302365", + "name" : "Recommendation Annotation PA166302365", "alternateDrugAvailable" : false, "classification" : { "id" : 1448526251, @@ -114844,24 +115956,24 @@ "implications" : [ "The guideline does not provide a description of the impact of a normal metabolizer phenotype on eliglustat." ], - "lookupKey" : {"CYP2D6": "2.0"}, + "lookupKey" : {"CYP2D6": "2.5"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166123486", "name" : "eliglustat", - "version" : 5 + "version" : 6 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182823", "name" : "Annotation of DPWG Guideline for eliglustat and CYP2D6", - "version" : 13 + "version" : 71 }, "text" : { - "id" : 1452103942, + "id" : 1452103944, "html" : "

The guideline does not provide a recommendation for eliglustat in normal metabolizers.

\n", "version" : 0 }, @@ -114869,8 +115981,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302341", - "name" : "Recommendation Annotation PA166302341", + "id" : "PA166302366", + "name" : "Recommendation Annotation PA166302366", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -114882,29 +115994,29 @@ "valid" : true, "version" : 1 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "This gene variation reduces the conversion of eliglustat to inactive metabolites. However, in the absence of CYP2D6 and CYP3A inhibitors, this does not result in a clinically significant increased risk of side effects." + "This gene variation increases the conversion of eliglustat to inactive metabolites. As a result, a normal dose is not effective. There is not enough scientific substantiation to suggest an effective dose for all UM." ], - "lookupKey" : {"CYP2D6": "1.0"}, + "lookupKey" : {"CYP2D6": "3.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166123486", "name" : "eliglustat", - "version" : 5 + "version" : 6 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182823", "name" : "Annotation of DPWG Guideline for eliglustat and CYP2D6", - "version" : 13 + "version" : 71 }, "text" : { - "id" : 1452103920, - "html" : "

Co-medication with BOTH a MODERATE to STRONG CYP2D6 INHIBITOR AND a MODERATE to STRONG CYP3A INHIBITOR:

\n\n

Strong CYP2D6 inhibitor: for example paroxetine, fluoxetine, quinidine, bupropione. Moderate CYP2D6 inhibitor: for example duloxetine, terbinafine, moclobemide, mirabegron, cinacalcet, dronedarone. Strong CYP3A inhibitor: for example ketoconazole, clarithromycin, itraconazole, cobicistat, indinavir, lopinavir, ritonavir, saquinavir, telaprevir, tipranavir, posaconazole, voriconazole, telithromycin, conivaptan, boceprevir. Moderate CYP3A inhibitor: for example erythromycin, ciprofloxacin, fluconazole, diltiazem, verapamil, aprepitant, atazanavir, darunavir, fosamprenavir, imatinib, cimetidine.

\n

Co-medication with a STRONG CYP2D6 INHIBITOR (e.g. paroxetine, fluoxetine, quinidine, bupropione):

\n\n

Co-medication with a MODERATE CYP2D6 INHIBITOR (for example duloxetine, terbinafine, moclobemide, mirabegron, cinacalcet, dronedarone):

\n\n

Co-medication with a STRONG CYP3A INHIBITOR (for example ketoconazole, clarithromycin, itraconazole, cobicistat, indinavir, lopinavir, ritonavir, saquinavir, telaprevir, tipranavir, posaconazole, voriconazole, telithromycin, conivaptan, boceprevir):

\n\n

Co-medication with a MODERATE CYP3A INHIBITOR (for example erythromycin, ciprofloxacin, fluconazole, diltiazem, verapamil, aprepitant, atazanavir, darunavir, fosamprenavir, imatinib, cimetidine):

\n\n

Co-medication with a STRONG CYP3A INDUCER (for example rifampicin, carbamazepine, phenobarbital, phenytoin, rifabutine, hypericum): Eliglustat is not recommended. The plasma concentration may decrease so sharply that a therapeutic effect cannot be achieved.

\n\n

NO co-medication with a moderate or strong CYP2D6 or CYP3A inhibitor or strong CYP3A inducer:

\n\n", + "id" : 1452103945, + "html" : "

Eliglustat is contra-indicated. Choose an alternative if possible.

\n", "version" : 0 }, "version" : 0 @@ -114935,14 +116047,14 @@ "objCls" : "Chemical", "id" : "PA166123486", "name" : "eliglustat", - "version" : 5 + "version" : 6 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182823", "name" : "Annotation of DPWG Guideline for eliglustat and CYP2D6", - "version" : 13 + "version" : 71 }, "text" : { "id" : 1452103946, @@ -114953,8 +116065,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302301", - "name" : "Recommendation Annotation PA166302301", + "id" : "PA166302368", + "name" : "Recommendation Annotation PA166302368", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -114966,37 +116078,37 @@ "valid" : true, "version" : 1 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "This gene variation reduces the conversion of eliglustat to inactive metabolites. However, in the absence of CYP2D6 and CYP3A inhibitors, this does not result in a clinically significant increased risk of side effects." + "This gene variation increases the conversion of eliglustat to inactive metabolites. As a result, a normal dose is not effective. There is not enough scientific substantiation to suggest an effective dose for all UM." ], - "lookupKey" : {"CYP2D6": "0.25"}, + "lookupKey" : {"CYP2D6": "≥3.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166123486", "name" : "eliglustat", - "version" : 5 + "version" : 6 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182823", "name" : "Annotation of DPWG Guideline for eliglustat and CYP2D6", - "version" : 13 + "version" : 71 }, "text" : { - "id" : 1452103880, - "html" : "

Co-medication with BOTH a MODERATE to STRONG CYP2D6 INHIBITOR AND a MODERATE to STRONG CYP3A INHIBITOR:

\n\n

Strong CYP2D6 inhibitor: for example paroxetine, fluoxetine, quinidine, bupropione. Moderate CYP2D6 inhibitor: for example duloxetine, terbinafine, moclobemide, mirabegron, cinacalcet, dronedarone. Strong CYP3A inhibitor: for example ketoconazole, clarithromycin, itraconazole, cobicistat, indinavir, lopinavir, ritonavir, saquinavir, telaprevir, tipranavir, posaconazole, voriconazole, telithromycin, conivaptan, boceprevir. Moderate CYP3A inhibitor: for example erythromycin, ciprofloxacin, fluconazole, diltiazem, verapamil, aprepitant, atazanavir, darunavir, fosamprenavir, imatinib, cimetidine.

\n

Co-medication with a STRONG CYP2D6 INHIBITOR (e.g. paroxetine, fluoxetine, quinidine, bupropione):

\n\n

Co-medication with a MODERATE CYP2D6 INHIBITOR (for example duloxetine, terbinafine, moclobemide, mirabegron, cinacalcet, dronedarone):

\n\n

Co-medication with a STRONG CYP3A INHIBITOR (for example ketoconazole, clarithromycin, itraconazole, cobicistat, indinavir, lopinavir, ritonavir, saquinavir, telaprevir, tipranavir, posaconazole, voriconazole, telithromycin, conivaptan, boceprevir):

\n\n

Co-medication with a MODERATE CYP3A INHIBITOR (for example erythromycin, ciprofloxacin, fluconazole, diltiazem, verapamil, aprepitant, atazanavir, darunavir, fosamprenavir, imatinib, cimetidine):

\n\n

Co-medication with a STRONG CYP3A INDUCER (for example rifampicin, carbamazepine, phenobarbital, phenytoin, rifabutine, hypericum): Eliglustat is not recommended. The plasma concentration may decrease so sharply that a therapeutic effect cannot be achieved.

\n\n

NO co-medication with a moderate or strong CYP2D6 or CYP3A inhibitor or strong CYP3A inducer:

\n\n", + "id" : 1452103947, + "html" : "

Eliglustat is contra-indicated. Choose an alternative if possible.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302371", - "name" : "Recommendation Annotation PA166302371", + "id" : "PA166302369", + "name" : "Recommendation Annotation PA166302369", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -115012,24 +116124,24 @@ "implications" : [ "This gene variation increases the conversion of eliglustat to inactive metabolites. As a result, a normal dose is not effective. There is not enough scientific substantiation to suggest an effective dose for all UM." ], - "lookupKey" : {"CYP2D6": "≥4.0"}, + "lookupKey" : {"CYP2D6": "≥3.25"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166123486", "name" : "eliglustat", - "version" : 5 + "version" : 6 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182823", "name" : "Annotation of DPWG Guideline for eliglustat and CYP2D6", - "version" : 13 + "version" : 71 }, "text" : { - "id" : 1452103950, + "id" : 1452103948, "html" : "

Eliglustat is contra-indicated. Choose an alternative if possible.

\n", "version" : 0 }, @@ -115037,49 +116149,50 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302362", - "name" : "Recommendation Annotation PA166302362", - "alternateDrugAvailable" : false, + "id" : "PA166302370", + "name" : "Recommendation Annotation PA166302370", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, "dosingInformation" : false, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on eliglustat." + "This gene variation increases the conversion of eliglustat to inactive metabolites. As a result, a normal dose is not effective. There is not enough scientific substantiation to suggest an effective dose for all UM." ], - "lookupKey" : {"CYP2D6": "1.5"}, + "lookupKey" : {"CYP2D6": "≥3.5"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166123486", "name" : "eliglustat", - "version" : 5 + "version" : 6 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182823", "name" : "Annotation of DPWG Guideline for eliglustat and CYP2D6", - "version" : 13 + "version" : 71 }, "text" : { - "id" : 1452103941, - "html" : "

The guideline does not provide a recommendation for eliglustat in normal metabolizers.

\n", + "id" : 1452103949, + "html" : "

Eliglustat is contra-indicated. Choose an alternative if possible.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302366", - "name" : "Recommendation Annotation PA166302366", + "id" : "PA166302371", + "name" : "Recommendation Annotation PA166302371", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -115095,24 +116208,24 @@ "implications" : [ "This gene variation increases the conversion of eliglustat to inactive metabolites. As a result, a normal dose is not effective. There is not enough scientific substantiation to suggest an effective dose for all UM." ], - "lookupKey" : {"CYP2D6": "3.0"}, + "lookupKey" : {"CYP2D6": "≥4.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166123486", "name" : "eliglustat", - "version" : 5 + "version" : 6 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182823", "name" : "Annotation of DPWG Guideline for eliglustat and CYP2D6", - "version" : 13 + "version" : 71 }, "text" : { - "id" : 1452103945, + "id" : 1452103950, "html" : "

Eliglustat is contra-indicated. Choose an alternative if possible.

\n", "version" : 0 }, @@ -115120,8 +116233,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302322", - "name" : "Recommendation Annotation PA166302322", + "id" : "PA166302372", + "name" : "Recommendation Annotation PA166302372", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -115133,29 +116246,61 @@ "valid" : true, "version" : 1 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "This gene variation reduces the conversion of eliglustat to inactive metabolites. However, in the absence of CYP2D6 and CYP3A inhibitors, this does not result in a clinically significant increased risk of side effects." + "This gene variation increases the conversion of eliglustat to inactive metabolites. As a result, a normal dose is not effective. There is not enough scientific substantiation to suggest an effective dose for all UM." ], - "lookupKey" : {"CYP2D6": "0.75"}, + "lookupKey" : {"CYP2D6": "≥5.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166123486", "name" : "eliglustat", - "version" : 5 + "version" : 6 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182823", "name" : "Annotation of DPWG Guideline for eliglustat and CYP2D6", - "version" : 13 + "version" : 71 }, "text" : { - "id" : 1452103901, - "html" : "

Co-medication with BOTH a MODERATE to STRONG CYP2D6 INHIBITOR AND a MODERATE to STRONG CYP3A INHIBITOR:

\n\n

Strong CYP2D6 inhibitor: for example paroxetine, fluoxetine, quinidine, bupropione. Moderate CYP2D6 inhibitor: for example duloxetine, terbinafine, moclobemide, mirabegron, cinacalcet, dronedarone. Strong CYP3A inhibitor: for example ketoconazole, clarithromycin, itraconazole, cobicistat, indinavir, lopinavir, ritonavir, saquinavir, telaprevir, tipranavir, posaconazole, voriconazole, telithromycin, conivaptan, boceprevir. Moderate CYP3A inhibitor: for example erythromycin, ciprofloxacin, fluconazole, diltiazem, verapamil, aprepitant, atazanavir, darunavir, fosamprenavir, imatinib, cimetidine.

\n

Co-medication with a STRONG CYP2D6 INHIBITOR (e.g. paroxetine, fluoxetine, quinidine, bupropione):

\n\n

Co-medication with a MODERATE CYP2D6 INHIBITOR (for example duloxetine, terbinafine, moclobemide, mirabegron, cinacalcet, dronedarone):

\n\n

Co-medication with a STRONG CYP3A INHIBITOR (for example ketoconazole, clarithromycin, itraconazole, cobicistat, indinavir, lopinavir, ritonavir, saquinavir, telaprevir, tipranavir, posaconazole, voriconazole, telithromycin, conivaptan, boceprevir):

\n\n

Co-medication with a MODERATE CYP3A INHIBITOR (for example erythromycin, ciprofloxacin, fluconazole, diltiazem, verapamil, aprepitant, atazanavir, darunavir, fosamprenavir, imatinib, cimetidine):

\n\n

Co-medication with a STRONG CYP3A INDUCER (for example rifampicin, carbamazepine, phenobarbital, phenytoin, rifabutine, hypericum): Eliglustat is not recommended. The plasma concentration may decrease so sharply that a therapeutic effect cannot be achieved.

\n\n

NO co-medication with a moderate or strong CYP2D6 or CYP3A inhibitor or strong CYP3A inducer:

\n\n", + "id" : 1452103951, + "html" : "

Eliglustat is contra-indicated. Choose an alternative if possible.

\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166302373", + "name" : "Recommendation Annotation PA166302373", + "alternateDrugAvailable" : true, + "dosingInformation" : false, + "implications" : [ + "This gene variation increases the conversion of eliglustat to inactive metabolites. As a result, a normal dose is not effective. There is not enough scientific substantiation to suggest an effective dose for all UM." + ], + "lookupKey" : {"CYP2D6": "≥6.0"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA166123486", + "name" : "eliglustat", + "version" : 6 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166182823", + "name" : "Annotation of DPWG Guideline for eliglustat and CYP2D6", + "version" : 71 + }, + "text" : { + "id" : 1452103952, + "html" : "

Eliglustat is contra-indicated. Choose an alternative if possible.

\n", "version" : 0 }, "version" : 0 @@ -115446,7 +116591,7 @@ "objCls" : "Chemical", "id" : "PA10074", "name" : "escitalopram", - "version" : 11 + "version" : 28 } ], "relatedGenes" : [ @@ -115455,72 +116600,71 @@ "id" : "PA124", "symbol" : "CYP2C19", "name" : "cytochrome P450 family 2 subfamily C member 19", - "version" : 7210 + "version" : 7266 } ], "source" : "DPWG", "summaryMarkdown" : { "id" : 1447982026, "html" : "

The Dutch Pharmacogenetics Working Group Guideline for escitalopram recommends for intermediate and poor metabolizers of CYP2C19 to not exceed the in the DPWG document specified doses and for CYP2C19 ultrarapid metabolizer to avoid escitalopram.

\n", - "version" : 1 + "version" : 3 }, "terms" : [], "textMarkdown" : { "id" : 1447982025, "html" : "

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

\n

May 2021 update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has made some minor changes to the text of the CYP2C19-escitalopram guideline. The table below has been updated to reflect this but the recommendations themselves have not changed.

\n

Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction between CYP2C19 and CYP2D6 and SSRIs. European journal of human genetics (2021)

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group published a paper with the guidelines as per the November 2018 update and further details on the assessed literature [Article:34782755].

\n

November 2018 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for escitalopram based on CYP2C19 genotype. They recommend to not exceed the below mentioned doses for intermediate metabolizer (for IM = 75% of the standard maximum dose) and poor metabolizer (for PM = 50% of the standard maximum dose). For CYP2C19 ultrarapid metabolizer, the recommendation is to avoid escitalopram.

\n

Wording in table taken from the Dutch guidelines November 2018 update and incorporating text changes from the May 2021 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
CYP2C19 UMescitalopramThe risk of switching to another antidepressant is increased as the gene variation leads to a reduction in the escitalopram plasma concentration.Avoid escitalopram. Antidepressants that are not metabolised or that are metabolised to a lesser extent by CYP2C19 are, for example, paroxetine or fluvoxamine.
CYP2C19 IMescitalopramThe risk of QT prolongation and torsades de pointes is theoretically increased because the gene variation leads to an increased escitalopram plasma concentration. If you follow the dose recommendation below, the increased plasma concentration and the theoretically increased risk of QT prolongation will be offset.Do not exceed the following doses (75% of the standard maximum dose): adults < 65 years: 15 mg/day, adults 65 years or older: 7.5 mg/day
CYP2C19 PMescitalopramThe risk of switching to another antidepressant is increased. In addition, the risk of QT prolongation and torsades de pointes is theoretically increased because the gene variation leads to an increased escitalopram plasma concentration. If you follow the dose recommendation below, the increased plasma concentration, the theoretically increased risk of QT prolongation and the increased risk of switching to another antidepressant will be offset.Do not exceed the following doses (50% of the standard maximum dose): adults < 65 years: 10 mg/day, adults 65 years or older: 5 mg/day
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for escitalopram and CYP2C19:

\n
\n

The Dutch Pharmacogenetics Working Group considers genotyping before starting escitalopram to be potentially beneficial. Genotyping can be considered on an individual patient basis. If, however, the genotype is available, the Dutch Pharmacogenetics Working Group recommends adhering to the gene-drug guideline.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n

2011 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for escitalopram based on the CYP2C19 genotype [Article:21412232]. They conclude to monitor plasma concentration and titrate dose to a maximum of 150% in response to efficacy and adverse drug event or select alternative drug (e.g. fluoxetine, paroxetine) for the CYP2C19 UM phenotype.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Phenotype (Genotype)Therapeutic Dose RecommendationLevel of EvidenceClinical Relevance
CYP2C19 PM (*2/*2, *2/*3, *3/*3)NonePublished controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpointsMinor clinical effect (statistically significant difference): QTc prolongation (<450 ms female, <470 ms male); international normalized ratio (INR) increase < 4.5. Kinetic effect (statistically significant difference)
CYP2C19 IM (*1/*2, *1/*3, *17/*2, *17/*3)NonePublished controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpointsMinor clinical effect (statistically significant difference): QTc prolongation (<450 ms female, <470 ms male); INR increase < 4.5. Kinetic effect (statistically significant difference)
CYP2C19 UM (*17/*17)Monitor plasma concentration and titrate dose to a maximum of 150% in response to efficacy and adverse drug event or select alternative drug (e.g. fluoxetine, paroxetine)Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpointsMinor clinical effect (statistically significant difference): QTc prolongation (<450 ms female, <470 ms male); INR increase < 4.5. Kinetic effect (statistically significant difference)
\n\n", - "version" : 20 + "version" : 25 }, "userId" : "matt", - "version" : 34 + "version" : 72 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166299133", - "name" : "Recommendation PA166299133", - "alternateDrugAvailable" : true, + "id" : "PA166299135", + "name" : "Recommendation PA166299135", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, "dosingInformation" : false, "implications" : [ - "The risk of switching to another antidepressant is increased as the gene variation leads to a reduction in the escitalopram plasma concentration." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on escitalopram." ], - "lookupKey" : {"CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA10074", "name" : "escitalopram", - "version" : 11 + "version" : 28 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104975", "name" : "Annotation of DPWG Guideline for escitalopram and CYP2C19", - "version" : 34 + "version" : 72 }, "text" : { - "id" : 1452061496, - "html" : "

Avoid escitalopram. Antidepressants that are not metabolised or that are metabolised to a lesser extent by CYP2C19 are, for example, paroxetine or fluvoxamine.

\n", + "id" : 1452061498, + "html" : "

The guideline does not provide a recommendation for escitalopram in normal metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299136", - "name" : "Recommendation PA166299136", - "alternateDrugAvailable" : false, + "id" : "PA166299133", + "name" : "Recommendation PA166299133", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -115531,73 +116675,74 @@ "valid" : true, "version" : 1 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "The risk of QT prolongation and torsades de pointes is theoretically increased because the gene variation leads to an increased escitalopram plasma concentration. If you follow the dose recommendation below, the increased plasma concentration and the theoretically increased risk of QT prolongation will be offset." + "The risk of switching to another antidepressant is increased as the gene variation leads to a reduction in the escitalopram plasma concentration." ], - "lookupKey" : {"CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA10074", "name" : "escitalopram", - "version" : 11 + "version" : 28 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104975", "name" : "Annotation of DPWG Guideline for escitalopram and CYP2C19", - "version" : 34 + "version" : 72 }, "text" : { - "id" : 1452061499, - "html" : "

Do not exceed the following doses (75% of the standard maximum dose): adults < 65 years 15 mg/day, =65 years 7.5 mg/day

\n", + "id" : 1452061496, + "html" : "

Avoid escitalopram. Antidepressants that are not metabolised or that are metabolised to a lesser extent by CYP2C19 are, for example, paroxetine or fluvoxamine.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299135", - "name" : "Recommendation PA166299135", + "id" : "PA166299136", + "name" : "Recommendation PA166299136", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on escitalopram." + "The risk of QT prolongation and torsades de pointes is theoretically increased because the gene variation leads to an increased escitalopram plasma concentration. If you follow the dose recommendation below, the increased plasma concentration and the theoretically increased risk of QT prolongation will be offset." ], - "lookupKey" : {"CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA10074", "name" : "escitalopram", - "version" : 11 + "version" : 28 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104975", "name" : "Annotation of DPWG Guideline for escitalopram and CYP2C19", - "version" : 34 + "version" : 72 }, "text" : { - "id" : 1452061498, - "html" : "

The guideline does not provide a recommendation for escitalopram in normal metabolizers.

\n", + "id" : 1452061499, + "html" : "

Do not exceed the following doses (75% of the standard maximum dose): adults < 65 years 15 mg/day, =65 years 7.5 mg/day

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", @@ -115625,21 +116770,21 @@ "objCls" : "Chemical", "id" : "PA10074", "name" : "escitalopram", - "version" : 11 + "version" : 28 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104975", "name" : "Annotation of DPWG Guideline for escitalopram and CYP2C19", - "version" : 34 + "version" : 72 }, "text" : { "id" : 1452061497, "html" : "

Do not exceed the following doses (50% of the standard maximum dose): adults < 65 years 10 mg/day, =65 years 5 mg/day

\n", "version" : 0 }, - "version" : 0 + "version" : 2 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166104975" @@ -115733,7 +116878,7 @@ "date" : "2019-05-23T00:00:00-07:00", "description" : "Annotation current with November 2018 DPWG Guideline release", "type" : "Update", - "version" : 0 + "version" : 1 }, { "id" : 1450820628, @@ -115897,7 +117042,7 @@ "objCls" : "Chemical", "id" : "PA449646", "name" : "flecainide", - "version" : 11 + "version" : 25 } ], "relatedGenes" : [ @@ -115906,30 +117051,30 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "DPWG", "summaryMarkdown" : { "id" : 1447981986, "html" : "

Reduce flecainide dose by 50% for CYP2D6 poor metabolizer (PM) and record an ECG and monitor the plasma concentration. Reduce flecainide dose to 75% of the standard dose for CYP2D6 intermediate metabolizer (IM) patients with indications other than diagnosis of Brugada syndrome and record an ECG and monitor the plasma concentration.

\n", - "version" : 1 + "version" : 2 }, "terms" : [], "textMarkdown" : { "id" : 1447981985, "html" : "

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

\n

November 2018 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for flecainide based on CYP2D6 genotype. They recommend reducing flecainide dose by 50% for CYP2D6 poor metabolizer (PM) and recording an ECG and monitor the plasma concentration. For CYP2D6 intermediate metabolizer (IM) patients with indications other than diagnosis of Brugada syndrome, they recommend reducing the dose to 75% of the standard dose and record an ECG and monitor the plasma concentration.

\n

Wording in table taken from the Dutch guidelines November 2018 update

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
CYP2D6 IMflecainideThe genetic variation reduces conversion of flecainide to inactive metabolites. This may increase the risk of side effects.1. Indications other than diagnosis of Brugada syndrome: reduce the dose to 75% of the standard dose and record an ECG and monitor the plasma concentration.2.Provocation test for diagnosis of Brugada syndrome:No action required.At a dose of 2.0 mg/kg body weight to a maximum of 150 mg, the response is better for patients with alleles that result in reduced activity.All 5 patients with these alleles and 20% of the patients with two fully active alleles exhibited a response within 30 minutes.
CYP2D6 PMflecanideThe genetic variation reduces conversion of flecainide to inactive metabolites. This increases the risk of side effects.1. reduce the dose to 50% of the standard dose and record an ECG and monitor the plasma concentration.
CYP2D6 UMflecanideThe genetic variation increases conversion of flecainide to inactive metabolites. A higher dose is possibly required as a result.There are no data about the pharmacokinetics and/or the effects of flecainide in UM. Monitor the plasma concentration as a precaution and record an ECG or select an alternative. Examples of anti-arrhythmic drugs that are not metabolized via CYP2D6 (or to a lesser extent) include sotalol, disopyramide, quinidine and amiodarone.
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for flecainide and CYP2D6:

\n
\n

The KNMP Pharmacogenetics Working Group considers genotyping before starting flecainide to be potentially\nbeneficial for the prevention of side effects and drug effectiveness. Genotyping can be considered on an individual patient basis. If, however, the genotype is available, the KNMP Pharmacogenetics Working Group recommends\nadhering to the gene-drug guideline.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n

2011 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for flecainide based on CYP2D6 genotypes [Article:21412232]. They recommend a lower dose for patients carrying the poor metabolizer (PM) alleles and intermediate metabolizer (IM) alleles.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Phenotype (Genotype)Therapeutic Dose RecommendationLevel of EvidenceClinical Relevance
PM (two inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) alleles)Reduce dose by 50%, record ECG, monitor plasma concentration.Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Minor clinical effect (S): QTc prolongation (<450 ms female, <470 ms male); INR increase < 4.5; Kinetic effect (S)
IM (two decreased-activity (*9, *10, *17, *29, *36, *41) alleles or carrying one active (*1, *2, *33, *35) and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele, or carrying one decreased-activity (*9, *10, *17, *29, *36, *41) allele and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele)Reduce dose by 25%, record ECG, monitor plasma concentration.Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Minor clinical effect (S): QTc prolongation (<450 ms female, <470 ms male); INR increase < 4.5; Kinetic effect (S)
UM (a gene duplication in absence of inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) or decreased-activity (*9, *10, *17, *29, *36, *41) alleles)Record ECG and monitor plasma concentration or select alternative drug (e.g., sotalol, disopyramide, quinidine, amiodarone).no evidence.--
\n\n", - "version" : 15 + "version" : 23 }, "userId" : "cfthorn", - "version" : 33 + "version" : 99 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166302392", - "name" : "Recommendation Annotation PA166302392", - "alternateDrugAvailable" : true, + "id" : "PA166302381", + "name" : "Recommendation Annotation PA166302381", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -115940,29 +117085,71 @@ "valid" : true, "version" : 1 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "The genetic variation increases conversion of flecainide to inactive metabolites. A higher dose is possibly required as a result." + "The genetic variation reduces conversion of flecainide to inactive metabolites. This increases the risk of side effects." ], - "lookupKey" : {"CYP2D6": "4.0"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"CYP2D6": "0.0"}, + "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449646", "name" : "flecainide", - "version" : 11 + "version" : 25 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104969", "name" : "Annotation of DPWG Guideline for flecainide and CYP2D6", - "version" : 33 + "version" : 99 }, "text" : { - "id" : 1452103971, - "html" : "

There are no data about the pharmacokinetics and/or the effects of flecainide in UM. Monitor the plasma concentration as a precaution and record an ECG or select an alternative. Examples of anti-arrhythmic drugs that are not metabolized via CYP2D6 (or to a lesser extent) include sotalol, disopyramide, quinidine and amiodarone.

\n", + "id" : 1452103960, + "html" : "

Reduce the dose to 50% of the standard dose and record an ECG and monitor the plasma concentration.

\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166302382", + "name" : "Recommendation Annotation PA166302382", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501929, + "description" : "Not Applicable", + "parents" : [], + "resource" : "Guideline Strength", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", + "valid" : true, + "version" : 1 + }, + "dosingInformation" : true, + "implications" : [ + "The genetic variation reduces conversion of flecainide to inactive metabolites. This may increase the risk of side effects." + ], + "lookupKey" : {"CYP2D6": "0.25"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA449646", + "name" : "flecainide", + "version" : 25 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104969", + "name" : "Annotation of DPWG Guideline for flecainide and CYP2D6", + "version" : 99 + }, + "text" : { + "id" : 1452103961, + "html" : "

Indications other than diagnosis of Brugada syndrome:

\n\n

Provocation test for diagnosis of Brugada syndrome:

\n\n", "version" : 0 }, "version" : 0 @@ -115993,14 +117180,14 @@ "objCls" : "Chemical", "id" : "PA449646", "name" : "flecainide", - "version" : 11 + "version" : 25 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104969", "name" : "Annotation of DPWG Guideline for flecainide and CYP2D6", - "version" : 33 + "version" : 99 }, "text" : { "id" : 1452103962, @@ -116011,9 +117198,9 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302396", - "name" : "Recommendation Annotation PA166302396", - "alternateDrugAvailable" : true, + "id" : "PA166302384", + "name" : "Recommendation Annotation PA166302384", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -116024,204 +117211,202 @@ "valid" : true, "version" : 1 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "The genetic variation increases conversion of flecainide to inactive metabolites. A higher dose is possibly required as a result." + "The genetic variation reduces conversion of flecainide to inactive metabolites. This may increase the risk of side effects." ], - "lookupKey" : {"CYP2D6": "≥4.0"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"CYP2D6": "0.75"}, + "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449646", "name" : "flecainide", - "version" : 11 + "version" : 25 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104969", "name" : "Annotation of DPWG Guideline for flecainide and CYP2D6", - "version" : 33 + "version" : 99 }, "text" : { - "id" : 1452103975, - "html" : "

There are no data about the pharmacokinetics and/or the effects of flecainide in UM. Monitor the plasma concentration as a precaution and record an ECG or select an alternative. Examples of anti-arrhythmic drugs that are not metabolized via CYP2D6 (or to a lesser extent) include sotalol, disopyramide, quinidine and amiodarone.

\n", + "id" : 1452103963, + "html" : "

Indications other than diagnosis of Brugada syndrome:

\n\n

Provocation test for diagnosis of Brugada syndrome:

\n\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302387", - "name" : "Recommendation Annotation PA166302387", + "id" : "PA166302385", + "name" : "Recommendation Annotation PA166302385", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on flecainide." + "The genetic variation reduces conversion of flecainide to inactive metabolites. This may increase the risk of side effects." ], - "lookupKey" : {"CYP2D6": "1.5"}, + "lookupKey" : {"CYP2D6": "1.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449646", "name" : "flecainide", - "version" : 11 + "version" : 25 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104969", "name" : "Annotation of DPWG Guideline for flecainide and CYP2D6", - "version" : 33 + "version" : 99 }, "text" : { - "id" : 1452103966, - "html" : "

The guideline does not provide a recommendation for flecainide in normal metabolizers.

\n", + "id" : 1452103964, + "html" : "

Indications other than diagnosis of Brugada syndrome:

\n\n

Provocation test for diagnosis of Brugada syndrome:

\n\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302391", - "name" : "Recommendation Annotation PA166302391", - "alternateDrugAvailable" : true, + "id" : "PA166302386", + "name" : "Recommendation Annotation PA166302386", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, "dosingInformation" : false, "implications" : [ - "The genetic variation increases conversion of flecainide to inactive metabolites. A higher dose is possibly required as a result." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on flecainide." ], - "lookupKey" : {"CYP2D6": "3.0"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"CYP2D6": "1.25"}, + "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449646", "name" : "flecainide", - "version" : 11 + "version" : 25 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104969", "name" : "Annotation of DPWG Guideline for flecainide and CYP2D6", - "version" : 33 + "version" : 99 }, "text" : { - "id" : 1452103970, - "html" : "

There are no data about the pharmacokinetics and/or the effects of flecainide in UM. Monitor the plasma concentration as a precaution and record an ECG or select an alternative. Examples of anti-arrhythmic drugs that are not metabolized via CYP2D6 (or to a lesser extent) include sotalol, disopyramide, quinidine and amiodarone.

\n", + "id" : 1452103965, + "html" : "

The guideline does not provide a recommendation for flecainide in normal metabolizers.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302395", - "name" : "Recommendation Annotation PA166302395", - "alternateDrugAvailable" : true, + "id" : "PA166302387", + "name" : "Recommendation Annotation PA166302387", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, "dosingInformation" : false, "implications" : [ - "The genetic variation increases conversion of flecainide to inactive metabolites. A higher dose is possibly required as a result." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on flecainide." ], - "lookupKey" : {"CYP2D6": "≥3.5"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"CYP2D6": "1.5"}, + "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449646", "name" : "flecainide", - "version" : 11 + "version" : 25 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104969", "name" : "Annotation of DPWG Guideline for flecainide and CYP2D6", - "version" : 33 + "version" : 99 }, "text" : { - "id" : 1452103974, - "html" : "

There are no data about the pharmacokinetics and/or the effects of flecainide in UM. Monitor the plasma concentration as a precaution and record an ECG or select an alternative. Examples of anti-arrhythmic drugs that are not metabolized via CYP2D6 (or to a lesser extent) include sotalol, disopyramide, quinidine and amiodarone.

\n", + "id" : 1452103966, + "html" : "

The guideline does not provide a recommendation for flecainide in normal metabolizers.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302382", - "name" : "Recommendation Annotation PA166302382", + "id" : "PA166302388", + "name" : "Recommendation Annotation PA166302388", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "The genetic variation reduces conversion of flecainide to inactive metabolites. This may increase the risk of side effects." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on flecainide." ], - "lookupKey" : {"CYP2D6": "0.25"}, + "lookupKey" : {"CYP2D6": "2.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449646", "name" : "flecainide", - "version" : 11 + "version" : 25 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104969", "name" : "Annotation of DPWG Guideline for flecainide and CYP2D6", - "version" : 33 + "version" : 99 }, "text" : { - "id" : 1452103961, - "html" : "

Indications other than diagnosis of Brugada syndrome:

\n\n

Provocation test for diagnosis of Brugada syndrome:

\n\n", + "id" : 1452103967, + "html" : "

The guideline does not provide a recommendation for flecainide in normal metabolizers.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302386", - "name" : "Recommendation Annotation PA166302386", + "id" : "PA166302389", + "name" : "Recommendation Annotation PA166302389", "alternateDrugAvailable" : false, "classification" : { "id" : 1448526251, @@ -116236,24 +117421,24 @@ "implications" : [ "The guideline does not provide a description of the impact of a normal metabolizer phenotype on flecainide." ], - "lookupKey" : {"CYP2D6": "1.25"}, + "lookupKey" : {"CYP2D6": "2.25"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449646", "name" : "flecainide", - "version" : 11 + "version" : 25 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104969", "name" : "Annotation of DPWG Guideline for flecainide and CYP2D6", - "version" : 33 + "version" : 99 }, "text" : { - "id" : 1452103965, + "id" : 1452103968, "html" : "

The guideline does not provide a recommendation for flecainide in normal metabolizers.

\n", "version" : 0 }, @@ -116284,14 +117469,14 @@ "objCls" : "Chemical", "id" : "PA449646", "name" : "flecainide", - "version" : 11 + "version" : 25 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104969", "name" : "Annotation of DPWG Guideline for flecainide and CYP2D6", - "version" : 33 + "version" : 99 }, "text" : { "id" : 1452103969, @@ -116302,8 +117487,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302394", - "name" : "Recommendation Annotation PA166302394", + "id" : "PA166302398", + "name" : "Recommendation Annotation PA166302398", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -116319,34 +117504,34 @@ "implications" : [ "The genetic variation increases conversion of flecainide to inactive metabolites. A higher dose is possibly required as a result." ], - "lookupKey" : {"CYP2D6": "≥3.25"}, + "lookupKey" : {"CYP2D6": "≥6.0"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449646", "name" : "flecainide", - "version" : 11 + "version" : 25 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104969", "name" : "Annotation of DPWG Guideline for flecainide and CYP2D6", - "version" : 33 + "version" : 99 }, "text" : { - "id" : 1452103973, + "id" : 1452103977, "html" : "

There are no data about the pharmacokinetics and/or the effects of flecainide in UM. Monitor the plasma concentration as a precaution and record an ECG or select an alternative. Examples of anti-arrhythmic drugs that are not metabolized via CYP2D6 (or to a lesser extent) include sotalol, disopyramide, quinidine and amiodarone.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302381", - "name" : "Recommendation Annotation PA166302381", - "alternateDrugAvailable" : false, + "id" : "PA166302397", + "name" : "Recommendation Annotation PA166302397", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -116357,38 +117542,38 @@ "valid" : true, "version" : 1 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "The genetic variation reduces conversion of flecainide to inactive metabolites. This increases the risk of side effects." + "The genetic variation increases conversion of flecainide to inactive metabolites. A higher dose is possibly required as a result." ], - "lookupKey" : {"CYP2D6": "0.0"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"CYP2D6": "≥5.0"}, + "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449646", "name" : "flecainide", - "version" : 11 + "version" : 25 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104969", "name" : "Annotation of DPWG Guideline for flecainide and CYP2D6", - "version" : 33 + "version" : 99 }, "text" : { - "id" : 1452103960, - "html" : "

Reduce the dose to 50% of the standard dose and record an ECG and monitor the plasma concentration.

\n", + "id" : 1452103976, + "html" : "

There are no data about the pharmacokinetics and/or the effects of flecainide in UM. Monitor the plasma concentration as a precaution and record an ECG or select an alternative. Examples of anti-arrhythmic drugs that are not metabolized via CYP2D6 (or to a lesser extent) include sotalol, disopyramide, quinidine and amiodarone.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302385", - "name" : "Recommendation Annotation PA166302385", - "alternateDrugAvailable" : false, + "id" : "PA166302396", + "name" : "Recommendation Annotation PA166302396", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -116399,37 +117584,37 @@ "valid" : true, "version" : 1 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "The genetic variation reduces conversion of flecainide to inactive metabolites. This may increase the risk of side effects." + "The genetic variation increases conversion of flecainide to inactive metabolites. A higher dose is possibly required as a result." ], - "lookupKey" : {"CYP2D6": "1.0"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"CYP2D6": "≥4.0"}, + "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449646", "name" : "flecainide", - "version" : 11 + "version" : 25 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104969", "name" : "Annotation of DPWG Guideline for flecainide and CYP2D6", - "version" : 33 + "version" : 99 }, "text" : { - "id" : 1452103964, - "html" : "

Indications other than diagnosis of Brugada syndrome:

\n\n

Provocation test for diagnosis of Brugada syndrome:

\n\n", + "id" : 1452103975, + "html" : "

There are no data about the pharmacokinetics and/or the effects of flecainide in UM. Monitor the plasma concentration as a precaution and record an ECG or select an alternative. Examples of anti-arrhythmic drugs that are not metabolized via CYP2D6 (or to a lesser extent) include sotalol, disopyramide, quinidine and amiodarone.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302398", - "name" : "Recommendation Annotation PA166302398", + "id" : "PA166302395", + "name" : "Recommendation Annotation PA166302395", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -116445,69 +117630,70 @@ "implications" : [ "The genetic variation increases conversion of flecainide to inactive metabolites. A higher dose is possibly required as a result." ], - "lookupKey" : {"CYP2D6": "≥6.0"}, + "lookupKey" : {"CYP2D6": "≥3.5"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449646", "name" : "flecainide", - "version" : 11 + "version" : 25 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104969", "name" : "Annotation of DPWG Guideline for flecainide and CYP2D6", - "version" : 33 + "version" : 99 }, "text" : { - "id" : 1452103977, + "id" : 1452103974, "html" : "

There are no data about the pharmacokinetics and/or the effects of flecainide in UM. Monitor the plasma concentration as a precaution and record an ECG or select an alternative. Examples of anti-arrhythmic drugs that are not metabolized via CYP2D6 (or to a lesser extent) include sotalol, disopyramide, quinidine and amiodarone.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302389", - "name" : "Recommendation Annotation PA166302389", - "alternateDrugAvailable" : false, + "id" : "PA166302394", + "name" : "Recommendation Annotation PA166302394", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, "dosingInformation" : false, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on flecainide." + "The genetic variation increases conversion of flecainide to inactive metabolites. A higher dose is possibly required as a result." ], - "lookupKey" : {"CYP2D6": "2.25"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"CYP2D6": "≥3.25"}, + "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449646", "name" : "flecainide", - "version" : 11 + "version" : 25 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104969", "name" : "Annotation of DPWG Guideline for flecainide and CYP2D6", - "version" : 33 + "version" : 99 }, "text" : { - "id" : 1452103968, - "html" : "

The guideline does not provide a recommendation for flecainide in normal metabolizers.

\n", + "id" : 1452103973, + "html" : "

There are no data about the pharmacokinetics and/or the effects of flecainide in UM. Monitor the plasma concentration as a precaution and record an ECG or select an alternative. Examples of anti-arrhythmic drugs that are not metabolized via CYP2D6 (or to a lesser extent) include sotalol, disopyramide, quinidine and amiodarone.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -116535,27 +117721,27 @@ "objCls" : "Chemical", "id" : "PA449646", "name" : "flecainide", - "version" : 11 + "version" : 25 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104969", "name" : "Annotation of DPWG Guideline for flecainide and CYP2D6", - "version" : 33 + "version" : 99 }, "text" : { "id" : 1452103972, "html" : "

There are no data about the pharmacokinetics and/or the effects of flecainide in UM. Monitor the plasma concentration as a precaution and record an ECG or select an alternative. Examples of anti-arrhythmic drugs that are not metabolized via CYP2D6 (or to a lesser extent) include sotalol, disopyramide, quinidine and amiodarone.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302384", - "name" : "Recommendation Annotation PA166302384", - "alternateDrugAvailable" : false, + "id" : "PA166302392", + "name" : "Recommendation Annotation PA166302392", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -116566,37 +117752,37 @@ "valid" : true, "version" : 1 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "The genetic variation reduces conversion of flecainide to inactive metabolites. This may increase the risk of side effects." + "The genetic variation increases conversion of flecainide to inactive metabolites. A higher dose is possibly required as a result." ], - "lookupKey" : {"CYP2D6": "0.75"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"CYP2D6": "4.0"}, + "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449646", "name" : "flecainide", - "version" : 11 + "version" : 25 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104969", "name" : "Annotation of DPWG Guideline for flecainide and CYP2D6", - "version" : 33 + "version" : 99 }, "text" : { - "id" : 1452103963, - "html" : "

Indications other than diagnosis of Brugada syndrome:

\n\n

Provocation test for diagnosis of Brugada syndrome:

\n\n", + "id" : 1452103971, + "html" : "

There are no data about the pharmacokinetics and/or the effects of flecainide in UM. Monitor the plasma concentration as a precaution and record an ECG or select an alternative. Examples of anti-arrhythmic drugs that are not metabolized via CYP2D6 (or to a lesser extent) include sotalol, disopyramide, quinidine and amiodarone.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302397", - "name" : "Recommendation Annotation PA166302397", + "id" : "PA166302391", + "name" : "Recommendation Annotation PA166302391", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -116612,69 +117798,28 @@ "implications" : [ "The genetic variation increases conversion of flecainide to inactive metabolites. A higher dose is possibly required as a result." ], - "lookupKey" : {"CYP2D6": "≥5.0"}, + "lookupKey" : {"CYP2D6": "3.0"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449646", "name" : "flecainide", - "version" : 11 + "version" : 25 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104969", "name" : "Annotation of DPWG Guideline for flecainide and CYP2D6", - "version" : 33 + "version" : 99 }, "text" : { - "id" : 1452103976, + "id" : 1452103970, "html" : "

There are no data about the pharmacokinetics and/or the effects of flecainide in UM. Monitor the plasma concentration as a precaution and record an ECG or select an alternative. Examples of anti-arrhythmic drugs that are not metabolized via CYP2D6 (or to a lesser extent) include sotalol, disopyramide, quinidine and amiodarone.

\n", "version" : 0 }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166302388", - "name" : "Recommendation Annotation PA166302388", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 1448526251, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on flecainide." - ], - "lookupKey" : {"CYP2D6": "2.0"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA449646", - "name" : "flecainide", - "version" : 11 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166104969", - "name" : "Annotation of DPWG Guideline for flecainide and CYP2D6", - "version" : 33 - }, - "text" : { - "id" : 1452103967, - "html" : "

The guideline does not provide a recommendation for flecainide in normal metabolizers.

\n", - "version" : 0 - }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166104969" @@ -116768,7 +117913,7 @@ "id" : "PA165987830", "symbol" : "HLA-B*57:01", "name" : "*57:01", - "version" : 6 + "version" : 21 } ], "relatedChemicals" : [ @@ -116776,7 +117921,7 @@ "objCls" : "Chemical", "id" : "PA164781042", "name" : "flucloxacillin", - "version" : 6 + "version" : 16 } ], "relatedGenes" : [ @@ -116785,7 +117930,7 @@ "id" : "PA35056", "symbol" : "HLA-B", "name" : "major histocompatibility complex, class I, B", - "version" : 40 + "version" : 2920 } ], "source" : "DPWG", @@ -116798,10 +117943,10 @@ "textMarkdown" : { "id" : 1450414936, "html" : "

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

\n

November 2018 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for flucloxacillin and HLA-B*57:01.

\n

Wording in table taken from the Dutch guidelines November 2018 update

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
ALLELE/GENOTYPE/PHENOTYPEDRUGDESCRIPTIONRECOMMENDATION
HLA-B*5701flucloxacillinHLA-B*5701-positive patients have an 80-fold elevated risk of flucloxacillin-induced liver injury. However, the incidence is low (1-2 per 1000 individuals).1. Regularly monitor the patient’s liver function
2. Choose an alternative if liver enzymes and/or bilirubin levels are elevated
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for flucloxacillin and HLA-B:

\n
\n

The KNMP Pharmacogenetics Working Group considers genotyping before starting flucloxacillin to be beneficial for\ndrug safety. It is advised to consider genotyping these patients before (or directly after) drug therapy has been initiated\nto guide drug selection.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n", - "version" : 6 + "version" : 8 }, "userId" : "cfthorn", - "version" : 14 + "version" : 34 }, "recommendations" : [ { @@ -116830,21 +117975,21 @@ "objCls" : "Chemical", "id" : "PA164781042", "name" : "flucloxacillin", - "version" : 6 + "version" : 16 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182810", "name" : "Annotation of DPWG Guideline for flucloxacillin and HLA-B", - "version" : 14 + "version" : 34 }, "text" : { "id" : 1452061460, "html" : "
    \n
  1. Regularly monitor the patient’s liver function
    2. \n
  2. Choose an alternative if liver enzymes and/or bilirubin levels are elevated
    3. \n
\n", "version" : 0 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166182810" @@ -116865,7 +118010,7 @@ "id" : 1451257822, "date" : "2020-08-31T00:00:00-07:00", "type" : "Create", - "version" : 0 + "version" : 1 }, { "id" : 1451698047, @@ -116943,7 +118088,7 @@ "objCls" : "Chemical", "id" : "PA449654", "name" : "flucytosine", - "version" : 7 + "version" : 22 } ], "relatedGenes" : [ @@ -116952,29 +118097,29 @@ "id" : "PA145", "symbol" : "DPYD", "name" : "dihydropyrimidine dehydrogenase", - "version" : 6907 + "version" : 6956 } ], "source" : "DPWG", "summaryMarkdown" : { "id" : 1451257820, "html" : "

The Dutch Pharmacogenetics Working Group Guideline for flucytosine states that patients with a DPYD activity score of 0 should avoid flucytosine. Patients with a DPYD activity score of 1 or 1.5 should be alert to the occurrence of severe side effects and flucytosine should be stopped if severe side effects occur.

\n", - "version" : 0 + "version" : 2 }, "terms" : [], "textMarkdown" : { "id" : 1451257821, "html" : "

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

\n

August 2020

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The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for flucytosine based on DPYD activity score.

\n

Wording in table taken from Dutch guidelines August 2020 update

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
DPD AS 0flucytosineA risk of life-threatening toxicity is increased by gene variation. A small proportion of flucytosine is converted to fluorouracil and patients with this gene variation are intolerant even to small quantities of fluorouracil.Avoid flucytosine
DPD AS 1flucytosineA very low risk of severe toxicity is increased by gene variation. A small proportion of flucytosine is converted to fluorouracil. Patients with this gene variation are more likely to react to fluorouracil, but generally tolerate low doses (approximately 50% of the standard fluorouracil dose).Be alert to the occurrence of severe side effects, such as leukopaenia, neutropaenia, thrombocytopaenia and diarrhoea. In the majority of cases, side effects of flucytosine occur in the first two to three weeks of the treatment. Flucytosine should be stopped if severe side effects occur.
DPD AS 1.5flucytosineA very low risk of severe toxicity is increased by gene variation. A small proportion of flucytosine is converted to fluorouracil. Patients with this gene variation are more likely to have a reaction to fluorouracil, but generally tolerate low doses (50-75% of the standard fluorouracil dose).Be alert to the occurrence of severe side effects, such as leukopaenia, neutropaenia, thrombocytopaenia and diarrhoea. In the majority of cases, side effects of flucytosine occur in the first two to three weeks of the treatment. Flucytosine should be stopped if severe side effects occur.
DPD FENOflucytosineA very low risk of severe toxicity is increased by gene variation. A small proportion of flucytosine is converted to fluorouracil. Patients with this gene variation are more likely to have a reaction to fluorouracil, but generally tolerate low doses (15-50% of the standard fluorouracil dose).Be alert to the occurrence of severe side effects, such as leukopaenia, neutropaenia, thrombocytopaenia and diarrhoea. In the majority of cases, side effects of flucytosine occur in the first two to three weeks of the treatment. Flucytosine should be stopped if severe side effects occur.
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for flucytosine and DPYD:

\n
\n

The KNMP Pharmacogenetics Working Group considers genotyping before starting flucytosine to be beneficial for drug safety. It is advised to genotype these patients before (or directly after) drug therapy has been initiated to guide drug selection.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n", - "version" : 5 + "version" : 6 }, "userId" : "katrin", - "version" : 12 + "version" : 40 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166299164", - "name" : "Recommendation PA166299164", + "id" : "PA166299161", + "name" : "Recommendation PA166299161", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -116988,145 +118133,155 @@ }, "dosingInformation" : false, "implications" : [ - "A very low risk of severe toxicity is increased by gene variation. A small proportion of flucytosine is converted to fluorouracil. Patients with this gene variation are more likely to react to fluorouracil, but generally tolerate low doses (approximately 50% of the standard fluorouracil dose)." + "A very low risk of severe toxicity is increased by gene variation. A small proportion of flucytosine is converted to fluorouracil. Patients with this gene variation are more likely to have a reaction to fluorouracil, but generally tolerate low doses (15-50% of the standard fluorouracil dose)." ], - "lookupKey" : {"DPYD": "1.0 (Intermediate Metabolizer)"}, + "lookupKey" : {"DPYD": "0.5 (Phenotyping)"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449654", "name" : "flucytosine", - "version" : 7 + "version" : 22 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166222801", "name" : "Annotation of DPWG Guideline for flucytosine and DPYD", - "version" : 12 + "version" : 40 }, "text" : { - "id" : 1452061527, - "html" : "\n", + "id" : 1452061524, + "html" : "\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301782", - "name" : "Recommendation Annotation PA166301782", + "id" : "PA166299164", + "name" : "Recommendation PA166299164", "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501929, + "description" : "Not Applicable", + "parents" : [], + "resource" : "Guideline Strength", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", + "valid" : true, + "version" : 1 + }, "dosingInformation" : false, "implications" : [ - "A very low risk of severe toxicity is increased by gene variation. A small proportion of flucytosine is converted to fluorouracil. Patients with this gene variation are more likely to have a reaction to fluorouracil, but generally tolerate low doses (15-50% of the standard fluorouracil dose)." + "A very low risk of severe toxicity is increased by gene variation. A small proportion of flucytosine is converted to fluorouracil. Patients with this gene variation are more likely to react to fluorouracil, but generally tolerate low doses (approximately 50% of the standard fluorouracil dose)." ], - "lookupKey" : {"DPYD": "1.0 (Phenotyping)"}, + "lookupKey" : {"DPYD": "1.0 (Intermediate Metabolizer)"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449654", "name" : "flucytosine", - "version" : 7 + "version" : 22 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166222801", "name" : "Annotation of DPWG Guideline for flucytosine and DPYD", - "version" : 12 + "version" : 40 }, "text" : { - "id" : 1452102461, - "html" : "\n", + "id" : 1452061527, + "html" : "\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299163", - "name" : "Recommendation PA166299163", + "id" : "PA166299162", + "name" : "Recommendation PA166299162", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, "dosingInformation" : false, "implications" : [ - "A very low risk of severe toxicity is increased by gene variation. A small proportion of flucytosine is converted to fluorouracil. Patients with this gene variation are more likely to have a reaction to fluorouracil, but generally tolerate low doses (50-75% of the standard fluorouracil dose)." + "The guideline does not provide a description of the impact of a DPYD activity score of 2 on flucytosine." ], - "lookupKey" : {"DPYD": "1.5 (Intermediate Metabolizer)"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"DPYD": "2.0 (Normal Metabolizer)"}, + "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449654", "name" : "flucytosine", - "version" : 7 + "version" : 22 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166222801", "name" : "Annotation of DPWG Guideline for flucytosine and DPYD", - "version" : 12 + "version" : 40 }, "text" : { - "id" : 1452061526, - "html" : "\n", + "id" : 1452061525, + "html" : "

The guideline does not provide a recommendation for flucytosine in patients with a DPYD activity score of 2.

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299162", - "name" : "Recommendation PA166299162", + "id" : "PA166299163", + "name" : "Recommendation PA166299163", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, "dosingInformation" : false, "implications" : [ - "The guideline does not provide a description of the impact of a DPYD activity score of 2 on flucytosine." + "A very low risk of severe toxicity is increased by gene variation. A small proportion of flucytosine is converted to fluorouracil. Patients with this gene variation are more likely to have a reaction to fluorouracil, but generally tolerate low doses (50-75% of the standard fluorouracil dose)." ], - "lookupKey" : {"DPYD": "2.0 (Normal Metabolizer)"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"DPYD": "1.5 (Intermediate Metabolizer)"}, + "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449654", "name" : "flucytosine", - "version" : 7 + "version" : 22 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166222801", "name" : "Annotation of DPWG Guideline for flucytosine and DPYD", - "version" : 12 + "version" : 40 }, "text" : { - "id" : 1452061525, - "html" : "

The guideline does not provide a recommendation for flucytosine in patients with a DPYD activity score of 2.

\n", + "id" : 1452061526, + "html" : "\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", @@ -117154,63 +118309,53 @@ "objCls" : "Chemical", "id" : "PA449654", "name" : "flucytosine", - "version" : 7 + "version" : 22 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166222801", "name" : "Annotation of DPWG Guideline for flucytosine and DPYD", - "version" : 12 + "version" : 40 }, "text" : { "id" : 1452061523, "html" : "

Avoid flucytosine

\n", "version" : 0 }, - "version" : 0 + "version" : 4 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299161", - "name" : "Recommendation PA166299161", + "id" : "PA166301782", + "name" : "Recommendation Annotation PA166301782", "alternateDrugAvailable" : false, - "classification" : { - "id" : 981501929, - "description" : "Not Applicable", - "parents" : [], - "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", - "valid" : true, - "version" : 1 - }, "dosingInformation" : false, "implications" : [ "A very low risk of severe toxicity is increased by gene variation. A small proportion of flucytosine is converted to fluorouracil. Patients with this gene variation are more likely to have a reaction to fluorouracil, but generally tolerate low doses (15-50% of the standard fluorouracil dose)." ], - "lookupKey" : {"DPYD": "0.5 (Phenotyping)"}, + "lookupKey" : {"DPYD": "1.0 (Phenotyping)"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449654", "name" : "flucytosine", - "version" : 7 + "version" : 22 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166222801", "name" : "Annotation of DPWG Guideline for flucytosine and DPYD", - "version" : 12 + "version" : 40 }, "text" : { - "id" : 1452061524, + "id" : 1452102461, "html" : "\n", "version" : 0 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166222801" @@ -117455,7 +118600,7 @@ "objCls" : "Chemical", "id" : "PA128406956", "name" : "fluorouracil", - "version" : 17 + "version" : 84 } ], "relatedGenes" : [ @@ -117464,23 +118609,23 @@ "id" : "PA145", "symbol" : "DPYD", "name" : "dihydropyrimidine dehydrogenase", - "version" : 6907 + "version" : 6956 } ], "source" : "DPWG", "summaryMarkdown" : { "id" : 1447981858, "html" : "

An alternative drug to fluorouracil is recommended for patients with a DPYD activity score of 0; if an alternative drug is not possible, the DPD activity should be determined and the initial dose adjusted accordingly. For patients with a DPYD activity score of 1 or 1.5, start with 50% of the standard dose or choose an alternative drug; adjustment of subsequent doses should be guided by toxicity and effectiveness. Patients with two partially functional alleles or one non-functional and one partially functional allele or two gene variants leading to partially functional alleles or a gene variant leading to a non-functional allele and a gene variant leading to a partially functional allele should have their DPD activity determined or should avoid fluorouracil/capecitabine. Tegafur is not an alternative for fluorouracil, as it is also metabolized by DPD. The DPWG evaluated DPYD genotyping as "essential" and recommend DPYD testing prior to initiating fluoropyrimidines.

\n", - "version" : 5 + "version" : 10 }, "terms" : [], "textMarkdown" : { "id" : 1447981857, "html" : "

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

\n

Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction of DPYD and fluoropyrimidines. European journal of human genetics (2019)

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The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group published a paper with the guidelines as per the August 2019 update including more details and scoring the clinical implementation PMID: 31745289.

\n

August 2019 Update

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The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for fluorouracil and capecitabine based on DPYD genotype. An alternative drug or reduction in dose is recommended for patients with DPYD activity scores of 0, 1 and 1.5. Patients with genotypes defined by the FENO group should have their DPD activity determined or should avoid fluorouracil/capecitabine. Tegafur is not an alternative, as it is also metabolized by DPD.

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Wording in table taken from the Dutch guidelines August 2019 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
Activity Score 0fluorouracil, cutaneousThe gene variation increases the risk of severe, potentially fatal toxicity. A reduced conversion of fluorouracil/capecitabine to inactive metabolites means that the normal dose is an overdose.Avoid fluorouracil.
NOTE: If a patient has two different genetic variations that lead to a non-functional DPD enzyme (e.g. *2A and* 13), this recommendation only applies if the variations are on a different allele. If both variations are on the same allele, this patient actually has gene activity score 1, for which no increased risk of severe, potentially fatal toxicity has been found with cutaneous use. These two situations can only be distinguished by determining the enzyme activity (phenotyping). This recommendation only applies if the patient has virtually no enzyme activity
Activity Score 0fluorouracil/capecitabine, systemicThe gene variation increases the risk of severe, potentially fatal toxicity. A reduced conversion of fluorouracil/capecitabine to inactive metabolites means that the standard dose is a more than 100-fold overdose.1. Avoid fluorouracil and capecitabine. Tegafur is not an alternative, as this is also metabolised by DPD.
2. If if is not possible to avoid fluorouracil and capecitabine: determine the residual DPD activity in mononuclear cells from peripheral blood and adjust the initial dose accordingly. A patient with 0.5% of the normal DPD activity tolerated 0.8% of the standard dose (150 mg capecitabine every 5 days). A patient with undetectable DPD activity tolerated 0.43% of the standard dose (150 mg capecitabine every 5 days with every third dose skipped).
Activity Score 1fluorouracil/capecitabineThe gene variation increases the risk of severe, potentially fatal toxicity. A reduced conversion of fluorouracil/capecitabine to inactive metabolites means that the normal dose is an overdose.Start with 50% of the standard dose or avoid fluorouracil and capecitabine. Adjustment of the subsequent dose should be guided by toxicity and effectiveness. However, in one study involving 17 patients with gene activity 1, the average dose after titration was 57% of the standard dose. Tegafur is not an alternative, as this is also metabolised by DPD.
Activity Score 1.5fluorouracil/capecitabineThe gene variation increases the risk of severe, potentially fatal toxicity. A reduced conversion of fluorouracil/capecitabine to inactive metabolites means that the normal dose is an overdose.Start with 50% of the standard dose or avoid fluorouracil and capecitabine. After starting treatment, the dose should be adjusted based on toxicity and effectiveness. In a study involving 17 patients with genotype 1/2846T, the average dose after titration was 64% of the standard dose. For 51 patients with genotype 1/1236A, the average dose after titration was 74% of the standard dose. Tegafur is not an alternative, as this is also metabolised by DPD.
FENOfluorouracil/capecitabineThe gene variation increases the risk of severe, potentially fatal, toxicity. A reduced conversion of fluorouracil/capecitabine to inactive metabolites means that the normal dose is an overdose.It is not possible to recommend a dose adjustment for this patient based on the genotype only.
Determine the residual DPD activity in mononuclear cells from peripheral blood and adjust the initial dose based on phenotype and genotype, or avoid fluorouracil and capecitabine. Tegafur is not an alternative, as this is also metabolized by DPD.
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for fluorouracil and DPYD:

\n
\n

The Dutch Pharmacogenetics Working Group considers genotyping before starting systemic fluorouracil or capecitabine to be essential for drug safety. Genotyping must be performed before drug therapy has been initiated to guide drug and dose selection.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n

November 2018 Update

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The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for fluorouracil and capecitabine based on DPYD genotype. An alternative drug or reduction in dose is recommended for patients with DPYD activity scores of 0, 0.5, 1 and 1.5. Tegafur is not an alternative, as it is also metabolized by DPD.

\n

Wording in table taken from the Dutch guidelines November 2018 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
Activity Score 0fluorouracil, cutaneousGenetic variation increases the risk of severe, potentially fatal toxicity. A reduced conversion of fluorouracil/capecitabine to inactive metabolites means that the normal dose is an overdose.Choose an alternative.
NOTE: If a patient has two different genetic variations that lead to a non-functional DPD enzyme (e.g. *2A and* 13), this recommendation only applies if the variations are on a different allele. If both variations are on the same allele, this patient has gene activity score 1, for which no increased risk of severe, potentially fatal toxicity has been found with cutaneous use. These two situations can only be distinguished by determining the enzyme activity (phenotyping).
Activity Score 0fluorouracil/capecitabine, systemicGenetic variation increases the risk of severe, potentially fatal toxicity. A reduced conversion of fluorouracil/capecitabine to inactive metabolites means that the standard dose is a more than 100-fold overdose.1. Choose an alternative. Tegafur is not an alternative, as this is also metabolised by DPD.
2. If an alternative is not possible: determine the residual DPD activity in mononuclear cells from peripheral blood and adjust the initial dose accordingly. A patient with 0.5% of the normal DPD activity tolerated 0.8% of the standard dose (150 mg capecitabine every 5 days). A patient with undetectable DPD activity tolerated 0.43% of the standard dose (150 mg capecitabine every 5 days with every third dose skipped). The average Caucasian DPD activity is 9.9 nmol/hour per mg protein. Or, adjust the initial dose based on toxicity and efficacy.
NOTE: If a patient has two different genetic variations that lead to a non-functional DPD enzyme (e.g. *2A and *13), this recommendation only applies if the variations are on a different allele. If both variations are on the same allele, this patient has gene activity score 1 and the recommendation for that gene activity score should be followed. These two situations can only be distinguished by determining the enzyme activity (phenotyping).
Activity Score 0.5fluorouracil/capecitabineGenetic variation increases the risk of severe, potentially fatal toxicity. A reduced conversion of fluorouracil/capecitabine to inactive metabolites means that the normal dose is an overdose.Start with 25% of the standard dose or choose an alternative. Adjustment of the initial dose should be guided by toxicity and effectiveness. Tegafur is not an alternative, as this is also metabolised by DPD.
NOTE: This recommendation only applies if the two genetic variations are on a different allele. If both variations are on the same allele, this patient has gene activity score 1 and the recommendation for that gene activity score should be followed. These two situations can only be distinguished by determining the enzyme activity (phenotyping).
Activity Score 1fluorouracil/capecitabineGenetic variation increases the risk of severe, potentially fatal toxicity. A reduced conversion of fluorouracil/capecitabine to inactive metabolites means that the normal dose is an overdose.Start with 50% of the standard dose or choose an alternative. Adjustment of the initial dose should be guided by toxicity and effectiveness. Tegafur is not an alternative, as this is also metabolised by DPD.
NB1: The dose reduction described here is well substantiated for *1/*2A and 1236A/1236A. The dose reduction for patients with 2846T (2846T/2846T or 1236A/2846T) is based on, among other factors, the dose reductions identified for *1/2846T.
NB2: If a patient has two different genetic variations that result in a partially functional DPD enzyme (e.g. 2846T and 1236A), this recommendation applies if the variations are on a different allele. If both variations are on the same allele, the gene activity score is between 1 and 1.5, depending on whether and how the two gene variations influence each other and on other factors that influence the DPD activity. Whether a gene activity score of 1 or 1.5 needs to be assigned in the case of two different genetic variations can only be determined by measuring the enzyme activity (phenotyping).
Activity Score 1.5fluorouracil/capecitabineGenetic variation increases the risk of severe, potentially fatal toxicity. A reduced conversion of fluorouracil/capecitabine to inactive metabolites means that the normal dose is an overdose.Start with 75% of the standard dose or choose an alternative. Adjustment of the initial dose should be guided by toxicity and effectiveness. Tegafur is not an alternative, as this is also metabolised by DPD.
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2011 Guideline

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The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for fluorouracil based on DPYD genotype [Article:21412232]. They recommend that an alternate drug be used for poor metabolizer patients, and a reduced dose or alternate drug for intermediate metabolizer patients.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Phenotype (Genotype)Therapeutic Dose RecommendationLevel of EvidenceClinical Relevance
PM (2 inactive alleles, 2 decreased activity alleles, or one inactive and one decreased activity alleles)Select alterantive drug. Tegafur is not a suitable alternative because this drug is also metabolized by DPD.Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Clinical effect (S): death; arrhythmia; unanticipated myelosuppression.
IM (1 active allele and 1 inactive or decreased activity allele)Reduce dose by 50% or select alternative drug. Tegafur is not a suitable alternative because this drug is also a substrate for DPD. Increase dose in response to toxicity and efficacy.Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Clinical effect (S): death; arrhythmia; unanticipated myelosuppression.
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele TypeAlleles
active*1, *4, *5, *6, *9A
decreased activity*9B, *10
inactive*2A, *3, *7, *8, *11, *12, *13, 496A>G, IVS10-15T>C, 1156G>T, 1845G>T
\n\n", - "version" : 18 + "version" : 27 }, "userId" : "carrillo", - "version" : 35 + "version" : 78 }, "recommendations" : [ { @@ -117509,53 +118654,62 @@ "objCls" : "Chemical", "id" : "PA128406956", "name" : "fluorouracil", - "version" : 17 + "version" : 84 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104939", "name" : "Annotation of DPWG Guideline for fluorouracil and DPYD", - "version" : 35 + "version" : 78 }, "text" : { "id" : 1452061535, "html" : "\n

Avoid fluorouracil.

\n

NOTE: If a patient has two different genetic variations that lead to a non-functional DPD enzyme (e.g. *2A and *13), this recommendation only applies if the variations are on a different allele. If both variations are on the same allele, this patient actually has a gene activity score 1, for which no increased risk of severe, potentially fatal toxicity has been found with cutaneous use. These two situations can only be distinguished by determining the enzyme activity (phenotyping). This recommendation only applies if the patient has virtually no enzyme activity.

\n\n

Avoid fluorouracil and capecitabine. Tegafur is not an alternative, as this is also metabolised by DPD.

\n

If it is not possible to avoid fluorouracil and capecitabine: determine the residual DPD activity in mononuclear cells from peripheral blood and adjust the initial dose accordingly.

\n

A patient with 0.5% of the normal DPD activity tolerated 0.8% of the standard dose (150 mg capecitabine every 5 days). A patient with undetectable DPD activity tolerated 0.43% of the standard dose (150 mg\ncapecitabine every 5 days with every third dose skipped)

\n", - "version" : 0 + "version" : 1 }, - "version" : 0 + "version" : 5 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166301783", - "name" : "Recommendation Annotation PA166301783", - "alternateDrugAvailable" : true, - "dosingInformation" : true, + "id" : "PA166299171", + "name" : "Recommendation PA166299171", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 1448526251, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : false, "implications" : [ - "The gene variation increases the risk of severe, potentially fatal toxicity. A reduced conversion of fluorouracil/capecitabine to inactive metabolites means that the normal dose is an overdose." + "The guideline does not provide a description of the impact of a DPYD activity score of 2 on fluorouracil." ], - "lookupKey" : {"DPYD": "1.0 (Phenotyping)"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"DPYD": "2.0 (Normal Metabolizer)"}, + "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA128406956", "name" : "fluorouracil", - "version" : 17 + "version" : 84 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104939", "name" : "Annotation of DPWG Guideline for fluorouracil and DPYD", - "version" : 35 + "version" : 78 }, "text" : { - "id" : 1452102462, - "html" : "

It is not possible to recommend a dose adjustment for this patient based on the genotype only.

\n\n", + "id" : 1452061534, + "html" : "

The guideline does not provide a recommendation for fluorouracil in patients with a DPYD activity score of 2.

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", @@ -117583,62 +118737,63 @@ "objCls" : "Chemical", "id" : "PA128406956", "name" : "fluorouracil", - "version" : 17 + "version" : 84 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104939", "name" : "Annotation of DPWG Guideline for fluorouracil and DPYD", - "version" : 35 + "version" : 78 }, "text" : { "id" : 1452061536, "html" : "

It is not possible to recommend a dose adjustment for this patient based on the genotype only.

\n\n", "version" : 0 }, - "version" : 0 + "version" : 4 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299171", - "name" : "Recommendation PA166299171", + "id" : "PA166299174", + "name" : "Recommendation PA166299174", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "The guideline does not provide a description of the impact of a DPYD activity score of 2 on fluorouracil." + "The gene variation increases the risk of severe, potentially fatal toxicity. A reduced conversion of fluorouracil/capecitabine to inactive metabolites means that the normal dose is an overdose." ], - "lookupKey" : {"DPYD": "2.0 (Normal Metabolizer)"}, + "lookupKey" : {"DPYD": "1.5 (Intermediate Metabolizer)"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA128406956", "name" : "fluorouracil", - "version" : 17 + "version" : 84 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104939", "name" : "Annotation of DPWG Guideline for fluorouracil and DPYD", - "version" : 35 + "version" : 78 }, "text" : { - "id" : 1452061534, - "html" : "

The guideline does not provide a recommendation for fluorouracil in patients with a DPYD activity score of 2.

\n", - "version" : 0 + "id" : 1452061537, + "html" : "

Start with 50% of the standard dose or avoid fluorouracil and capecitabine.

\n

After starting treatment, the dose should be adjusted based on toxicity and effectiveness. In a study involving 17 patients with genotype 1/2846T, the average dose after titration was 64% of the standard dose. For 51 patients with genotype 1/1236A, the average dose after titration was 74% of the standard dose. Tegafur is not an alternative, as this is also metabolised by DPD.

\n", + "version" : 1 }, - "version" : 0 + "version" : 4 }, { "objCls" : "Recommendation Annotation", @@ -117666,63 +118821,53 @@ "objCls" : "Chemical", "id" : "PA128406956", "name" : "fluorouracil", - "version" : 17 + "version" : 84 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104939", "name" : "Annotation of DPWG Guideline for fluorouracil and DPYD", - "version" : 35 + "version" : 78 }, "text" : { "id" : 1452061538, "html" : "

Start with 50% of the standard dose or avoid fluorouracil and capecitabine.

\n

Adjustment of the subsequent dose should be guided by toxicity and effectiveness. However, in one study involving 17 patients with gene activity 1, the average dose after titration was 57% of the standard dose. Tegafur is not an alternative, as this is also metabolised by DPD.

\n", - "version" : 0 + "version" : 1 }, - "version" : 0 + "version" : 4 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299174", - "name" : "Recommendation PA166299174", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 981501929, - "description" : "Not Applicable", - "parents" : [], - "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", - "valid" : true, - "version" : 1 - }, + "id" : "PA166301783", + "name" : "Recommendation Annotation PA166301783", + "alternateDrugAvailable" : true, "dosingInformation" : true, "implications" : [ "The gene variation increases the risk of severe, potentially fatal toxicity. A reduced conversion of fluorouracil/capecitabine to inactive metabolites means that the normal dose is an overdose." ], - "lookupKey" : {"DPYD": "1.5 (Intermediate Metabolizer)"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"DPYD": "1.0 (Phenotyping)"}, + "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA128406956", "name" : "fluorouracil", - "version" : 17 + "version" : 84 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104939", "name" : "Annotation of DPWG Guideline for fluorouracil and DPYD", - "version" : 35 + "version" : 78 }, "text" : { - "id" : 1452061537, - "html" : "

Start with 50% of the standard dose or avoid fluorouracil and capecitabine.

\n

After starting treatment, the dose should be adjusted based on toxicity and effectiveness. In a study involving 17 patients with genotype 1/2846T, the average dose after titration was 64% of the standard dose. For 51 patients with genotype 1/1236A, the average dose after titration was 74% of the standard dose. Tegafur is not an alternative, as this is also metabolised by DPD.

\n", + "id" : 1452102462, + "html" : "

It is not possible to recommend a dose adjustment for this patient based on the genotype only.

\n\n", "version" : 0 }, - "version" : 0 + "version" : 2 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166104939" @@ -117901,7 +119046,7 @@ "date" : "2019-05-27T00:00:00-07:00", "description" : "Annotation current with November 2018 DPWG Guideline release", "type" : "Update", - "version" : 0 + "version" : 1 }, { "id" : 1450820667, @@ -118094,7 +119239,7 @@ "objCls" : "Chemical", "id" : "PA449841", "name" : "haloperidol", - "version" : 14 + "version" : 41 } ], "relatedGenes" : [ @@ -118103,30 +119248,30 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "DPWG", "summaryMarkdown" : { "id" : 1447981994, "html" : "

The recommendation for CYP2D6 poor metabolizers is to use 60% of the normal dose of haloperidol and for CYP2D6 ultrarapid metabolizers to use 1.5 times the normal dose or to choose an alternative to haloperidol.

\n", - "version" : 2 + "version" : 4 }, "terms" : [], "textMarkdown" : { "id" : 1447981993, "html" : "

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

\n

Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction between CYP2D6, CYP3A4 and CYP1A2 and antipsychotics. European journal of human genetics (2023)

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group published a paper with the guidelines for haloperidol and CYP2D6 as per the May 2021 guidelines and further details on the assessed literature [Article:37002327]. Wording in the poor and ultrarapid metabolizer recommendation changed from "standard" to "normal" and is reflected in the table below.

\n

May 2021 update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has made changes to the CYP2D6 PM and UM recommendation for haloperidol. They recommend 60% of the standard dose of haloperidol for CYP2D6 poor metabolizer (PM) and 1.5 times the standard dose or to select an alternative drug for CYP2D6 ultrarapid metabolizers (UM).

\n

Wording in table taken from the Dutch guidelines May 2021 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
CYP2D6 IMhaloperidolThe genetic variation results in a higher plasma concentration, but the effect is small and no clinically significant effects were found.NO action is required for this gene-drug interaction.
CYP2D6 PMhaloperidolThere are indications for an increased risk of side effects. The genetic variation leads to decreased conversion of haloperidol, resulting in plasma concentrations that are approximately 1.7-fold higher.Use 60% of the normal dose.
CYP2D6 UMhaloperidolThere are indications of a risk of reduced effectiveness. The genetic variation leads to an increased conversion of haloperidol, resulting in a plasma concentration that is approximately 40% lower.Use 1.5 times the normal dose or choose an alternative.
Antipsychotics that are not metabolised by CYP2D6 - or to a much lesser extent - include, for example, flupentixol, penfluridol, quetiapine, olanzapine or clozapine.
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for haloperidol and CYP2D6:

\n
\n

The Dutch Pharmacogenetics Working Group considers genotyping before starting haloperidol to be potentially beneficial for the prevention of side effects and for drug efficacy. Genotyping can be considered on an individual patient basis. If, however, the genotype is available, the Dutch Pharmacogenetics Working Group recommends adhering to the gene-drug guideline.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n

November 2018 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for haloperidol based on CYP2D6 genotype. They recommend reducing haloperidol dose by 50% or select an alternative drug for CYP2D6 poor metabolizer (PM).

\n

Wording in table taken from the Dutch guidelines November 2018 update

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
CYP2D6 IMhaloperidolNO action is required for this gene-drug interaction.
CYP2D6 PMhaloperidolThe genetic polymorphism leads to decreased metabolic capacity of CYP2D6, which may cause increased plasma concentrations of haloperidol and the active metabolite.1. Advise the prescriber to: 1. decrease the initial dose to 50% of the standard initial dose and adjust the dose according to the effect, 2. or prescribe an alternative. Anti-psychotics that are not metabolised via CYP2D6 - or to a much lesser extent - include, for example, flupentixol, fluphenazine, quetiapine, olanzapine or clozapine.
CYP2D6 UMhaloperidolThe genetic polymorphism leads to increased metabolic capacity of CYP2D6, which may cause decreased plasma concentrations of haloperidol and the active metabolite reduced haloperidol.It is not possible to offer substantiated advice for dose adjustment due to the limited amount of available literature. 1. Advise the prescriber to: 1. be alert to possible reduced plasma concentrations of haloperidol and reduced haloperidol and increase the dose based on results of therapeutic drug monitoring, 2. or prescribe an alternative according to the current guidelines. Anti-psychotics that are not metabolised via CYP2D6 - or to a much lesser extent - include, for example, flupentixol, fluphenazine, quetiapine, olanzapine or clozapine.
\n

2011 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for haloperidol based on CYP2D6 genotype [Article:21412232]. They recommend dose reduction for poor metabolizer patients.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Phenotype (Genotype)Therapeutic Dose RecommendationLevel of EvidenceClinical Relevance
PM (2 inactive alleles)Reduce dose by 50% or select alternative drug (e.g., pimozide, flupenthixol, fluphenazine, quetiapine, olanzapine, clozapine).Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Clinical effect (S): long-standing discomfort (48-168 hr) without permanent injury e.g. failure of therapy with tricyclic antidepressants, atypical antipsychotic drugs; extrapyramidal side effects; parkinsonism; ADE resulting from increased bioavailability of tricyclic antidepressants, metoprolol, propafenone (central effects e.g. dizziness); INR 4.5-6.0; neutropenia 1.0-1.5x109/l; leucopenia 2.0-3.0x109/l; thrombocytopenia 50-75x109/l.
IM (2 decreased activity alleles, or 1 active and 1 inactive allele, or 1 decreased activity and 1 inactive allele)None.Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Minor clinical effect (S): QTc prolongation (<450 ms women, <470 ms men); INR increase < 4.5 Kinetic effect (S).
UM (gene duplication in absence of inactive or decreased activity alleles)Insufficient data to allow calculation of dose adjustent. Be alert to decreased haloperidol plasma concentration and adjust maintenance dose in response to haloperidol plasma concentration or select alternative drug (e.g., pimozide, flupenthixol, fluphenazine, quetiapine, olanzapine, clozapine).Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Clinical effect (S): long-standing discomfort (48-168 hr) without permanent injury e.g. failure of therapy with tricyclic antidepressants, atypical antipsychotic drugs; extrapyramidal side effects; parkinsonism; ADE resulting from increased bioavailability of tricyclic antidepressants, metoprolol, propafenone (central effects e.g. dizziness); INR 4.5-6.0; neutropenia 1.0-1.5x109/l; leucopenia 2.0-3.0x109/l; thrombocytopenia 50-75x109/l.
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele TypeAlleles
active*1, *2, *33, *35
decreased activity*9, *10, *17, *29, *36, *41
inactive*3-*8, *11-*16, *19-*21, *38, *40, *42
\n\n", - "version" : 18 + "version" : 27 }, "userId" : "lgong", - "version" : 34 + "version" : 103 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166302410", - "name" : "Recommendation Annotation PA166302410", - "alternateDrugAvailable" : true, + "id" : "PA166302399", + "name" : "Recommendation Annotation PA166302399", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -118139,35 +119284,35 @@ }, "dosingInformation" : true, "implications" : [ - "There are indications of a risk of reduced effectiveness. The genetic variation leads to an increased conversion of haloperidol, resulting in a plasma concentration that isapproximately 40% lower." + "There are indications for an increased risk of side effects. The genetic variation leads to decreased conversion of haloperidol, resulting in plasma concentrations that are approximately 1.7-fold higher." ], - "lookupKey" : {"CYP2D6": "4.0"}, + "lookupKey" : {"CYP2D6": "0.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449841", "name" : "haloperidol", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104988", "name" : "Annotation of DPWG Guideline for haloperidol and CYP2D6", - "version" : 34 + "version" : 103 }, "text" : { - "id" : 1452103989, - "html" : "

Use 1.5 times the normal dose or choose an alternative.

\n

Antipsychotics that are not metabolised by CYP2D6 - or to a much lesser extent - include, for example, flupentixol, penfluridol, quetiapine, olanzapine or clozapine.

\n", + "id" : 1452103978, + "html" : "

Use 60% of the normal dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302401", - "name" : "Recommendation Annotation PA166302401", + "id" : "PA166302400", + "name" : "Recommendation Annotation PA166302400", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -118183,24 +119328,24 @@ "implications" : [ "The genetic variation results in a higher plasma concentration, but the effect is small and no clinically significant effects were found." ], - "lookupKey" : {"CYP2D6": "0.5"}, + "lookupKey" : {"CYP2D6": "0.25"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449841", "name" : "haloperidol", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104988", "name" : "Annotation of DPWG Guideline for haloperidol and CYP2D6", - "version" : 34 + "version" : 103 }, "text" : { - "id" : 1452103980, + "id" : 1452103979, "html" : "

NO action is required for this gene-drug interaction.

\n", "version" : 0 }, @@ -118208,9 +119353,9 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302414", - "name" : "Recommendation Annotation PA166302414", - "alternateDrugAvailable" : true, + "id" : "PA166302401", + "name" : "Recommendation Annotation PA166302401", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -118221,79 +119366,80 @@ "valid" : true, "version" : 1 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "There are indications of a risk of reduced effectiveness. The genetic variation leads to an increased conversion of haloperidol, resulting in a plasma concentration that isapproximately 40% lower." + "The genetic variation results in a higher plasma concentration, but the effect is small and no clinically significant effects were found." ], - "lookupKey" : {"CYP2D6": "≥4.0"}, + "lookupKey" : {"CYP2D6": "0.5"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449841", "name" : "haloperidol", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104988", "name" : "Annotation of DPWG Guideline for haloperidol and CYP2D6", - "version" : 34 + "version" : 103 }, "text" : { - "id" : 1452103993, - "html" : "

Use 1.5 times the normal dose or choose an alternative.

\n

Antipsychotics that are not metabolised by CYP2D6 - or to a much lesser extent - include, for example, flupentixol, penfluridol, quetiapine, olanzapine or clozapine.

\n", + "id" : 1452103980, + "html" : "

NO action is required for this gene-drug interaction.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302405", - "name" : "Recommendation Annotation PA166302405", + "id" : "PA166302402", + "name" : "Recommendation Annotation PA166302402", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, "dosingInformation" : false, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on haloperidol." + "The genetic variation results in a higher plasma concentration, but the effect is small and no clinically significant effects were found." ], - "lookupKey" : {"CYP2D6": "1.5"}, + "lookupKey" : {"CYP2D6": "0.75"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449841", "name" : "haloperidol", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104988", "name" : "Annotation of DPWG Guideline for haloperidol and CYP2D6", - "version" : 34 + "version" : 103 }, "text" : { - "id" : 1452103984, - "html" : "

The guideline does not provide a recommendation for haloperidol in normal metabolizers.

\n", + "id" : 1452103981, + "html" : "

NO action is required for this gene-drug interaction.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302409", - "name" : "Recommendation Annotation PA166302409", - "alternateDrugAvailable" : true, + "id" : "PA166302403", + "name" : "Recommendation Annotation PA166302403", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -118304,121 +119450,119 @@ "valid" : true, "version" : 1 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "There are indications of a risk of reduced effectiveness. The genetic variation leads to an increased conversion of haloperidol, resulting in a plasma concentration that isapproximately 40% lower." + "The genetic variation results in a higher plasma concentration, but the effect is small and no clinically significant effects were found." ], - "lookupKey" : {"CYP2D6": "3.0"}, + "lookupKey" : {"CYP2D6": "1.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449841", "name" : "haloperidol", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104988", "name" : "Annotation of DPWG Guideline for haloperidol and CYP2D6", - "version" : 34 + "version" : 103 }, "text" : { - "id" : 1452103988, - "html" : "

Use 1.5 times the normal dose or choose an alternative.

\n

Antipsychotics that are not metabolised by CYP2D6 - or to a much lesser extent - include, for example, flupentixol, penfluridol, quetiapine, olanzapine or clozapine.

\n", + "id" : 1452103982, + "html" : "

NO action is required for this gene-drug interaction.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302400", - "name" : "Recommendation Annotation PA166302400", + "id" : "PA166302404", + "name" : "Recommendation Annotation PA166302404", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, "dosingInformation" : false, "implications" : [ - "The genetic variation results in a higher plasma concentration, but the effect is small and no clinically significant effects were found." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on haloperidol." ], - "lookupKey" : {"CYP2D6": "0.25"}, + "lookupKey" : {"CYP2D6": "1.25"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449841", "name" : "haloperidol", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104988", "name" : "Annotation of DPWG Guideline for haloperidol and CYP2D6", - "version" : 34 + "version" : 103 }, "text" : { - "id" : 1452103979, - "html" : "

NO action is required for this gene-drug interaction.

\n", + "id" : 1452103983, + "html" : "

The guideline does not provide a recommendation for haloperidol in normal metabolizers.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302413", - "name" : "Recommendation Annotation PA166302413", - "alternateDrugAvailable" : true, + "id" : "PA166302405", + "name" : "Recommendation Annotation PA166302405", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "There are indications of a risk of reduced effectiveness. The genetic variation leads to an increased conversion of haloperidol, resulting in a plasma concentration that isapproximately 40% lower." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on haloperidol." ], - "lookupKey" : {"CYP2D6": "≥3.5"}, + "lookupKey" : {"CYP2D6": "1.5"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449841", "name" : "haloperidol", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104988", "name" : "Annotation of DPWG Guideline for haloperidol and CYP2D6", - "version" : 34 + "version" : 103 }, "text" : { - "id" : 1452103992, - "html" : "

Use 1.5 times the normal dose or choose an alternative.

\n

Antipsychotics that are not metabolised by CYP2D6 - or to a much lesser extent - include, for example, flupentixol, penfluridol, quetiapine, olanzapine or clozapine.

\n", + "id" : 1452103984, + "html" : "

The guideline does not provide a recommendation for haloperidol in normal metabolizers.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302404", - "name" : "Recommendation Annotation PA166302404", + "id" : "PA166302406", + "name" : "Recommendation Annotation PA166302406", "alternateDrugAvailable" : false, "classification" : { "id" : 1448526251, @@ -118433,24 +119577,24 @@ "implications" : [ "The guideline does not provide a description of the impact of a normal metabolizer phenotype on haloperidol." ], - "lookupKey" : {"CYP2D6": "1.25"}, + "lookupKey" : {"CYP2D6": "2.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449841", "name" : "haloperidol", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104988", "name" : "Annotation of DPWG Guideline for haloperidol and CYP2D6", - "version" : 34 + "version" : 103 }, "text" : { - "id" : 1452103983, + "id" : 1452103985, "html" : "

The guideline does not provide a recommendation for haloperidol in normal metabolizers.

\n", "version" : 0 }, @@ -118458,42 +119602,41 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302399", - "name" : "Recommendation Annotation PA166302399", + "id" : "PA166302407", + "name" : "Recommendation Annotation PA166302407", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "There are indications for an increased risk of side effects. The genetic variation leads to decreased conversion of haloperidol, resulting in plasma concentrations that are approximately 1.7-fold higher." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on haloperidol." ], - "lookupKey" : {"CYP2D6": "0.0"}, + "lookupKey" : {"CYP2D6": "2.25"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449841", "name" : "haloperidol", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104988", "name" : "Annotation of DPWG Guideline for haloperidol and CYP2D6", - "version" : 34 + "version" : 103 }, "text" : { - "id" : 1452103978, - "html" : "

Use 60% of the normal dose.

\n", + "id" : 1452103986, + "html" : "

The guideline does not provide a recommendation for haloperidol in normal metabolizers.

\n", "version" : 0 }, "version" : 0 @@ -118523,14 +119666,14 @@ "objCls" : "Chemical", "id" : "PA449841", "name" : "haloperidol", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104988", "name" : "Annotation of DPWG Guideline for haloperidol and CYP2D6", - "version" : 34 + "version" : 103 }, "text" : { "id" : 1452103987, @@ -118539,6 +119682,132 @@ }, "version" : 0 }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166302409", + "name" : "Recommendation Annotation PA166302409", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981501929, + "description" : "Not Applicable", + "parents" : [], + "resource" : "Guideline Strength", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", + "valid" : true, + "version" : 1 + }, + "dosingInformation" : true, + "implications" : [ + "There are indications of a risk of reduced effectiveness. The genetic variation leads to an increased conversion of haloperidol, resulting in a plasma concentration that isapproximately 40% lower." + ], + "lookupKey" : {"CYP2D6": "3.0"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA449841", + "name" : "haloperidol", + "version" : 41 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104988", + "name" : "Annotation of DPWG Guideline for haloperidol and CYP2D6", + "version" : 103 + }, + "text" : { + "id" : 1452103988, + "html" : "

Use 1.5 times the normal dose or choose an alternative.

\n

Antipsychotics that are not metabolised by CYP2D6 - or to a much lesser extent - include, for example, flupentixol, penfluridol, quetiapine, olanzapine or clozapine.

\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166302410", + "name" : "Recommendation Annotation PA166302410", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981501929, + "description" : "Not Applicable", + "parents" : [], + "resource" : "Guideline Strength", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", + "valid" : true, + "version" : 1 + }, + "dosingInformation" : true, + "implications" : [ + "There are indications of a risk of reduced effectiveness. The genetic variation leads to an increased conversion of haloperidol, resulting in a plasma concentration that isapproximately 40% lower." + ], + "lookupKey" : {"CYP2D6": "4.0"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA449841", + "name" : "haloperidol", + "version" : 41 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104988", + "name" : "Annotation of DPWG Guideline for haloperidol and CYP2D6", + "version" : 103 + }, + "text" : { + "id" : 1452103989, + "html" : "

Use 1.5 times the normal dose or choose an alternative.

\n

Antipsychotics that are not metabolised by CYP2D6 - or to a much lesser extent - include, for example, flupentixol, penfluridol, quetiapine, olanzapine or clozapine.

\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166302411", + "name" : "Recommendation Annotation PA166302411", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981501929, + "description" : "Not Applicable", + "parents" : [], + "resource" : "Guideline Strength", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", + "valid" : true, + "version" : 1 + }, + "dosingInformation" : true, + "implications" : [ + "There are indications of a risk of reduced effectiveness. The genetic variation leads to an increased conversion of haloperidol, resulting in a plasma concentration that isapproximately 40% lower." + ], + "lookupKey" : {"CYP2D6": "≥3.0"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA449841", + "name" : "haloperidol", + "version" : 41 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104988", + "name" : "Annotation of DPWG Guideline for haloperidol and CYP2D6", + "version" : 103 + }, + "text" : { + "id" : 1452103990, + "html" : "

Use 1.5 times the normal dose or choose an alternative.

\n

Antipsychotics that are not metabolised by CYP2D6 - or to a much lesser extent - include, for example, flupentixol, penfluridol, quetiapine, olanzapine or clozapine.

\n", + "version" : 0 + }, + "version" : 0 + }, { "objCls" : "Recommendation Annotation", "id" : "PA166302412", @@ -118565,14 +119834,14 @@ "objCls" : "Chemical", "id" : "PA449841", "name" : "haloperidol", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104988", "name" : "Annotation of DPWG Guideline for haloperidol and CYP2D6", - "version" : 34 + "version" : 103 }, "text" : { "id" : 1452103991, @@ -118583,50 +119852,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302403", - "name" : "Recommendation Annotation PA166302403", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 981501929, - "description" : "Not Applicable", - "parents" : [], - "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", - "valid" : true, - "version" : 1 - }, - "dosingInformation" : false, - "implications" : [ - "The genetic variation results in a higher plasma concentration, but the effect is small and no clinically significant effects were found." - ], - "lookupKey" : {"CYP2D6": "1.0"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA449841", - "name" : "haloperidol", - "version" : 14 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166104988", - "name" : "Annotation of DPWG Guideline for haloperidol and CYP2D6", - "version" : 34 - }, - "text" : { - "id" : 1452103982, - "html" : "

NO action is required for this gene-drug interaction.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166302416", - "name" : "Recommendation Annotation PA166302416", + "id" : "PA166302413", + "name" : "Recommendation Annotation PA166302413", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -118642,24 +119869,24 @@ "implications" : [ "There are indications of a risk of reduced effectiveness. The genetic variation leads to an increased conversion of haloperidol, resulting in a plasma concentration that isapproximately 40% lower." ], - "lookupKey" : {"CYP2D6": "≥6.0"}, + "lookupKey" : {"CYP2D6": "≥3.5"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449841", "name" : "haloperidol", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104988", "name" : "Annotation of DPWG Guideline for haloperidol and CYP2D6", - "version" : 34 + "version" : 103 }, "text" : { - "id" : 1452103995, + "id" : 1452103992, "html" : "

Use 1.5 times the normal dose or choose an alternative.

\n

Antipsychotics that are not metabolised by CYP2D6 - or to a much lesser extent - include, for example, flupentixol, penfluridol, quetiapine, olanzapine or clozapine.

\n", "version" : 0 }, @@ -118667,49 +119894,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302407", - "name" : "Recommendation Annotation PA166302407", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 1448526251, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on haloperidol." - ], - "lookupKey" : {"CYP2D6": "2.25"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA449841", - "name" : "haloperidol", - "version" : 14 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166104988", - "name" : "Annotation of DPWG Guideline for haloperidol and CYP2D6", - "version" : 34 - }, - "text" : { - "id" : 1452103986, - "html" : "

The guideline does not provide a recommendation for haloperidol in normal metabolizers.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166302411", - "name" : "Recommendation Annotation PA166302411", + "id" : "PA166302414", + "name" : "Recommendation Annotation PA166302414", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -118725,24 +119911,24 @@ "implications" : [ "There are indications of a risk of reduced effectiveness. The genetic variation leads to an increased conversion of haloperidol, resulting in a plasma concentration that isapproximately 40% lower." ], - "lookupKey" : {"CYP2D6": "≥3.0"}, + "lookupKey" : {"CYP2D6": "≥4.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449841", "name" : "haloperidol", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104988", "name" : "Annotation of DPWG Guideline for haloperidol and CYP2D6", - "version" : 34 + "version" : 103 }, "text" : { - "id" : 1452103990, + "id" : 1452103993, "html" : "

Use 1.5 times the normal dose or choose an alternative.

\n

Antipsychotics that are not metabolised by CYP2D6 - or to a much lesser extent - include, for example, flupentixol, penfluridol, quetiapine, olanzapine or clozapine.

\n", "version" : 0 }, @@ -118750,9 +119936,9 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302402", - "name" : "Recommendation Annotation PA166302402", - "alternateDrugAvailable" : false, + "id" : "PA166302415", + "name" : "Recommendation Annotation PA166302415", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -118763,37 +119949,37 @@ "valid" : true, "version" : 1 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "The genetic variation results in a higher plasma concentration, but the effect is small and no clinically significant effects were found." + "There are indications of a risk of reduced effectiveness. The genetic variation leads to an increased conversion of haloperidol, resulting in a plasma concentration that isapproximately 40% lower." ], - "lookupKey" : {"CYP2D6": "0.75"}, + "lookupKey" : {"CYP2D6": "≥5.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449841", "name" : "haloperidol", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104988", "name" : "Annotation of DPWG Guideline for haloperidol and CYP2D6", - "version" : 34 + "version" : 103 }, "text" : { - "id" : 1452103981, - "html" : "

NO action is required for this gene-drug interaction.

\n", + "id" : 1452103994, + "html" : "

Use 1.5 times the normal dose or choose an alternative.

\n

Antipsychotics that are not metabolised by CYP2D6 - or to a much lesser extent - include, for example, flupentixol, penfluridol, quetiapine, olanzapine or clozapine.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302415", - "name" : "Recommendation Annotation PA166302415", + "id" : "PA166302416", + "name" : "Recommendation Annotation PA166302416", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -118809,69 +119995,28 @@ "implications" : [ "There are indications of a risk of reduced effectiveness. The genetic variation leads to an increased conversion of haloperidol, resulting in a plasma concentration that isapproximately 40% lower." ], - "lookupKey" : {"CYP2D6": "≥5.0"}, + "lookupKey" : {"CYP2D6": "≥6.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449841", "name" : "haloperidol", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104988", "name" : "Annotation of DPWG Guideline for haloperidol and CYP2D6", - "version" : 34 + "version" : 103 }, "text" : { - "id" : 1452103994, + "id" : 1452103995, "html" : "

Use 1.5 times the normal dose or choose an alternative.

\n

Antipsychotics that are not metabolised by CYP2D6 - or to a much lesser extent - include, for example, flupentixol, penfluridol, quetiapine, olanzapine or clozapine.

\n", "version" : 0 }, "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166302406", - "name" : "Recommendation Annotation PA166302406", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 1448526251, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on haloperidol." - ], - "lookupKey" : {"CYP2D6": "2.0"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA449841", - "name" : "haloperidol", - "version" : 14 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166104988", - "name" : "Annotation of DPWG Guideline for haloperidol and CYP2D6", - "version" : 34 - }, - "text" : { - "id" : 1452103985, - "html" : "

The guideline does not provide a recommendation for haloperidol in normal metabolizers.

\n", - "version" : 0 - }, - "version" : 0 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166104988" @@ -118993,7 +120138,7 @@ "date" : "2021-04-22T00:00:00-07:00", "description" : "Added extended dosing", "type" : "Update", - "version" : 0 + "version" : 1 }, { "id" : 1451704203, @@ -119042,7 +120187,7 @@ "date" : "2023-05-05T00:00:00-07:00", "description" : "Switched the recommendation and description for UM and IM", "type" : "Update", - "version" : 0 + "version" : 1 }, { "id" : 1452146514, @@ -119073,7 +120218,7 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "relatedGenes" : [ @@ -119082,70 +120227,71 @@ "id" : "PA124", "symbol" : "CYP2C19", "name" : "cytochrome P450 family 2 subfamily C member 19", - "version" : 7210 + "version" : 7266 } ], "source" : "DPWG", "summaryMarkdown" : { "id" : 1447981890, "html" : "

CYP2C19 poor metabolizers should receive 70% of the standard dose of imipramine, or imipramine should be avoided in these patients. Patients should be monitored for the effect and side effects or the plasma concentrations of imipramine and desipramine in order to set the maintenance dose.

\n", - "version" : 1 + "version" : 3 }, "terms" : [], "textMarkdown" : { "id" : 1447981889, "html" : "

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

\n

November 2018 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for imipramine based on CYP2C19 genotype. Patients who are CYP2C19 poor metabolizers should receive 70% of the standard dose of imipramine or imipramine should be avoided. Patients should be monitored for the effect and side effects or the plasma concentrations of imipramine and desipramine in order to set the maintenance dose. No action is required for CYP2C19 intermediate or ultra-rapid metabolizers.

\n

Wording in table taken from the Dutch guidelines November 2018 update

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
CYP2C19 PMimipramineThe risk of side effects is increased. The gene variation results in an increase in the plasma concentration of imipramine+desipramine.Use 70% of the standard dose and monitor the effect and side effects or the imipramine and desipramine plasma concentrations to determine the maintenance dose, or, avoid imipramine. Antidepressants that are not or to a lesser extent metabolised by CYP2C19 include, for example, nortriptyline, fluvoxamine and mirtazapine.
CYP2C19 IMimipramineThe genetic variation increases imipramine plasma concentrations, but not imipramine+desipramine plasma concentrations, which govern effectiveness and side effects.NO action is required for this gene-drug interaction.
CYP2C19 UMimipramineThe genetic variation decreases imipramine plasma concentrations, but not imipramine+desipramine plasma concentrations, which govern effectiveness and side effects.NO action is required for this gene-drug interaction
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for imipramine and CYP2C19:

\n
\n

The KNMP Pharmacogenetics Working Group considers genotyping before starting imipramine to be potentially beneficial. Genotyping can be considered on an individual patient basis. If, however, the genotype is available, the KNMP Pharmacogenetics Working Group recommends adhering to the gene-drug guideline.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n

2011 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for imipramine based on CYP2C19 genotype [Article:21412232].

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Phenotype (Genotype)Therapeutic Dose RecommendationLevel of EvidenceClinical Relevance
CYP2C19 PM (*2/*2, *2/*3, *3/*3)Reduce dose by 30% and monitor plasma concentration of imipramine and desipramine or select alternative drug (e.g. fluvoxamine, mirtazapine)Published controlled studies of moderate quality# relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpointsMinor clinical effect (statistically significant difference): QTc prolongation (<450 ms female, <470 ms male); international normalized ratio increase < 4.5 Kinetic effect (statistically significant difference)
CYP2C19 IM (*1/*2, *1/*3, *17/*2, *17/*3)Insufficient data to allow calculation of dose adjustment. Select alternative drug (e.g. fluvoxamine, mirtazapine)Published controlled studies of moderate quality# relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpointsMinor clinical effect (statistically significant difference): QTc prolongation (<450 ms female, <470 ms male); international normalized ratio increase < 4.5 Kinetic effect (statistically significant difference)
CYP2C19 UM (*17/*17)Noneno data was retrieved with the literature searchno data was retrieved with the literature search
\n\n", - "version" : 18 + "version" : 23 }, "userId" : "katrin", - "version" : 33 + "version" : 72 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166299204", - "name" : "Recommendation PA166299204", + "id" : "PA166299202", + "name" : "Recommendation PA166299202", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, "dosingInformation" : false, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on imipramine." + "The genetic variation decreases imipramine plasma concentrations, but not imipramine+desipramine plasma concentrations, which govern effectiveness and side effects." ], - "lookupKey" : {"CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104954", "name" : "Annotation of DPWG Guideline for imipramine and CYP2C19", - "version" : 33 + "version" : 72 }, "text" : { - "id" : 1452061567, - "html" : "

The guideline does not provide a recommendation for imipramine in normal metabolizers.

\n", - "version" : 0 + "id" : 1452061565, + "html" : "

NO action is required for this gene-drug interaction

\n", + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299203", - "name" : "Recommendation PA166299203", + "id" : "PA166299201", + "name" : "Recommendation PA166299201", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -119157,79 +120303,78 @@ "valid" : true, "version" : 1 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "The genetic variation increases imipramine plasma concentrations, but not imipramine+desipramine plasma concentrations, which govern effectiveness and side effects." + "The risk of side effects is increased. The gene variation results in an increase in the plasma concentration of imipramine+desipramine." ], - "lookupKey" : {"CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104954", "name" : "Annotation of DPWG Guideline for imipramine and CYP2C19", - "version" : 33 + "version" : 72 }, "text" : { - "id" : 1452061566, - "html" : "

NO action is required for this gene-drug interaction.

\n", + "id" : 1452061564, + "html" : "

Use 70% of the standard dose and monitor the effect and side effects or the imipramine and desipramine plasma concentrations to determine the maintenance dose, or, avoid imipramine. Antidepressants that are not or to a lesser extent metabolised by CYP2C19 include, for example, nortriptyline, fluvoxamine and mirtazapine.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299201", - "name" : "Recommendation PA166299201", + "id" : "PA166299204", + "name" : "Recommendation PA166299204", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "The risk of side effects is increased. The gene variation results in an increase in the plasma concentration of imipramine+desipramine." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on imipramine." ], - "lookupKey" : {"CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104954", "name" : "Annotation of DPWG Guideline for imipramine and CYP2C19", - "version" : 33 + "version" : 72 }, "text" : { - "id" : 1452061564, - "html" : "

Use 70% of the standard dose and monitor the effect and side effects or the imipramine and desipramine plasma concentrations to determine the maintenance dose, or, avoid imipramine. Antidepressants that are not or to a lesser extent metabolised by CYP2C19 include, for example, nortriptyline, fluvoxamine and mirtazapine.

\n", + "id" : 1452061567, + "html" : "

The guideline does not provide a recommendation for imipramine in normal metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299202", - "name" : "Recommendation PA166299202", + "id" : "PA166299203", + "name" : "Recommendation PA166299203", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -119243,30 +120388,30 @@ }, "dosingInformation" : false, "implications" : [ - "The genetic variation decreases imipramine plasma concentrations, but not imipramine+desipramine plasma concentrations, which govern effectiveness and side effects." + "The genetic variation increases imipramine plasma concentrations, but not imipramine+desipramine plasma concentrations, which govern effectiveness and side effects." ], - "lookupKey" : {"CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104954", "name" : "Annotation of DPWG Guideline for imipramine and CYP2C19", - "version" : 33 + "version" : 72 }, "text" : { - "id" : 1452061565, - "html" : "

NO action is required for this gene-drug interaction

\n", - "version" : 0 + "id" : 1452061566, + "html" : "

NO action is required for this gene-drug interaction.

\n", + "version" : 1 }, - "version" : 0 + "version" : 2 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166104954" @@ -119538,7 +120683,7 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "relatedGenes" : [ @@ -119547,29 +120692,29 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "DPWG", "summaryMarkdown" : { "id" : 1447982002, "html" : "

CYP2D6 poor metabolizers should receive 30% of the standard dose of imipramine, CYP2D6 intermediate metabolizers should receive 70% of the standard dose, and CYP2D6 ultra-rapid metabolizers should receive 1.7 times the standard dose. Patients should be monitored for the effect and side effects or the plasma concentrations of imipramine and desipramine in order to set the maintenance dose.

\n", - "version" : 1 + "version" : 2 }, "terms" : [], "textMarkdown" : { "id" : 1447982001, "html" : "

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

\n

November 2018 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for imipramine based on CYP2D6 genotype. Patients who are CYP2D6 poor, intermediate or ultra-rapid metabolizers should receive an adjusted imipramine dose, and have the effect and side effects or plasma concentrations of imipramine and desipramine monitored in order to set the maintenance dose.

\n

Wording in table taken from the Dutch guidelines November 2018 update

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
CYP2D6 PMimipramineThe risk of side effects may be increased, because the gene variation leads to increased plasma concentrations of imipramine and the active metabolite desipramine.Use 30% of the standard dose and monitor the effect and side effects or the plasma concentrations of imipramine and desipramine in order to set the maintenance dose. The therapeutic range is 150-300 ng/mL for the sum of the imipramine and desipramine plasma concentrations. Values exceeding 500 ng/mL are considered toxic.
CYP2D6 IMimipramineThe risk of side effects may be increased, because the gene variation leads to increased plasma concentrations of imipramine and desipramine.Use 70% of the standard dose and monitor the effect and side effects or the plasma concentrations of imipramine and desipramine in order to set the maintenance dose. The therapeutic range is 150-300 ng/mL for the sum of the imipramine and desipramine plasma concentrations. Values exceeding 500 ng/mL are considered toxic.
CYP2D6 UMimipramineThe risk of ineffectiveness and cardiotoxic side effects may be increased. The gene variation leads to reduced plasma concentrations of imipramine and the active metabolite desipramine and to increased plasma concentrations of the potentially cardiotoxic hydroxy metabolites.Use 1.7 times the standard dose and monitor the effect and side effects or the plasma concentrations of imipramine and desipramine in order to set the maintenance dose. If a dose increase is not wanted due to the potentially cardiotoxic hydroxy metabolites: avoid imipramine. Antidepressants that are not metabolised by CYP2D6 - or to a lesser extent - include, for example, citalopram and sertraline.
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for imipramine and CYP2D6:

\n
\n

The Dutch Pharmacogenetics Working Group considers genotyping before starting imipramine to be potentially beneficial for the prevention of side effects. Genotyping can be considered on an individual patient basis. If, however, the genotype is available, the Dutch Pharmacogenetics Working Group recommends adhering to the gene-drug guideline.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n

2011 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for imipramine based on CYP2D6 genotype [Article:21412232]. They recommend reducing the dose for poor and intermediate metabolizer patients, and selecting an alternative drug for ultra metabolizers.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Phenotype (Genotype)Therapeutic Dose RecommendationLevel of EvidenceClinical Relevance
PM (2 inactive alleles)Reduce dose by 70% and monitor imipramine and desipramine plasma concentrations.Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Clinical effect (S): long-standing discomfort (48-168 hr) without permanent injury e.g. failure of therapy with tricyclic antidepressants, atypical antipsychotic drugs; extrapyramidal side effects; parkinsonism; ADE resulting from increased bioavailability of tricyclic antidepressants, metoprolol, propafenone (central effects e.g. dizziness); INR 4.5-6.0; neutropenia 1.0-1.5x109/l; leucopenia 2.0-3.0x109/l; thrombocytopenia 50-75x109/l
IM (2 decreased activity alleles, or 1 active and 1 inactive allele, or 1 decreased activity and 1 inactive allele)Reduce dose by 30% and monitor imipramine and desipramine plasma concentrations.Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Minor clinical effect (S): QTc prolongation (<450 ms men, <470 ms women); INR increase < 4.5. Kinetic effect (S).
UM (gene duplication in absence of inactive or decreased activity alleles)Select alternative drug (e.g., citalopram, sertraline) or increase dose by 70% and monitor imipramine and desipramine plasma concentrations.Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Minor clinical effect (S): QTc prolongation (<450 ms men, <470 ms women); INR increase < 4.5. Kinetic effect (S).
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele TypeAlleles
active*1, *2, *33, *35
decreased activity*9, *10, *17, *29, *36, *41
inactive*3-*8, *11-*16, *19-*21, *38, *40, *42
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Use 1.7 times the standard dose and monitor the effect and side effects or the plasma concentrations of imipramine and desipramine in order to set the maintenance dose.

\n

If a dose increase is not wanted due to the potentially cardiotoxic hydroxy metabolites: avoid imipramine. Antidepressants that are not metabolised by CYP2D6 - or to a lesser extent - include, for example, citalopram and sertraline.

\n", "version" : 0 }, @@ -119610,49 +120755,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302462", - "name" : "Recommendation Annotation PA166302462", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 1448526251, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on imipramine." - ], - "lookupKey" : {"CYP2D6": "1.5"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA449969", - "name" : "imipramine", - "version" : 15 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166104972", - "name" : "Annotation of DPWG Guideline for imipramine and CYP2D6", - "version" : 34 - }, - "text" : { - "id" : 1452104041, - "html" : "

The guideline does not provide a recommendation for imipramine in normal metabolizers.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166302466", - "name" : "Recommendation Annotation PA166302466", + "id" : "PA166302482", + "name" : "Recommendation Annotation PA166302482", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -119668,24 +120772,24 @@ "implications" : [ "The risk of ineffectiveness and cardiotoxic side effects may be increased. The gene variation leads to reduced plasma concentrations of imipramine and the active metabolite desipramine and to increased plasma concentrations of the potentially cardiotoxic hydroxy metabolites." ], - "lookupKey" : {"CYP2D6": "3.0"}, + "lookupKey" : {"CYP2D6": "≥3.5"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104972", "name" : "Annotation of DPWG Guideline for imipramine and CYP2D6", - "version" : 34 + "version" : 99 }, "text" : { - "id" : 1452104045, + "id" : 1452104061, "html" : "

Use 1.7 times the standard dose and monitor the effect and side effects or the plasma concentrations of imipramine and desipramine in order to set the maintenance dose.

\n

If a dose increase is not wanted due to the potentially cardiotoxic hydroxy metabolites: avoid imipramine. Antidepressants that are not metabolised by CYP2D6 - or to a lesser extent - include, for example, citalopram and sertraline.

\n", "version" : 0 }, @@ -119707,14 +120811,14 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104972", "name" : "Annotation of DPWG Guideline for imipramine and CYP2D6", - "version" : 34 + "version" : 99 }, "text" : { "id" : 1452104080, @@ -119725,9 +120829,9 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302417", - "name" : "Recommendation Annotation PA166302417", - "alternateDrugAvailable" : false, + "id" : "PA166302502", + "name" : "Recommendation Annotation PA166302502", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -119740,117 +120844,77 @@ }, "dosingInformation" : true, "implications" : [ - "The risk of side effects may be increased, because the gene variation leads to increased plasma concentrations of imipramine and the active metabolite desipramine." - ], - "lookupKey" : {"CYP2D6": "0.0"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA449969", - "name" : "imipramine", - "version" : 15 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166104972", - "name" : "Annotation of DPWG Guideline for imipramine and CYP2D6", - "version" : 34 - }, - "text" : { - "id" : 1452103996, - "html" : "

Use 30% of the standard dose and monitor the effect and side effects or the plasma concentrations of imipramine and desipramine in order to set the maintenance dose. The therapeutic range is 150-300 ng/mL for the sum of the imipramine and desipramine plasma concentrations. Values exceeding 500 ng/mL are considered toxic.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166302461", - "name" : "Recommendation Annotation PA166302461", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 1448526251, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on imipramine." + "The risk of ineffectiveness and cardiotoxic side effects may be increased. The gene variation leads to reduced plasma concentrations of imipramine and the active metabolite desipramine and to increased plasma concentrations of the potentially cardiotoxic hydroxy metabolites." ], - "lookupKey" : {"CYP2D6": "1.25"}, + "lookupKey" : {"CYP2D6": "≥5.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104972", "name" : "Annotation of DPWG Guideline for imipramine and CYP2D6", - "version" : 34 + "version" : 99 }, "text" : { - "id" : 1452104040, - "html" : "

The guideline does not provide a recommendation for imipramine in normal metabolizers.

\n", + "id" : 1452104081, + "html" : "

Use 1.7 times the standard dose and monitor the effect and side effects or the plasma concentrations of imipramine and desipramine in order to set the maintenance dose.

\n

If a dose increase is not wanted due to the potentially cardiotoxic hydroxy metabolites: avoid imipramine. Antidepressants that are not metabolised by CYP2D6 - or to a lesser extent - include, for example, citalopram and sertraline.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302465", - "name" : "Recommendation Annotation PA166302465", - "alternateDrugAvailable" : false, + "id" : "PA166302503", + "name" : "Recommendation Annotation PA166302503", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on imipramine." + "The risk of ineffectiveness and cardiotoxic side effects may be increased. The gene variation leads to reduced plasma concentrations of imipramine and the active metabolite desipramine and to increased plasma concentrations of the potentially cardiotoxic hydroxy metabolites." ], - "lookupKey" : {"CYP2D6": "2.5"}, + "lookupKey" : {"CYP2D6": "≥6.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104972", "name" : "Annotation of DPWG Guideline for imipramine and CYP2D6", - "version" : 34 + "version" : 99 }, "text" : { - "id" : 1452104044, - "html" : "

The guideline does not provide a recommendation for imipramine in normal metabolizers.

\n", + "id" : 1452104082, + "html" : "

Use 1.7 times the standard dose and monitor the effect and side effects or the plasma concentrations of imipramine and desipramine in order to set the maintenance dose.

\n

If a dose increase is not wanted due to the potentially cardiotoxic hydroxy metabolites: avoid imipramine. Antidepressants that are not metabolised by CYP2D6 - or to a lesser extent - include, for example, citalopram and sertraline.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302443", - "name" : "Recommendation Annotation PA166302443", + "id" : "PA166302417", + "name" : "Recommendation Annotation PA166302417", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -119864,27 +120928,27 @@ }, "dosingInformation" : true, "implications" : [ - "The risk of side effects may be increased, because the gene variation leads to increased plasma concentrations of imipramine and desipramine." + "The risk of side effects may be increased, because the gene variation leads to increased plasma concentrations of imipramine and the active metabolite desipramine." ], - "lookupKey" : {"CYP2D6": "1.0"}, + "lookupKey" : {"CYP2D6": "0.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104972", "name" : "Annotation of DPWG Guideline for imipramine and CYP2D6", - "version" : 34 + "version" : 99 }, "text" : { - "id" : 1452104022, - "html" : "

Use 70% of the standard dose and monitor the effect and side effects or the plasma concentrations of imipramine and desipramine in order to set the maintenance dose. The therapeutic range is 150-300 ng/mL for the sum of the imipramine and desipramine plasma concentrations. Values exceeding 500 ng/mL are considered toxic.

\n", + "id" : 1452103996, + "html" : "

Use 30% of the standard dose and monitor the effect and side effects or the plasma concentrations of imipramine and desipramine in order to set the maintenance dose. The therapeutic range is 150-300 ng/mL for the sum of the imipramine and desipramine plasma concentrations. Values exceeding 500 ng/mL are considered toxic.

\n", "version" : 0 }, "version" : 0 @@ -119915,14 +120979,14 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104972", "name" : "Annotation of DPWG Guideline for imipramine and CYP2D6", - "version" : 34 + "version" : 99 }, "text" : { "id" : 1452104000, @@ -119933,9 +120997,9 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302482", - "name" : "Recommendation Annotation PA166302482", - "alternateDrugAvailable" : true, + "id" : "PA166302441", + "name" : "Recommendation Annotation PA166302441", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -119948,68 +121012,27 @@ }, "dosingInformation" : true, "implications" : [ - "The risk of ineffectiveness and cardiotoxic side effects may be increased. The gene variation leads to reduced plasma concentrations of imipramine and the active metabolite desipramine and to increased plasma concentrations of the potentially cardiotoxic hydroxy metabolites." - ], - "lookupKey" : {"CYP2D6": "≥3.5"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA449969", - "name" : "imipramine", - "version" : 15 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166104972", - "name" : "Annotation of DPWG Guideline for imipramine and CYP2D6", - "version" : 34 - }, - "text" : { - "id" : 1452104061, - "html" : "

Use 1.7 times the standard dose and monitor the effect and side effects or the plasma concentrations of imipramine and desipramine in order to set the maintenance dose.

\n

If a dose increase is not wanted due to the potentially cardiotoxic hydroxy metabolites: avoid imipramine. Antidepressants that are not metabolised by CYP2D6 - or to a lesser extent - include, for example, citalopram and sertraline.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166302464", - "name" : "Recommendation Annotation PA166302464", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 1448526251, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on imipramine." + "The risk of side effects may be increased, because the gene variation leads to increased plasma concentrations of imipramine and desipramine." ], - "lookupKey" : {"CYP2D6": "2.25"}, + "lookupKey" : {"CYP2D6": "0.5"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104972", "name" : "Annotation of DPWG Guideline for imipramine and CYP2D6", - "version" : 34 + "version" : 99 }, "text" : { - "id" : 1452104043, - "html" : "

The guideline does not provide a recommendation for imipramine in normal metabolizers.

\n", + "id" : 1452104020, + "html" : "

Use 70% of the standard dose and monitor the effect and side effects or the plasma concentrations of imipramine and desipramine in order to set the maintenance dose. The therapeutic range is 150-300 ng/mL for the sum of the imipramine and desipramine plasma concentrations. Values exceeding 500 ng/mL are considered toxic.

\n", "version" : 0 }, "version" : 0 @@ -120040,14 +121063,14 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104972", "name" : "Annotation of DPWG Guideline for imipramine and CYP2D6", - "version" : 34 + "version" : 99 }, "text" : { "id" : 1452104021, @@ -120058,9 +121081,9 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302468", - "name" : "Recommendation Annotation PA166302468", - "alternateDrugAvailable" : true, + "id" : "PA166302443", + "name" : "Recommendation Annotation PA166302443", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -120073,111 +121096,109 @@ }, "dosingInformation" : true, "implications" : [ - "The risk of ineffectiveness and cardiotoxic side effects may be increased. The gene variation leads to reduced plasma concentrations of imipramine and the active metabolite desipramine and to increased plasma concentrations of the potentially cardiotoxic hydroxy metabolites." + "The risk of side effects may be increased, because the gene variation leads to increased plasma concentrations of imipramine and desipramine." ], - "lookupKey" : {"CYP2D6": "≥3.0"}, + "lookupKey" : {"CYP2D6": "1.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104972", "name" : "Annotation of DPWG Guideline for imipramine and CYP2D6", - "version" : 34 + "version" : 99 }, "text" : { - "id" : 1452104047, - "html" : "

Use 1.7 times the standard dose and monitor the effect and side effects or the plasma concentrations of imipramine and desipramine in order to set the maintenance dose.

\n

If a dose increase is not wanted due to the potentially cardiotoxic hydroxy metabolites: avoid imipramine. Antidepressants that are not metabolised by CYP2D6 - or to a lesser extent - include, for example, citalopram and sertraline.

\n", + "id" : 1452104022, + "html" : "

Use 70% of the standard dose and monitor the effect and side effects or the plasma concentrations of imipramine and desipramine in order to set the maintenance dose. The therapeutic range is 150-300 ng/mL for the sum of the imipramine and desipramine plasma concentrations. Values exceeding 500 ng/mL are considered toxic.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302481", - "name" : "Recommendation Annotation PA166302481", - "alternateDrugAvailable" : true, + "id" : "PA166302461", + "name" : "Recommendation Annotation PA166302461", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "The risk of ineffectiveness and cardiotoxic side effects may be increased. The gene variation leads to reduced plasma concentrations of imipramine and the active metabolite desipramine and to increased plasma concentrations of the potentially cardiotoxic hydroxy metabolites." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on imipramine." ], - "lookupKey" : {"CYP2D6": "≥3.25"}, + "lookupKey" : {"CYP2D6": "1.25"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104972", "name" : "Annotation of DPWG Guideline for imipramine and CYP2D6", - "version" : 34 + "version" : 99 }, "text" : { - "id" : 1452104060, - "html" : "

Use 1.7 times the standard dose and monitor the effect and side effects or the plasma concentrations of imipramine and desipramine in order to set the maintenance dose.

\n

If a dose increase is not wanted due to the potentially cardiotoxic hydroxy metabolites: avoid imipramine. Antidepressants that are not metabolised by CYP2D6 - or to a lesser extent - include, for example, citalopram and sertraline.

\n", + "id" : 1452104040, + "html" : "

The guideline does not provide a recommendation for imipramine in normal metabolizers.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302503", - "name" : "Recommendation Annotation PA166302503", - "alternateDrugAvailable" : true, + "id" : "PA166302462", + "name" : "Recommendation Annotation PA166302462", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "The risk of ineffectiveness and cardiotoxic side effects may be increased. The gene variation leads to reduced plasma concentrations of imipramine and the active metabolite desipramine and to increased plasma concentrations of the potentially cardiotoxic hydroxy metabolites." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on imipramine." ], - "lookupKey" : {"CYP2D6": "≥6.0"}, + "lookupKey" : {"CYP2D6": "1.5"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104972", "name" : "Annotation of DPWG Guideline for imipramine and CYP2D6", - "version" : 34 + "version" : 99 }, "text" : { - "id" : 1452104082, - "html" : "

Use 1.7 times the standard dose and monitor the effect and side effects or the plasma concentrations of imipramine and desipramine in order to set the maintenance dose.

\n

If a dose increase is not wanted due to the potentially cardiotoxic hydroxy metabolites: avoid imipramine. Antidepressants that are not metabolised by CYP2D6 - or to a lesser extent - include, for example, citalopram and sertraline.

\n", + "id" : 1452104041, + "html" : "

The guideline does not provide a recommendation for imipramine in normal metabolizers.

\n", "version" : 0 }, "version" : 0 @@ -120207,14 +121228,14 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104972", "name" : "Annotation of DPWG Guideline for imipramine and CYP2D6", - "version" : 34 + "version" : 99 }, "text" : { "id" : 1452104042, @@ -120225,9 +121246,91 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302441", - "name" : "Recommendation Annotation PA166302441", + "id" : "PA166302464", + "name" : "Recommendation Annotation PA166302464", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 1448526251, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : false, + "implications" : [ + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on imipramine." + ], + "lookupKey" : {"CYP2D6": "2.25"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA449969", + "name" : "imipramine", + "version" : 46 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104972", + "name" : "Annotation of DPWG Guideline for imipramine and CYP2D6", + "version" : 99 + }, + "text" : { + "id" : 1452104043, + "html" : "

The guideline does not provide a recommendation for imipramine in normal metabolizers.

\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166302465", + "name" : "Recommendation Annotation PA166302465", "alternateDrugAvailable" : false, + "classification" : { + "id" : 1448526251, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : false, + "implications" : [ + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on imipramine." + ], + "lookupKey" : {"CYP2D6": "2.5"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA449969", + "name" : "imipramine", + "version" : 46 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104972", + "name" : "Annotation of DPWG Guideline for imipramine and CYP2D6", + "version" : 99 + }, + "text" : { + "id" : 1452104044, + "html" : "

The guideline does not provide a recommendation for imipramine in normal metabolizers.

\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166302466", + "name" : "Recommendation Annotation PA166302466", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -120240,27 +121343,27 @@ }, "dosingInformation" : true, "implications" : [ - "The risk of side effects may be increased, because the gene variation leads to increased plasma concentrations of imipramine and desipramine." + "The risk of ineffectiveness and cardiotoxic side effects may be increased. The gene variation leads to reduced plasma concentrations of imipramine and the active metabolite desipramine and to increased plasma concentrations of the potentially cardiotoxic hydroxy metabolites." ], - "lookupKey" : {"CYP2D6": "0.5"}, + "lookupKey" : {"CYP2D6": "3.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104972", "name" : "Annotation of DPWG Guideline for imipramine and CYP2D6", - "version" : 34 + "version" : 99 }, "text" : { - "id" : 1452104020, - "html" : "

Use 70% of the standard dose and monitor the effect and side effects or the plasma concentrations of imipramine and desipramine in order to set the maintenance dose. The therapeutic range is 150-300 ng/mL for the sum of the imipramine and desipramine plasma concentrations. Values exceeding 500 ng/mL are considered toxic.

\n", + "id" : 1452104045, + "html" : "

Use 1.7 times the standard dose and monitor the effect and side effects or the plasma concentrations of imipramine and desipramine in order to set the maintenance dose.

\n

If a dose increase is not wanted due to the potentially cardiotoxic hydroxy metabolites: avoid imipramine. Antidepressants that are not metabolised by CYP2D6 - or to a lesser extent - include, for example, citalopram and sertraline.

\n", "version" : 0 }, "version" : 0 @@ -120291,14 +121394,14 @@ "objCls" : "Chemical", "id" : "PA449969", "name" : "imipramine", - "version" : 15 + "version" : 46 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104972", "name" : "Annotation of DPWG Guideline for imipramine and CYP2D6", - "version" : 34 + "version" : 99 }, "text" : { "id" : 1452104046, @@ -120306,6 +121409,48 @@ "version" : 0 }, "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166302468", + "name" : "Recommendation Annotation PA166302468", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981501929, + "description" : "Not Applicable", + "parents" : [], + "resource" : "Guideline Strength", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", + "valid" : true, + "version" : 1 + }, + "dosingInformation" : true, + "implications" : [ + "The risk of ineffectiveness and cardiotoxic side effects may be increased. The gene variation leads to reduced plasma concentrations of imipramine and the active metabolite desipramine and to increased plasma concentrations of the potentially cardiotoxic hydroxy metabolites." + ], + "lookupKey" : {"CYP2D6": "≥3.0"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA449969", + "name" : "imipramine", + "version" : 46 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104972", + "name" : "Annotation of DPWG Guideline for imipramine and CYP2D6", + "version" : 99 + }, + "text" : { + "id" : 1452104047, + "html" : "

Use 1.7 times the standard dose and monitor the effect and side effects or the plasma concentrations of imipramine and desipramine in order to set the maintenance dose.

\n

If a dose increase is not wanted due to the potentially cardiotoxic hydroxy metabolites: avoid imipramine. Antidepressants that are not metabolised by CYP2D6 - or to a lesser extent - include, for example, citalopram and sertraline.

\n", + "version" : 0 + }, + "version" : 0 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166104972" @@ -120605,7 +121750,7 @@ "id" : "PA166115842", "symbol" : "UGT1A1*28", "name" : "*28", - "version" : 16 + "version" : 34 } ], "relatedChemicals" : [ @@ -120613,7 +121758,7 @@ "objCls" : "Chemical", "id" : "PA450085", "name" : "irinotecan", - "version" : 17 + "version" : 59 } ], "relatedGenes" : [ @@ -120622,29 +121767,29 @@ "id" : "PA420", "symbol" : "UGT1A1", "name" : "UDP glucuronosyltransferase 1 family, polypeptide A1", - "version" : 6110 + "version" : 6350 } ], "source" : "DPWG", "summaryMarkdown" : { "id" : 1447981882, "html" : "

Dose reductions are recommended for irinotecan for patients who are UGT1A1 *28/*28 or UGT1A1 PM, starting with 70% of starting dose and increasing as tolerated, guided by neutrophil count.

\n", - "version" : 1 + "version" : 3 }, "terms" : [], "textMarkdown" : { "id" : 1447981881, "html" : "

Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction between UGT1A1 and irinotecan. European journal of human genetics (2022)

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group published a paper with the guidelines as per the May 2021 update including more details and scoring the clinical implementation [Article:36443464][Article:36797469]. Table 2 of the publication has made some minor changes to the recommendation column to replace "standard" with "normal" dose. The table below has been updated to reflect this. Supplementary Table 1 includes a list of UGT1A1 alleles and the corresponding metabolic capacity.

\n

May 2021 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has made some minor changes to the names of some phenotype groups in this guideline. The table below has been updated to reflect this but the recommendations themselves have not changed.

\n

November 2018 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for irinotecan based on UGT1A1 genotype. They recommend reducing the initial dose for patients who are poor metabolizers or homozygotes for UGT1A1*28.

\n

Wording in table taken from the Dutch guidelines November 2018 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
UGT1A1 *1/*28irinotecanThis genetic variation (*1/*28) is more common in Western populations than the wild-type (*1/*1). This means that treatment is largely geared to patients with this genetic variation. Adjustment of the treatment is therefore not useful.NO action is needed for this gene-drug interaction
UGT1A1 *28/*28irinotecanSerious, life-threatening adverse events occur more often in patients with this genetic variation. The genetic variation reduces conversion of irinotecan to inactive metabolites.Start with 70% of the normala dose. If the patient tolerates this initial dose, the dose can be increased, guided by the neutrophil count.
UGT1A1 IM otherbirinotecanThis genetic variation (IM) is more common in Western populations than the wild-type (*1/*1). This means that treatment is largely geared to patients with this genetic variation. Adjustment of the treatment is therefore not useful.NO action is needed for this gene-drug interaction.
UGT1A1 PM otherbirinotecanSerious, life-threatening adverse events occur more often in patients with this genetic variation. The genetic variation reduces conversion of irinotecan to inactive metabolites.Start with 70% of the normal dosea. If the patient tolerates this initial dose, the dose can be increased, guided by the neutrophil count.
\n

a The normal dose is defined as the dose the patient would receive if he/she would not have a gene variant.\nb These groups are referred to in the DPWG recommendation PDF as 'IM ANDERS' and 'PM ANDERS', which use the Dutch word 'anders'. PharmGKB has translated these as 'IM other' and PM other', respectively.

\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for irinotecan and UGT1A1:

\n
\n

The KNMP Pharmacogenetics Working Group considers genotyping before starting irinotecan to be essential for drug safety. Genotyping must be performed before drug therapy has been initiated to guide drug and dose selection.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n

2011 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for irinotecan based on UGT1A1 genotype [Article:21412232]. They recommend reducing the dose for *28 homozygous patients receiving more than 250 mg/m2.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Phenotype (Genotype)Therapeutic Dose RecommendationLevel of EvidenceClinical Relevance
*1/*28None.Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints..Clinical effect (S): death; arrhythmia; unanticipated myelosuppression.
*28/*28Dose >250mg/m2: reduce initial dose by 30%. Increase dose in response to neutrophil count. Dose <=250mg/m2: no dose adjustment.Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Clinical effect (S): Failure of lifesaving therapy e.g. anticipated myelosuppression; prevention of breast cancer relapse; arrhythmia; neutropenia < 0.5x109/l; leucopenia < 1.0x109/l; thrombocytopenia < 25x109/l; life-threatening complications from diarrhea.
\n\n", - "version" : 21 + "version" : 27 }, "userId" : "alie", - "version" : 38 + "version" : 157 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166299190", - "name" : "Recommendation PA166299190", + "id" : "PA166299191", + "name" : "Recommendation PA166299191", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -120656,37 +121801,37 @@ "valid" : true, "version" : 1 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "This genetic variation (IM) is more common in Western populations than the wild-type (*1/*1). This means that treatment is largely geared to patients with this genetic variation. Adjustment of the treatment is therefore not useful." + "Serious, life-threatening adverse events occur more often in patients with this genetic variation. The genetic variation reduces conversion of irinotecan to inactive metabolites." ], - "lookupKey" : {"UGT1A1": "Intermediate Metabolizer"}, + "lookupKey" : {"UGT1A1": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450085", "name" : "irinotecan", - "version" : 17 + "version" : 59 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104951", "name" : "Annotation of DPWG Guideline for irinotecan and UGT1A1", - "version" : 38 + "version" : 157 }, "text" : { - "id" : 1452061553, - "html" : "

NO action is needed for this gene-drug interaction.

\n", + "id" : 1452061554, + "html" : "

Start with 70% of the normal dose If the patient tolerates this initial dose, the dose can be increased, guided by the neutrophil count.

\n

The normal dose is defined as the dose the patient would receive if he/she would not have a gene variant.

\n", "version" : 0 }, - "version" : 0 + "version" : 8 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166303201", - "name" : "Recommendation Annotation PA166303201", + "id" : "PA166299189", + "name" : "Recommendation PA166299189", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -120698,120 +121843,120 @@ "valid" : true, "version" : 1 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "Serious, life-threatening adverse events occur more often in patients with this genetic variation. The genetic variation reduces conversion of irinotecan to inactive metabolites." + "This genetic variation (*1/*28) is more common in Western populations than the wild-type (*1/*1). This means that treatment is largely geared to patients with this genetic variation. Adjustment of the treatment is therefore not useful. Note that DPWG considers the *36 allele to be clinically equivalent to the *1 allele." ], - "lookupKey" : {"UGT1A1": {"*28": 2}}, + "lookupKey" : {"UGT1A1": {"*1": 1, "*28": 1}}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450085", "name" : "irinotecan", - "version" : 17 + "version" : 59 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104951", "name" : "Annotation of DPWG Guideline for irinotecan and UGT1A1", - "version" : 38 + "version" : 157 }, "text" : { - "id" : 1452108720, - "html" : "

Start with 70% of the normal dose If the patient tolerates this initial dose, the dose can be increased, guided by the neutrophil count.

\n

The normal dose is defined as the dose the patient would receive if he/she would not have a gene variant.

\n", + "id" : 1452061552, + "html" : "

NO action is needed for this gene-drug interaction.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299189", - "name" : "Recommendation PA166299189", + "id" : "PA166299188", + "name" : "Recommendation PA166299188", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, "dosingInformation" : false, "implications" : [ - "This genetic variation (*1/*28) is more common in Western populations than the wild-type (*1/*1). This means that treatment is largely geared to patients with this genetic variation. Adjustment of the treatment is therefore not useful. Note that DPWG considers the *36 allele to be clinically equivalent to the *1 allele." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on irinotecan." ], - "lookupKey" : {"UGT1A1": {"*1": 1, "*28": 1}}, + "lookupKey" : {"UGT1A1": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450085", "name" : "irinotecan", - "version" : 17 + "version" : 59 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104951", "name" : "Annotation of DPWG Guideline for irinotecan and UGT1A1", - "version" : 38 + "version" : 157 }, "text" : { - "id" : 1452061552, - "html" : "

NO action is needed for this gene-drug interaction.

\n", + "id" : 1452061551, + "html" : "

The guideline does not provide a recommendation for irinotecan in normal metabolizers

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299188", - "name" : "Recommendation PA166299188", + "id" : "PA166299190", + "name" : "Recommendation PA166299190", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, "dosingInformation" : false, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on irinotecan." + "This genetic variation (IM) is more common in Western populations than the wild-type (*1/*1). This means that treatment is largely geared to patients with this genetic variation. Adjustment of the treatment is therefore not useful." ], - "lookupKey" : {"UGT1A1": "Normal Metabolizer"}, + "lookupKey" : {"UGT1A1": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450085", "name" : "irinotecan", - "version" : 17 + "version" : 59 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104951", "name" : "Annotation of DPWG Guideline for irinotecan and UGT1A1", - "version" : 38 + "version" : 157 }, "text" : { - "id" : 1452061551, - "html" : "

The guideline does not provide a recommendation for irinotecan in normal metabolizers

\n", + "id" : 1452061553, + "html" : "

NO action is needed for this gene-drug interaction.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299191", - "name" : "Recommendation PA166299191", + "id" : "PA166303201", + "name" : "Recommendation Annotation PA166303201", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -120827,24 +121972,56 @@ "implications" : [ "Serious, life-threatening adverse events occur more often in patients with this genetic variation. The genetic variation reduces conversion of irinotecan to inactive metabolites." ], - "lookupKey" : {"UGT1A1": "Poor Metabolizer"}, + "lookupKey" : {"UGT1A1": {"*28": 2}}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450085", "name" : "irinotecan", - "version" : 17 + "version" : 59 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104951", "name" : "Annotation of DPWG Guideline for irinotecan and UGT1A1", - "version" : 38 + "version" : 157 }, "text" : { - "id" : 1452061554, + "id" : 1452108720, + "html" : "

Start with 70% of the normal dose If the patient tolerates this initial dose, the dose can be increased, guided by the neutrophil count.

\n

The normal dose is defined as the dose the patient would receive if he/she would not have a gene variant.

\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166313041", + "name" : "Recommendation Annotation PA166313041", + "alternateDrugAvailable" : false, + "dosingInformation" : true, + "implications" : [ + "Serious, life-threatening adverse events occur more often in patients with this genetic variation. The genetic variation reduces conversion of irinotecan to inactive metabolites." + ], + "lookupKey" : {"UGT1A1": {"*80+*28": 2}}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA450085", + "name" : "irinotecan", + "version" : 59 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104951", + "name" : "Annotation of DPWG Guideline for irinotecan and UGT1A1", + "version" : 157 + }, + "text" : { + "id" : 1452221720, "html" : "

Start with 70% of the normal dose If the patient tolerates this initial dose, the dose can be increased, guided by the neutrophil count.

\n

The normal dose is defined as the dose the patient would receive if he/she would not have a gene variant.

\n", "version" : 0 }, @@ -120866,14 +122043,14 @@ "objCls" : "Chemical", "id" : "PA450085", "name" : "irinotecan", - "version" : 17 + "version" : 59 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104951", "name" : "Annotation of DPWG Guideline for irinotecan and UGT1A1", - "version" : 38 + "version" : 157 }, "text" : { "id" : 1452221721, @@ -120881,44 +122058,68 @@ "version" : 0 }, "version" : 0 - }, + } + ], + "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166104951" + }, + { + "citations" : [ { - "objCls" : "Recommendation Annotation", - "id" : "PA166313041", - "name" : "Recommendation Annotation PA166313041", - "alternateDrugAvailable" : false, - "dosingInformation" : true, - "implications" : [ - "Serious, life-threatening adverse events occur more often in patients with this genetic variation. The genetic variation reduces conversion of irinotecan to inactive metabolites." + "id" : 15156470, + "title" : "Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction of CYP2C9, HLA-A and HLA-B with anti-epileptic drugs.", + "_sameAs" : "https://www.ncbi.nlm.nih.gov/pubmed/38570725", + "authors" : [ + "Manson Lisanne E N", + "Nijenhuis Marga", + "Soree Bianca", + "de Boer-Veger Nienke J", + "Buunk Anne-Marie", + "Houwink Elisa J F", + "Risselada Arne", + "Rongen Gerard A P J M", + "van Schaik Ron H N", + "Swen Jesse J", + "Touw Daan J", + "van Westrhenen Roos", + "Deneer Vera H M", + "Guchelaar Henk-Jan" ], - "lookupKey" : {"UGT1A1": {"*80+*28": 2}}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ + "crossReferences" : [ { - "objCls" : "Chemical", - "id" : "PA450085", - "name" : "irinotecan", - "version" : 17 + "id" : 1452435716, + "resource" : "PubMed", + "resourceId" : "38570725", + "_url" : "https://www.ncbi.nlm.nih.gov/pubmed/38570725", + "version" : 0 + }, + { + "id" : 1452435717, + "resource" : "DOI", + "resourceId" : "10.1038/s41431-024-01572-4", + "_url" : "http://dx.doi.org/10.1038%2Fs41431-024-01572-4", + "version" : 0 } ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166104951", - "name" : "Annotation of DPWG Guideline for irinotecan and UGT1A1", - "version" : 38 - }, - "text" : { - "id" : 1452221720, - "html" : "

Start with 70% of the normal dose If the patient tolerates this initial dose, the dose can be increased, guided by the neutrophil count.

\n

The normal dose is defined as the dose the patient would receive if he/she would not have a gene variant.

\n", - "version" : 0 - }, - "version" : 0 + "day" : -1, + "hasKeyword" : true, + "journal" : "European journal of human genetics : EJHG", + "meshDiseases" : [], + "meshTerms" : [], + "month" : 4, + "nonHuman" : false, + "objCls" : "Literature", + "pediatric" : false, + "pgkbPublication" : false, + "pubDate" : "2024-04-01T00:00:00-07:00", + "summary" : "By developing evidence-based pharmacogenetics guidelines to optimize pharmacotherapy, the Dutch Pharmacogenetics Working Group (DPWG) aims to advance the implementation of pharmacogenetics (PGx). This guideline outlines the gene-drug interaction of CYP2C9 and HLA-B with phenytoin, HLA-A and HLA-B with carbamazepine and HLA-B with oxcarbazepine and lamotrigine. A systematic review was performed and pharmacotherapeutic recommendations were developed. For CYP2C9 intermediate and poor metabolisers, the DPWG recommends lowering the daily dose of phenytoin and adjust based on effect and serum concentration after 7-10 days. For HLA-B*15:02 carriers, the risk of severe cutaneous adverse events associated with phenytoin, carbamazepine, oxcarbazepine, and lamotrigine is strongly increased. For carbamazepine, this risk is also increased in HLA-B*15:11 and HLA-A*31:01 carriers. For HLA-B*15:02, HLA-B*15:11 and HLA-A*31:01 positive patients, the DPWG recommends choosing an alternative anti-epileptic drug. If not possible, it is recommended to advise the patient to report any rash while using carbamazepine, lamotrigine, oxcarbazepine or phenytoin immediately. Carbamazepine should not be used in an HLA-B*15:02 positive patient. DPWG considers CYP2C9 genotyping before the start of phenytoin \"essential\" for toxicity prevention. For patients with an ancestry in which the abovementioned HLA-alleles are prevalent, the DPWG considers HLA-B*15:02 genotyping before the start of carbamazepine, phenytoin, oxcarbazepine, and lamotrigine \"beneficial\", as well as genotyping for HLA-B*15:11 and HLA-A*31:01 before initiating carbamazepine.", + "terms" : [ + {"id":1451577480,"resource":"PGx Paper Types","term":"Implementation","termId":"pgxPaperTypes:1451577480"} + ], + "type" : "Literature", + "version" : 4, + "year" : 2024 } ], - "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166104951" - }, - { - "citations" : [], "guideline" : { "objCls" : "Guideline Annotation", "id" : "PA166265341", @@ -120933,7 +122134,7 @@ "id" : 1451698102, "date" : "2022-02-28T00:00:00-08:00", "type" : "Create", - "version" : 0 + "version" : 1 }, { "id" : 1451704254, @@ -120997,9 +122198,18 @@ "description" : "Updated excerpt on testing.", "type" : "Update", "version" : 0 + }, + { + "id" : 1452439763, + "date" : "2024-04-11T06:33:38.626-07:00", + "description" : "Added 2024 publication.", + "type" : "Update", + "version" : 0 } ], - "literature" : [], + "literature" : [ + {"id":15156470,"title":"Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction of CYP2C9, HLA-A and HLA-B with anti-epileptic drugs.","_sameAs":"https://www.ncbi.nlm.nih.gov/pubmed/38570725","crossReferences":[{"id":1452435716,"resource":"PubMed","resourceId":"38570725","_url":"https://www.ncbi.nlm.nih.gov/pubmed/38570725"},{"id":1452435717,"resource":"DOI","resourceId":"10.1038/s41431-024-01572-4","_url":"http://dx.doi.org/10.1038%2Fs41431-024-01572-4"}],"objCls":"Literature","pubDate":"2024-04-01T00:00:00-07:00","terms":[{"id":1451577480,"resource":"PGx Paper Types","term":"Implementation","termId":"pgxPaperTypes:1451577480"}],"type":"Literature"} + ], "otherPrescribingGuidance" : true, "pediatric" : false, "recommendation" : true, @@ -121009,7 +122219,7 @@ "id" : "PA165954769", "symbol" : "HLA-B*15:02", "name" : "*15:02", - "version" : 5 + "version" : 21 } ], "relatedChemicals" : [ @@ -121017,7 +122227,7 @@ "objCls" : "Chemical", "id" : "PA450164", "name" : "lamotrigine", - "version" : 7 + "version" : 38 } ], "relatedGenes" : [ @@ -121026,7 +122236,7 @@ "id" : "PA35056", "symbol" : "HLA-B", "name" : "major histocompatibility complex, class I, B", - "version" : 40 + "version" : 2920 } ], "source" : "DPWG", @@ -121039,94 +122249,94 @@ "textMarkdown" : { "id" : 1451698101, "html" : "

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

\n

May 2021

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for lamotrigine based on HLA-B*15:02.

\n

Wording in table taken from the Dutch guidelines May 2021 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
HLA-B*1502lamotrigineThe life-threatening cutaneous side effect Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) occurs more often in patients with this genetic variation. Based on the estimated risk for all patients and the increase by a factor 3.6 for patients with this genetic variation, the risk of lamotrigine-induced SJS/TEN in patients with HLA-B*1502 is estimated at 0.4%.Carefully weigh the risk of SJS/TEN against the benefits.
Avoid lamotrigine if an alternative is available. Carbamazepine carries a much higher risk of SJS/TEN in these patients and is therefore not an alternative. A similar risk has been reported for phenytoin as for lamotrigine. The same applies to oxcarbazepine, but the most severe forms (SJS/TEN overlap and TEN) have not been observed with oxcarbazepine.
If it is not possible to avoid this medication, then advise the patient to report any skin rash immediately
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for lamotrigine and HLA:

\n
\n

HLA-B*1502 has not been detected in a sample of 1350 Dutch persons (Allele Frequency Net Database:\nhttp://www.allelefrequencies.net). For this reason, the KNMP Pharmacogenetics Working Group does not consider\ngenotyping of Dutch patients in general before starting lamotrigine to be useful.\nHowever, the HLA-B*1502 frequency is high in Asians, except for Japanese and Koreans. In Japanese the HLAB*1502 frequency is very low (< 0.1%). In Korea, it is less than 1% in some populations and more than 1% in other\npopulations, with a mean of approximately 2% according to the SmPC of carbamazepine. The KNMP Pharmacogenetics Working Group considers genotyping of patients of Asian descent other than Japanese descent before\nstarting lamotrigine to be beneficial for drug safety. It is advised to consider genotyping these patients before (or\ndirectly after) drug therapy has been initiated to guide drug selection.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n", - "version" : 4 + "version" : 6 }, "userId" : "katrin", - "version" : 9 + "version" : 36 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166299278", - "name" : "Recommendation PA166299278", - "alternateDrugAvailable" : true, + "id" : "PA166299277", + "name" : "Recommendation PA166299277", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, "dosingInformation" : false, "implications" : [ - "The life-threatening cutaneous side effect Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) occurs more often in patients with this genetic variation. Based on the estimated risk for all patients and the increase by a factor 3.6 for patients with this genetic variation, the risk of lamotrigine-induced SJS/TEN in patients with HLA-B*1502 is estimated at 0.4%." + "The guideline does not provide a description of the impact of the absence of HLA-B*15:02 alleles on lamotrigine." ], - "lookupKey" : {"HLA-B": "*15:02 positive"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"HLA-B": "*15:02 negative"}, + "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450164", "name" : "lamotrigine", - "version" : 7 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166265341", "name" : "Annotation of DPWG Guideline for lamotrigine and HLA-B", - "version" : 9 + "version" : 36 }, "text" : { - "id" : 1452061641, - "html" : "\n", + "id" : 1452061640, + "html" : "

The guideline does not provide a recommendation for lamotrigine in patients with no HLA-B*15:02 alleles or negative for the HLA-B*15:02 test.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299277", - "name" : "Recommendation PA166299277", - "alternateDrugAvailable" : false, + "id" : "PA166299278", + "name" : "Recommendation PA166299278", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, "dosingInformation" : false, "implications" : [ - "The guideline does not provide a description of the impact of the absence of HLA-B*15:02 alleles on lamotrigine." + "The life-threatening cutaneous side effect Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) occurs more often in patients with this genetic variation. Based on the estimated risk for all patients and the increase by a factor 3.6 for patients with this genetic variation, the risk of lamotrigine-induced SJS/TEN in patients with HLA-B*1502 is estimated at 0.4%." ], - "lookupKey" : {"HLA-B": "*15:02 negative"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"HLA-B": "*15:02 positive"}, + "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450164", "name" : "lamotrigine", - "version" : 7 + "version" : 38 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166265341", "name" : "Annotation of DPWG Guideline for lamotrigine and HLA-B", - "version" : 9 + "version" : 36 }, "text" : { - "id" : 1452061640, - "html" : "

The guideline does not provide a recommendation for lamotrigine in patients with no HLA-B*15:02 alleles or negative for the HLA-B*15:02 test.

\n", + "id" : 1452061641, + "html" : "\n", "version" : 0 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166265341" @@ -121328,7 +122538,7 @@ "objCls" : "Chemical", "id" : "PA450180", "name" : "lansoprazole", - "version" : 16 + "version" : 40 } ], "relatedGenes" : [ @@ -121337,112 +122547,112 @@ "id" : "PA124", "symbol" : "CYP2C19", "name" : "cytochrome P450 family 2 subfamily C member 19", - "version" : 7210 + "version" : 7266 } ], "source" : "DPWG", "summaryMarkdown" : { "id" : 1447981988, "html" : "

For CYP2C19 ultrarapid metabolizers who are undergoing H. pylori eradication therapy, use a 4-fold higher dose. For CYP2C19 ultrarapid metabolizers with other indications, be alert to reduced effectiveness and, if necessary, use a 4-fold higher dose.

\n", - "version" : 1 + "version" : 3 }, "terms" : [], "textMarkdown" : { "id" : 1447981987, "html" : "

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

\n

November 2018 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for lansoprazole based on CYP2C19 genotype. Patients who are CYP2C19 ultrarapid metabolizers who are undergoing H. pylori eradication therapy should receive a 4-fold higher dose. In CYP2C19 ultrarapid metabolizer patients with other indications, be alert to reduced effectiveness, and, if necessary, use a 4-fold higher dose. Patients should be advised to report persisting symptoms of dyspepsia.

\n

Wording in table taken from the Dutch guidelines November 2018 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
CYP2C19 PMlansoprazoleThe higher plasma concentration of lansoprazole results in an increase in the therapeutic effectiveness, without an increase in the incidence of side effects.NO action is needed for this gene-drug interaction.
CYP2C19 IMlansoprazoleThe higher plasma concentration of lansoprazole results in an increase in the therapeutic effectiveness, without an increase in the incidence of side effects.NO action is needed for this gene-drug interaction.
CYP2C19 UMlansoprazoleThe genetic variation may reduce lansoprazole plasma concentrations and therefore lansoprazole effectiveness.For Helicobacter pylori ERADICATION THERAPY: 1. Use a 4-fold higher dose. 2. Advise the patient to contact their doctor if symptoms of dyspepsia persist.
OTHER INDICATIONS: 1. Be alert to reduced effectiveness. 2. If necessary, use a 4-fold higher dose. 3. Advise the patient to report persisting symptoms of dyspepsia.
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for lansoprazole and CYP2C19:

\n
\n

The Dutch Pharmacogenetics Working Group considers genotyping before starting lansoprazole to be potentially beneficial for drug efficacy. Genotyping can be considered on an individual patient basis. If, however, the genotype is available, the Dutch Pharmacogenetics Working Group recommends adhering to the gene-drug guideline.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n

2011 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for lansoprazole based on CYP2C19 genotype [Article:21412232]. For the CYP2C19 UM phenotype, they conclude to be extra alert to insufficient response and recommend to consider dose increase by 200%.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Phenotype (Genotype)Therapeutic Dose RecommendationLevel of EvidenceClinical Relevance
CYP2C19 PM (*2/*2, *2/*3, *3/*3)NonePublished controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpointsPositive clinical effects
CYP2C19 IM (*1/*2, *1/*3, *17/*2, *17/*3)NonePublished controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpointsPositive clinical effects
CYP2C19 UM (*17/*17)Helicobacter pylori eradication: increase dose by 200%. Be extra alert to insufficient response
Other: be extra alert to insufficient response. Consider dose increase by 200%		no data was retrieved with the literature searchno data was retrieved with the literature search
\n\n", - "version" : 17 + "version" : 26 }, "userId" : "lgong", - "version" : 31 + "version" : 72 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166299062", - "name" : "Recommendation PA166299062", + "id" : "PA166299060", + "name" : "Recommendation PA166299060", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, "dosingInformation" : false, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on lansoprazole." + "The higher plasma concentration of lansoprazole results in an increase in the therapeutic effectiveness, without an increase in the incidence of side effects." ], - "lookupKey" : {"CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450180", "name" : "lansoprazole", - "version" : 16 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104987", "name" : "Annotation of DPWG Guideline for lansoprazole and CYP2C19", - "version" : 31 + "version" : 72 }, "text" : { - "id" : 1452061425, - "html" : "

The guideline does not provide a recommendation for lansoprazole in normal metabolizers.

\n", - "version" : 0 + "id" : 1452061423, + "html" : "

NO action is needed for this gene-drug interaction.

\n", + "version" : 1 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299061", - "name" : "Recommendation PA166299061", + "id" : "PA166299062", + "name" : "Recommendation PA166299062", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, "dosingInformation" : false, "implications" : [ - "The higher plasma concentration of lansoprazole results in an increase in the therapeutic effectiveness, without an increase in the incidence of side effects." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on lansoprazole." ], - "lookupKey" : {"CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450180", "name" : "lansoprazole", - "version" : 16 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104987", "name" : "Annotation of DPWG Guideline for lansoprazole and CYP2C19", - "version" : 31 + "version" : 72 }, "text" : { - "id" : 1452061424, - "html" : "

NO action is needed for this gene-drug interaction.

\n", + "id" : 1452061425, + "html" : "

The guideline does not provide a recommendation for lansoprazole in normal metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299060", - "name" : "Recommendation PA166299060", + "id" : "PA166299063", + "name" : "Recommendation PA166299063", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -121454,37 +122664,37 @@ "valid" : true, "version" : 1 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "The higher plasma concentration of lansoprazole results in an increase in the therapeutic effectiveness, without an increase in the incidence of side effects." + "The genetic variation may reduce lansoprazole plasma concentrations and therefore lansoprazole effectiveness." ], - "lookupKey" : {"CYP2C19": "Poor Metabolizer"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"CYP2C19": "Ultrarapid Metabolizer"}, + "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450180", "name" : "lansoprazole", - "version" : 16 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104987", "name" : "Annotation of DPWG Guideline for lansoprazole and CYP2C19", - "version" : 31 + "version" : 72 }, "text" : { - "id" : 1452061423, - "html" : "

NO action is needed for this gene-drug interaction.

\n", + "id" : 1452061426, + "html" : "

For Helicobacter pylori ERADICATION THERAPY: 1. Use a 4-fold higher dose. 2. Advise the patient to contact their doctor if symptoms of dyspepsia persist.\nOTHER INDICATIONS: 1. Be alert to reduced effectiveness. 2. If necessary, use a 4-fold higher dose. 3. Advise the patient to report persisting symptoms of dyspepsia.

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299063", - "name" : "Recommendation PA166299063", + "id" : "PA166299061", + "name" : "Recommendation PA166299061", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -121496,32 +122706,32 @@ "valid" : true, "version" : 1 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "The genetic variation may reduce lansoprazole plasma concentrations and therefore lansoprazole effectiveness." + "The higher plasma concentration of lansoprazole results in an increase in the therapeutic effectiveness, without an increase in the incidence of side effects." ], - "lookupKey" : {"CYP2C19": "Ultrarapid Metabolizer"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"CYP2C19": "Intermediate Metabolizer"}, + "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450180", "name" : "lansoprazole", - "version" : 16 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104987", "name" : "Annotation of DPWG Guideline for lansoprazole and CYP2C19", - "version" : 31 + "version" : 72 }, "text" : { - "id" : 1452061426, - "html" : "

For Helicobacter pylori ERADICATION THERAPY: 1. Use a 4-fold higher dose. 2. Advise the patient to contact their doctor if symptoms of dyspepsia persist.\nOTHER INDICATIONS: 1. Be alert to reduced effectiveness. 2. If necessary, use a 4-fold higher dose. 3. Advise the patient to report persisting symptoms of dyspepsia.

\n", - "version" : 0 + "id" : 1452061424, + "html" : "

NO action is needed for this gene-drug interaction.

\n", + "version" : 1 }, - "version" : 0 + "version" : 2 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166104987" @@ -121636,7 +122846,7 @@ "objCls" : "Chemical", "id" : "PA450379", "name" : "mercaptopurine", - "version" : 31 + "version" : 73 } ], "relatedGenes" : [ @@ -121645,7 +122855,7 @@ "id" : "PA134963132", "symbol" : "NUDT15", "name" : "nudix hydrolase 15", - "version" : 11 + "version" : 39 } ], "source" : "DPWG", @@ -121658,52 +122868,53 @@ "textMarkdown" : { "id" : 1450821372, "html" : "

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

\n

May 2020 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for mercaptopurine based on NUDT15 genotype. They recommend reducing the initial dose for patients that are intermediate metabolizers and selecting an alternative drug or reducing the initial dose for patients that are poor metabolizers. They removed the sentence "Monitoring should be performed at an increased frequency." from the previous recommendation.

\n

Wording in table taken from the Dutch guidelines May 2020 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
NUDT15 IMmercaptopurineGrade >= 2 leukopaenia occurs in 42% of these patients with standard therapy. The genetic variation increases the concentration of the fully activated metabolite of azathioprine and mercaptopurine.- IMMUNOSUPPRESSION:start with 50% of the standard dose. Adjustment of the initial dose should be performed based on toxicity (monitoring of the blood counts) and efficacy.
Note: The percentage of 50% is based on the analogy with TPMT, for which the gene variants have a comparable effect on toxicity to those of NUDT15. A percentage of < 70% was calculated for NUDT15, but there were insufficient data available to calculate the exact percentage.
Note: Dose adjustment based on the total of 6-TGN metabolites is not possible for these patients, as they develop toxicity within the therapeutic range that applies for patients without gene variants.
- LEUKAEMIA: start at 50% of the standard mercaptopurine dose, or start with the standard dose and reduce to 50% if side effects necessitate a dose reduction. It is not known whether dose reduction in advance results in the same efficacy as dose reduction based on toxicity. Adjustment of the initial dose should be performed based on toxicity (monitoring of the blood counts) and efficacy. Monitoring should be performed at an increased frequency.
Note: The percentage of 50% is based on the analogy with TPMT, for which the gene variants have a comparable effect on toxicity to those of NUDT15. A percentage of < 70% was calculated for NUDT15, but there were insufficient data available to calculate the exact percentage.
Note: Dose adjustment based on the total of 6-TGN metabolites is not possible for these patients, as they develop toxicity within the therapeutic range that applies for patients without gene variants.
Note: more stringent dose reductions are necessary if the patient is also TPMT IM or TPMT PM.
NUDT15 PMmercaptopurineGrade >= 2 leukopaenia occurs in 96% of these patients with standard therapy. The genetic variation increases the concentration of the fully activated metabolite of azathioprine and mercaptopurine.- avoid azathioprine and mercaptopurine. If it is not possible to avoid azathioprine and mercaptopurine: use 10% of the standard dose and advise patients to seek medical attention when symptoms of myelosuppression (such as severe sore throat in combination with fever, regular nosebleeds and tendency to bruising) occur. Any adjustment of the initial dose should be guided by toxicity (monitoring of blood counts) and efficacy.
Note: The percentage of 10% is based on the analogy with TPMT, for which the gene variants have a comparable effect on toxicity to those of NUDT15. A percentage of < 20% was calculated for NUDT15 PM, but there were insufficient data available to calculate the exact percentage.
Note: Dose adjustment based on the total of 6-TGN metabolites is not possible for these patients, as they develop toxicity within the therapeutic range that applies for patients without gene variants.
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for azathioprine and NUDT15:

\n
\n

The Dutch Pharmacogenetics Working Group considers genotyping before starting azathioprine or 6-mercaptopurine to be essential for drug safety. Genotyping must be performed before drug therapy has been initiated to guide drug and dose selection.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n

August 2019 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for mercaptopurine based on NUDT15 genotype. They recommend reducing the initial dose for patients that are intermediate metabolizers and selecting an alternative drug or reducing the initial dose for patients that are poor metabolizers. They updated the wording for the intermediate metabolizer recommendation, reflected in the table below.

\n

Wording in table taken from the Dutch guidelines August 2019 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
NUDT15 IMmercaptopurineGrade = 2 leukopaenia occurs in 42% of these patients with standard therapy. The genetic variation increases the concentration of the fully activated metabolite of azathioprine and mercaptopurine.- IMMUNOSUPPRESSION:start with 50% of the standard dose. Adjustment of the initial dose should be performed based on toxicity (monitoring of the blood counts) and efficacy. Monitoring should be performed at an increased frequency.
Note: The percentage of 50% is based on the analogy with TPMT, for which the gene variants have a comparable effect on toxicity to those of NUDT15. A percentage of < 70% was calculated for NUDT15, but there were insufficient data available to calculate the exact percentage.
Note: Dose adjustment based on the total of 6-TGN metabolites is not possible for these patients, as they develop toxicity within the therapeutic range that applies for patients without gene variants.
- LEUKAEMIA: start at 50% of the standard mercaptopurine dose, or start with the standard dose and reduce to 50% if side effects necessitate a dose reduction. It is not known whether dose reduction in advance results in the same efficacy as dose reduction based on toxicity. Adjustment of the initial dose should be performed based on toxicity (monitoring of the blood counts) and efficacy. Monitoring should be performed at an increased frequency.
Note: The percentage of 50% is based on the analogy with TPMT, for which the gene variants have a comparable effect on toxicity to those of NUDT15. A percentage of < 70% was calculated for NUDT15, but there were insufficient data available to calculate the exact percentage.
Note: Dose adjustment based on the total of 6-TGN metabolites is not possible for these patients, as they develop toxicity within the therapeutic range that applies for patients without gene variants.
Note: more stringent dose reductions are necessary if the patient is also TPMT IM.
NUDT15 PMmercaptopurineGrade = 2 leukopaenia occurs in 96% of these patients with standard therapy. The genetic variation increases the concentration of the fully activated metabolite of azathioprine and mercaptopurine.- avoid azathioprine and mercaptopurine. If it is not possible to avoid azathioprine and mercaptopurine: use 10% of the standard dose and advise patients to seek medical attention when symptoms of myelosuppression (such as severe sore throat in combination with fever, regular nosebleeds and tendency to bruising) occur. Any adjustment of the initial dose should be guided by toxicity (monitoring of blood counts) and efficacy. Monitoring should be performed at an increased frequency.
Note: The percentage of 10% is based on the analogy with TPMT, for which the gene variants have a comparable effect on toxicity to those of NUDT15. A percentage of < 20% was calculated for NUDT15 PM, but there were insufficient data available to calculate the exact percentage.
Note: Dose adjustment based on the total of 6-TGN metabolites is not possible for these patients, as they develop toxicity within the therapeutic range that applies for patients without gene variants.
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The guideline does not provide a recommendation for mercaptopurine in normal metabolizers

\n", - "version" : 0 + "id" : 1452061453, + "html" : "

Avoid azathioprine and mercaptopurine.

\n

If it is not possible to avoid azathioprine and mercaptopurine: use 10% of the standard dose and advise patients to seek medical attention when symptoms of myelosuppression (such as severe sore throat in combination with fever, regular nosebleeds and tendency to bruising) occur. Any adjustment of the initial dose should be guided by toxicity (monitoring of blood counts) and efficacy.

\n

Note: The percentage of 10% is based on the analogy with TPMT, for which the gene variants have a comparable effect on toxicity to those of NUDT15. A percentage of < 20% was calculated for NUDT15 PM, but there were insufficient data available to calculate the exact percentage.\nNote: Dose adjustment based on the total of 6-TGN metabolites is not possible for these patients, as they develop toxicity within the therapeutic range that applies for patients without gene variants.

\n", + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", @@ -121731,63 +122942,62 @@ "objCls" : "Chemical", "id" : "PA450379", "name" : "mercaptopurine", - "version" : 31 + "version" : 73 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166184613", "name" : "Annotation of DPWG Guideline for mercaptopurine and NUDT15", - "version" : 11 + "version" : 54 }, "text" : { "id" : 1452061454, "html" : "\n

Note: The percentage of 50% is based on the analogy with TPMT, for which the gene variants have a comparable effect on toxicity to those of NUDT15. A percentage of < 70% was calculated for NUDT15, but there were insufficient data available to calculate the exact percentage.\nNote: Dose adjustment based on the total of 6-TGN metabolites is not possible for these patients, as they develop toxicity within the therapeutic range that applies for patients without gene variants.\nNote: more stringent dose reductions are necessary if the patient is also TPMT IM or TPMT PM.

\n", - "version" : 0 + "version" : 1 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299090", - "name" : "Recommendation PA166299090", - "alternateDrugAvailable" : true, + "id" : "PA166299092", + "name" : "Recommendation PA166299092", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "Grade ≥2 leukopaenia occurs in 96% of these patients with standard therapy. The genetic variation increases the concentration of the fully activated metabolite of azathioprine and mercaptopurine." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on mercaptopurine." ], - "lookupKey" : {"NUDT15": "Poor Metabolizer"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"NUDT15": "Normal Metabolizer"}, + "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450379", "name" : "mercaptopurine", - "version" : 31 + "version" : 73 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166184613", "name" : "Annotation of DPWG Guideline for mercaptopurine and NUDT15", - "version" : 11 + "version" : 54 }, "text" : { - "id" : 1452061453, - "html" : "

Avoid azathioprine and mercaptopurine.

\n

If it is not possible to avoid azathioprine and mercaptopurine: use 10% of the standard dose and advise patients to seek medical attention when symptoms of myelosuppression (such as severe sore throat in combination with fever, regular nosebleeds and tendency to bruising) occur. Any adjustment of the initial dose should be guided by toxicity (monitoring of blood counts) and efficacy.

\n

Note: The percentage of 10% is based on the analogy with TPMT, for which the gene variants have a comparable effect on toxicity to those of NUDT15. A percentage of < 20% was calculated for NUDT15 PM, but there were insufficient data available to calculate the exact percentage.\nNote: Dose adjustment based on the total of 6-TGN metabolites is not possible for these patients, as they develop toxicity within the therapeutic range that applies for patients without gene variants.

\n", + "id" : 1452061455, + "html" : "

The guideline does not provide a recommendation for mercaptopurine in normal metabolizers

\n", "version" : 0 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166184613" @@ -122004,140 +123214,140 @@ "id" : "PA165819268", "symbol" : "TPMT*1", "name" : "*1", - "version" : 16 + "version" : 30 }, { "objCls" : "Haplotype", "id" : "PA165819280", "symbol" : "TPMT*10", "name" : "*10", - "version" : 15 + "version" : 31 }, { "objCls" : "Haplotype", "id" : "PA165819281", "symbol" : "TPMT*11", "name" : "*11", - "version" : 15 + "version" : 31 }, { "objCls" : "Haplotype", "id" : "PA165819282", "symbol" : "TPMT*12", "name" : "*12", - "version" : 15 + "version" : 31 }, { "objCls" : "Haplotype", "id" : "PA165819283", "symbol" : "TPMT*13", "name" : "*13", - "version" : 15 + "version" : 31 }, { "objCls" : "Haplotype", "id" : "PA165819284", "symbol" : "TPMT*14", "name" : "*14", - "version" : 14 + "version" : 30 }, { "objCls" : "Haplotype", "id" : "PA165819285", "symbol" : "TPMT*15", "name" : "*15", - "version" : 14 + "version" : 30 }, { "objCls" : "Haplotype", "id" : "PA165819286", "symbol" : "TPMT*16", "name" : "*16", - "version" : 15 + "version" : 31 }, { "objCls" : "Haplotype", "id" : "PA165819287", "symbol" : "TPMT*17", "name" : "*17", - "version" : 15 + "version" : 31 }, { "objCls" : "Haplotype", "id" : "PA165819288", "symbol" : "TPMT*18", "name" : "*18", - "version" : 15 + "version" : 31 }, { "objCls" : "Haplotype", "id" : "PA165819269", "symbol" : "TPMT*2", "name" : "*2", - "version" : 15 + "version" : 32 }, { "objCls" : "Haplotype", "id" : "PA165819270", "symbol" : "TPMT*3A", "name" : "*3A", - "version" : 16 + "version" : 33 }, { "objCls" : "Haplotype", "id" : "PA165819271", "symbol" : "TPMT*3B", "name" : "*3B", - "version" : 15 + "version" : 32 }, { "objCls" : "Haplotype", "id" : "PA165819272", "symbol" : "TPMT*3C", "name" : "*3C", - "version" : 15 + "version" : 32 }, { "objCls" : "Haplotype", "id" : "PA165819274", "symbol" : "TPMT*4", "name" : "*4", - "version" : 14 + "version" : 31 }, { "objCls" : "Haplotype", "id" : "PA165819275", "symbol" : "TPMT*5", "name" : "*5", - "version" : 15 + "version" : 31 }, { "objCls" : "Haplotype", "id" : "PA165819276", "symbol" : "TPMT*6", "name" : "*6", - "version" : 15 + "version" : 31 }, { "objCls" : "Haplotype", "id" : "PA165819277", "symbol" : "TPMT*7", "name" : "*7", - "version" : 15 + "version" : 31 }, { "objCls" : "Haplotype", "id" : "PA165819278", "symbol" : "TPMT*8", "name" : "*8", - "version" : 15 + "version" : 31 }, { "objCls" : "Haplotype", "id" : "PA165819279", "symbol" : "TPMT*9", "name" : "*9", - "version" : 15 + "version" : 31 } ], "relatedChemicals" : [ @@ -122145,7 +123355,7 @@ "objCls" : "Chemical", "id" : "PA450379", "name" : "mercaptopurine", - "version" : 31 + "version" : 73 } ], "relatedGenes" : [ @@ -122154,23 +123364,23 @@ "id" : "PA356", "symbol" : "TPMT", "name" : "thiopurine S-methyltransferase", - "version" : 7545 + "version" : 7628 } ], "source" : "DPWG", "summaryMarkdown" : { "id" : 1447981856, "html" : "

Select an alternative drug or reduce the initial dose of mercaptopurine for patients that are TPMT poor metabolizers and reduce initial dose for patients that are TPMT intermediate metabolizers.

\n", - "version" : 1 + "version" : 3 }, "terms" : [], "textMarkdown" : { "id" : 1447981855, "html" : "

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

\n

May 2020 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for mercaptopurine based on TPMT genotype. They recommend reducing the initial dose for patients that are intermediate metabolizers and selecting an alternative drug or reducing the initial dose for patients that are poor metabolizers. They removed the sentence "The frequency of monitoring should be increased." from the previous recommendation.

\n

Wording in table taken from the Dutch guidelines May 2020 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
TPMT IMmercaptopurineGrade ≥ 2 leukopaenia occurs in 23% of these patients with normal therapy for immunosuppression. The genetic variation increases the quantity of the active metabolites of azathioprine and mercaptopurine.-IMMUNOSUPPRESSION:
Start with 50% of the standard dose. Adjustment of the initial dose should be guided by toxicity (monitoring of blood counts) and effectiveness. Dose adjustment is not required for doses lower than 1.5 mg/kg per day for azathioprine or 0.75 mg/kg per day for mercaptopurine.
-LEUKAEMIA:
Start with 50% of the standard mercaptopurine dose, or start with the standard dose and reduce to 50% if side effects necessitate a dose reduction
It is not known whether dose reduction in advance results in the same efficacy as dose reduction based on toxicity. The initial dose should be adjusted based on toxicity (monitoring of the blood counts) and efficacy.
Note: more stringent dose reductions are necessary if the patient is also NUDT15 IM or NUDT15 PM.
TPMT PMmercaptopurineGrade ≥ 2 leukopaenia and intolerance occurred in 98% of these patients with standard therapy. The gene variation increases the quantities of the active metabolites of azathioprine and mercaptopurine.Choose an alternative or start with 10% of the standard dose.
Any adjustment of the initial dose should be guided by toxicity (monitoring of blood counts) and effectiveness.
If the dose is decreased: advise patients to seek medical attention when symptoms of myelosuppression (such as severe sore throat in combination with fever, regular nosebleeds and tendency to bruising) occur
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for azathioprine and TPMT:

\n
\n

The Dutch Pharmacogenetics Working Group considers genotyping before starting azathioprine or 6-mercaptopurine to be essential for drug safety. Genotyping must be performed before drug therapy has been initiated to guide drug and dose selection.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n

August 2019 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for azathioprine based on TPMT genotype. They recommend reducing the initial dose for patients that are intermediate metabolizers and selecting an alternative drug or reducing the initial dose for patients that are poor metabolizers.

\n

Wording in table taken from the Dutch guidelines August 2019 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
TPMT IMmercaptopurineThe genetic variation reduces the conversion of azathioprine and mercaptopurine to mainly inactive metabolites. This increases the risk of serious, life-threatening adverse events such as myelosuppression.-IMMUNOSUPPRESSION
Start with 50% of the standard dose
Adjustment of the initial dose should be guided by toxicity (monitoring of blood counts) and effectiveness.
The frequency of monitoring should be increased.
Dose adjustment is not required for doses lower than 1.5 mg/kg per day for azathioprine or 0.75 mg/kg per day for mercaptopurine.
-LEUKAEMIA:
start with 50% of the standard mercaptopurine dose, or start with the standard dose and reduce to 50% if side effects necessitate a dose reduction
It is not known whether dose reduction in advance results in the same efficacy as dose reduction based on toxicity. The initial dose should be adjusted based on toxicity (monitoring of the blood counts) and efficacy.
Monitoring should be performed at an increased frequency.
Note: more stringent dose reductions are necessary if the patient is also NUDT15 IM.
TPMT PMmercaptopurineThe genetic variation reduces the conversion of azathioprine and mercaptopurine to mainly inactive metabolites. This increases the risk of serious, life-threatening adverse events such as myelosuppression.1. Choose an alternative or start with 10% of the standard dose.
Any adjustment of the initial dose should be guided by toxicity (monitoring of blood counts) and effectiveness. The frequency of monitoring should be increased.
2. If the dose is decreased: advise patients to seek medical attention when symptoms of myelosuppression (such as severe sore throat in combination with fever, regular nosebleeds and tendency to bruising) occur
\n

November 2018 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for mercaptopurine based on TPMT genotype. They recommend reducing the initial dose for patients that are intermediate metabolizers and selecting an alternative drug or reducing the initial dose for patients that are poor metabolizers.

\n

Wording in table taken from the Dutch guidelines November 2018 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
TPMT IMmercaptopurineThe genetic variation reduces the conversion of azathioprine and mercaptopurine to mainly inactive metabolites. This increases the risk of serious, life-threatening adverse events such as myelosuppression.Start with 50% of the standard dose. Adjustment of the initial dose should be guided by toxicity (monitoring of blood counts) and effectiveness. The frequency of monitoring should be increased. Dose adjustment is not required for doses lower than 1.5 mg/kg per day for azathioprine or 0.75 mg/kg per day for mercaptopurine.
TPMT PMmercaptopurineThe genetic variation reduces the conversion of azathioprine and mercaptopurine to mainly inactive metabolites. This increases the risk of serious, life-threatening adverse events such as myelosuppression.1. Choose an alternative or start with 10% of the standard dose.Any adjustment of the initial dose should be guided by toxicity (monitoring of blood counts) and effectiveness. The frequency of monitoring should be increased. 2. If the dose is decreased: advise patients to seek medical attention when symptoms of myelosuppression (such as severe sore throat in combination with fever, regular nosebleeds and tendency to bruising) occur.
\n

2011 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for mercaptopurine based on TPMT genotype [Article:21412232]. They recommend selecting an alternative drug or reducing the initial dose for patients carrying inactive alleles.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Phenotype (Genotype)Therapeutic Dose RecommendationLevel of EvidenceClinical Relevance
IM (one inactive allele: *2, *3, *4-*18)Select alternative drug or reduce dose by 50%. Increase dose in response of hematologic monitoring and efficacy.Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Clinical effect (S): Failure of lifesaving therapy e.g. anticipated myelosuppression; prevention of breast cancer relapse; arrhythmia; neutropenia < 0.5x109/l; leucopenia < 1.0x109/l; thrombocytopenia < 25x109/l; life-threatening complications from diarrhea.
PM (two inactive alleles: *2, *3, *4-*18)Select alternative drug or reduce dose by 90%. Increase dose in response of hematologic monitoring and efficacy.Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Clinical effect (S): death; arrhythmia; unanticipated myelosuppression.
\n\n", - "version" : 20 + "version" : 26 }, "userId" : "alie", - "version" : 33 + "version" : 89 }, "recommendations" : [ { @@ -122198,21 +123408,21 @@ "objCls" : "Chemical", "id" : "PA450379", "name" : "mercaptopurine", - "version" : 31 + "version" : 73 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104952", "name" : "Annotation of DPWG Guideline for mercaptopurine and TPMT", - "version" : 33 + "version" : 89 }, "text" : { "id" : 1452061531, "html" : "

The guideline does not provide a recommendation for mercaptopurine in normal metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", @@ -122240,21 +123450,21 @@ "objCls" : "Chemical", "id" : "PA450379", "name" : "mercaptopurine", - "version" : 31 + "version" : 73 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104952", "name" : "Annotation of DPWG Guideline for mercaptopurine and TPMT", - "version" : 33 + "version" : 89 }, "text" : { "id" : 1452061533, "html" : "

Choose an alternative or start with 10% of the standard dose. Any adjustment of the initial dose should be guided by toxicity (monitoring of blood counts) and effectiveness. If the dose is decreased: advise patients to seek medical attention when symptoms of myelosuppression (such as severe sore throat in combination with fever, regular nosebleeds and tendency to bruising) occur.

\n", "version" : 1 }, - "version" : 1 + "version" : 4 }, { "objCls" : "Recommendation Annotation", @@ -122282,21 +123492,21 @@ "objCls" : "Chemical", "id" : "PA450379", "name" : "mercaptopurine", - "version" : 31 + "version" : 73 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104952", "name" : "Annotation of DPWG Guideline for mercaptopurine and TPMT", - "version" : 33 + "version" : 89 }, "text" : { "id" : 1452061532, "html" : "

IMMUNOSUPPRESSION: Start with 50% of the standard dose. Adjustment of the initial dose should be guided by toxicity (monitoring of blood counts) and effectiveness. Dose adjustment is not required for doses lower than 1.5 mg/kg per day for azathioprine or 0.75 mg/kg per day for mercaptopurine.\nLEUKAEMIA: Start with 50% of the standard mercaptopurine dose, or start with the standard dose and reduce to 50% if side effects necessitate a dose reduction. It is not known whether dose reduction in advance results in the same efficacy as dose reduction based on toxicity. The initial dose should be adjusted based on toxicity (monitoring of the blood counts) and efficacy. Note: more stringent dose reductions are necessary if the patient is also NUDT15 IM or NUDT15 PM.

\n", "version" : 1 }, - "version" : 1 + "version" : 3 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166104952" @@ -122390,7 +123600,7 @@ "date" : "2019-05-27T00:00:00-07:00", "description" : "Annotation current with November 2018 DPWG Guideline release", "type" : "Update", - "version" : 0 + "version" : 2 }, { "id" : 1450820225, @@ -122582,7 +123792,7 @@ "objCls" : "Chemical", "id" : "PA450480", "name" : "metoprolol", - "version" : 15 + "version" : 37 } ], "relatedGenes" : [ @@ -122591,30 +123801,30 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "DPWG", "summaryMarkdown" : { "id" : 1447982028, "html" : "

For CYP2D6 poor and intermediate metabolizer patients, if a GRADUAL REDUCTION in HEART RATE is desired, or in the event of SYMPTOMATIC BRADYCARDIA, use smaller steps in dose titration and/or prescribe no more than 25% or 50% of the standard dose, respectively. For CYP2D6 ultra metabolizers, use the maximum dose for the relevant indication as a target dose, and if the effectiveness is still insufficient: increase the dose based on effectiveness and side effects to 2.5 times the standard dose or select an alternative drug.

\n", - "version" : 2 + "version" : 3 }, "terms" : [], "textMarkdown" : { "id" : 1447982027, "html" : "

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

\n

February 2022 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has made some minor changes to the text of their recommendations for CYP2D6 intermediate or poor metabolizers taking metoprolol. The table below has been updated to reflect this but the recommendations themselves have not changed. See the DPWG February 2022 guidelines.

\n

November 2018 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for metoprolol based on CYP2D6 genotype. For CYP2D6 poor and intermediate metabolizer patients, if a GRADUAL REDUCTION in HEART RATE is desired, or in the event of SYMPTOMATIC BRADYCARDIA, increase the dose in smaller steps and/or prescribe no more than 25% or 50% of the standard dose, respectively. For CYP2D6 ultra metabolizers, use the maximum dose for the relevant indication as a target dose, and if the effectiveness is still insufficient: increase the dose based on effectiveness and side effects to 2.5 times the standard dose or select an alternative drug.

\n

Wording in table taken from the Dutch guidelines November 2018 update

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
CYP2D6 IMmetoprololThe gene variation reduces the conversion of metoprolol to inactive metabolites. However, the clinical consequences are limited mainly to the occurrence of asymptomatic bradycardia.If a GRADUAL REDUCTION in HEART RATE is desired, or in the event of SYMPTOMATIC BRADYCARDIA: 1. use smaller steps in dose titration and/or prescribe no more than 50% of the standard dose. OTHER CASES: 1. no action required
CYP2D6 PMmetoprololThe gene variation reduces the conversion of metoprolol to inactive metabolites. However, the clinical consequences are limited mainly to the occurrence of asymptomatic bradycardia.If a GRADUAL REDUCTION in HEART RATE is desired, or in the event of SYMPTOMATIC BRADYCARDIA: 1.use smaller steps in dose titration and/or prescribe no more than 25% of the standard dose. OTHER CASES: 1. no action required
CYP2D6 UMmetoprololThe gene variation increases the conversion of metoprolol to inactive metabolites. This can increase the dose requirement. However, with a target dose of 200 mg/day, there was no effect on the blood pressure and hardly any effect on the reduction of the heart rate.1. use the maximum dose for the relevant indication as a target dose. 2. if the effectiveness is still insufficient: increase the dose based on effectiveness and side effects to 2.5 times the standard dose or select an alternative. Possible alternatives include: HEART FAILURE: bisoprolol or carvedilol. Bisoprolol: advantage: not metabolised by CYP2D6; disadvantage: elimination depends on the kidney function. Carvedilol: advantage: elimination does not depend on the kidney function; disadvantage: is metabolised (to a lesser extent than metoprolol) by CYP2D6. OTHER INDICATIONS: atenolol or bisoprolol. Neither is metabolised by CYP2D6.
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for metoprolol and CYP2D6:

\n
\n

The KNMP Pharmacogenetics Working Group considers genotyping before starting metoprolol to be potentially\nbeneficial for the prevention of side effects and drug effectiveness. Genotyping can be considered on an individual\npatient basis. If, however, the genotype is available, the KNMP Pharmacogenetics Working Group recommends\nadhering to the gene-drug guideline.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n

2011 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for metoprolol based on CYP2D6 genotype [Article:21412232]. They recommend either selecting another drug or dose reduction for poor and intermediate metabolizer patients, with dose titration for ultra metabolizers.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Phenotype (Genotype)Therapeutic Dose RecommendationLevel of EvidenceClinical Relevance
PM (2 inactive alleles)Heart failure: select alternative drug (e.g., bisoprolol, carvedilol) or reduce dose by 75%. Other indications: be alert to ADEs (e.g., bradycardia, cold extremities) or select alternative drug (e.g., atenolol, bisoprolol).Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Clinical effect (S): long-standing discomfort (48-168 hr) without permanent injury e.g. failure of therapy with tricyclic antidepressants, atypical antipsychotic drugs; extrapyramidal side effects; parkinsonism; ADE resulting from increased bioavailability of tricyclic antidepressants, metoprolol, propafenone (central effects e.g. dizziness); INR 4.5-6.0; neutropenia 1.0-1.5x109/l; leucopenia 2.0-3.0x109/l; thrombocytopenia 50-75x109/l.
IM (2 decreased activity alleles, or 1 active and 1 inactive allele, or 1 decreased activity and 1 inactive allele)Heart failure: select alternative drug (e.g., bisoprolol, carvedilol) or reduce dose by 50%. Other indications: be alert to ADEs (e.g., bradycardia, cold extremities) or select alternative drug (e.g., atenolol, bisoprolol).Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Clinical effect (S): short-lived discomfort (< 48 hr) without permanent injury: e.g. reduced decrease in resting heart rate; reduction in exercise tachycardia; decreased pain relief from oxycodone; ADE resulting from increased bioavailability of atomoxetine (decreased appetite, insomnia, sleep disturbance etc); neutropenia > 1.5x109/l; leucopenia > 3.0x109/l; thrombocytopenia > 75x109/l; moderate diarrhea not affecting daily activities; reduced glucose increase following oral glucose tolerance test.
UM (gene duplication in absence of inactive or decreased activity alleles)Heart failure: select alternative drug (e.g., bisoprolol, carvedilol) or titrate dose to a maximum of 250% of the normal dose in response to efficacy and ADE. Other indications: select alternative drug (e.g., atenolol, bisoprolol) or titrate dose to a maximum of 250% of the normal dose in response to efficacy and ADE.Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Clinical effect (S): long-standing discomfort (> 168 hr), permanent symptom or invalidating injury e.g. failure of prophylaxis of atrial fibrillation; venous thromboembolism; decreased effect of clopidogrel on inhibition of platelet aggregation; ADE resulting from increased bioavailability of phenytoin; INR > 6.0; neutropenia 0.5-1.0x109/l; leucopenia 1.0-2.0x109/l; thrombocytopenia 25-50x109/l; severe diarrhea.
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele TypeAlleles
active*1, *2, *33, *35
decreased activity*9, *10, *17, *29, *36, *41
inactive*3-*8, *11-*16, *19-*21, *38, *40, *42
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Use the maximum dose for the relevant indication as a target dose.

\n

If the effectiveness is still insufficient: increase the dose based on effectiveness and side effects to 2.5 times the standard dose or select an alternative.

\n

Possible alternatives include: HEART FAILURE: bisoprolol or carvedilol. Bisoprolol: advantage: not metabolised by CYP2D6; disadvantage: elimination depends on the kidney function. Carvedilol: advantage: elimination does not depend on the kidney function; disadvantage: is metabolised (to a lesser extent than metoprolol) by CYP2D6. OTHER INDICATIONS: atenolol or bisoprolol. Neither is metabolised by CYP2D6.

\n", + "id" : 1452104100, + "html" : "

If a GRADUAL REDUCTION in HEART RATE is desired, or in the event of SYMPTOMATIC BRADYCARDIA:

\n\n

OTHER CASES:

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If a GRADUAL REDUCTION in HEART RATE is desired, or in the event of SYMPTOMATIC BRADYCARDIA:

\n\n

OTHER CASES:

\n\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166302523", + "name" : "Recommendation Annotation PA166302523", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501929, + "description" : "Not Applicable", + "parents" : [], + "resource" : "Guideline Strength", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", + "valid" : true, + "version" : 1 + }, + "dosingInformation" : true, + "implications" : [ + "The gene variation reduces the conversion of metoprolol to inactive metabolites. However, the clinical consequences are limited mainly to the occurrence of asymptomatic bradycardia." + ], + "lookupKey" : {"CYP2D6": "0.5"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA450480", + "name" : "metoprolol", + "version" : 37 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104995", + "name" : "Annotation of DPWG Guideline for metoprolol and CYP2D6", + "version" : 103 + }, + "text" : { + "id" : 1452104102, + "html" : "

If a GRADUAL REDUCTION in HEART RATE is desired, or in the event of SYMPTOMATIC BRADYCARDIA:

\n\n

OTHER CASES:

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Use the maximum dose for the relevant indication as a target dose.

\n

If the effectiveness is still insufficient: increase the dose based on effectiveness and side effects to 2.5 times the standard dose or select an alternative.

\n

Possible alternatives include: HEART FAILURE: bisoprolol or carvedilol. Bisoprolol: advantage: not metabolised by CYP2D6; disadvantage: elimination depends on the kidney function. Carvedilol: advantage: elimination does not depend on the kidney function; disadvantage: is metabolised (to a lesser extent than metoprolol) by CYP2D6. OTHER INDICATIONS: atenolol or bisoprolol. Neither is metabolised by CYP2D6.

\n", + "id" : 1452104104, + "html" : "

If a GRADUAL REDUCTION in HEART RATE is desired, or in the event of SYMPTOMATIC BRADYCARDIA:

\n\n

OTHER CASES:

\n\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302528", - "name" : "Recommendation Annotation PA166302528", + "id" : "PA166302526", + "name" : "Recommendation Annotation PA166302526", "alternateDrugAvailable" : false, "classification" : { "id" : 1448526251, @@ -122754,24 +124048,24 @@ "implications" : [ "The guideline does not provide a description of the impact of a normal metabolizer phenotype on metoprolol." ], - "lookupKey" : {"CYP2D6": "2.0"}, + "lookupKey" : {"CYP2D6": "1.25"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450480", "name" : "metoprolol", - "version" : 15 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104995", "name" : "Annotation of DPWG Guideline for metoprolol and CYP2D6", - "version" : 35 + "version" : 103 }, "text" : { - "id" : 1452104107, + "id" : 1452104105, "html" : "

The guideline does not provide a recommendation for metoprolol in normal metabolizers.

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Use the maximum dose for the relevant indication as a target dose.

\n

If the effectiveness is still insufficient: increase the dose based on effectiveness and side effects to 2.5 times the standard dose or select an alternative.

\n

Possible alternatives include: HEART FAILURE: bisoprolol or carvedilol. Bisoprolol: advantage: not metabolised by CYP2D6; disadvantage: elimination depends on the kidney function. Carvedilol: advantage: elimination does not depend on the kidney function; disadvantage: is metabolised (to a lesser extent than metoprolol) by CYP2D6. OTHER INDICATIONS: atenolol or bisoprolol. Neither is metabolised by CYP2D6.

\n", + "id" : 1452104106, + "html" : "

The guideline does not provide a recommendation for metoprolol in normal metabolizers.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302523", - "name" : "Recommendation Annotation PA166302523", + "id" : "PA166302528", + "name" : "Recommendation Annotation PA166302528", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "The gene variation reduces the conversion of metoprolol to inactive metabolites. However, the clinical consequences are limited mainly to the occurrence of asymptomatic bradycardia." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on metoprolol." ], - "lookupKey" : {"CYP2D6": "0.5"}, + "lookupKey" : {"CYP2D6": "2.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450480", "name" : "metoprolol", - "version" : 15 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104995", "name" : "Annotation of DPWG Guideline for metoprolol and CYP2D6", - "version" : 35 + "version" : 103 }, "text" : { - "id" : 1452104102, - "html" : "

If a GRADUAL REDUCTION in HEART RATE is desired, or in the event of SYMPTOMATIC BRADYCARDIA:

\n\n

OTHER CASES:

\n\n", + "id" : 1452104107, + "html" : "

The guideline does not provide a recommendation for metoprolol in normal metabolizers.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302536", - "name" : "Recommendation Annotation PA166302536", - "alternateDrugAvailable" : true, + "id" : "PA166302529", + "name" : "Recommendation Annotation PA166302529", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "The gene variation increases the conversion of metoprolol to inactive metabolites. This can increase the dose requirement. However, with a target dose of 200 mg/day, there was no effect on the blood pressure and hardly any effect on the reduction of the heart rate." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on metoprolol." ], - "lookupKey" : {"CYP2D6": "≥4.0"}, + "lookupKey" : {"CYP2D6": "2.25"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450480", "name" : "metoprolol", - "version" : 15 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104995", "name" : "Annotation of DPWG Guideline for metoprolol and CYP2D6", - "version" : 35 + "version" : 103 }, "text" : { - "id" : 1452104115, - "html" : "

Use the maximum dose for the relevant indication as a target dose.

\n

If the effectiveness is still insufficient: increase the dose based on effectiveness and side effects to 2.5 times the standard dose or select an alternative.

\n

Possible alternatives include: HEART FAILURE: bisoprolol or carvedilol. Bisoprolol: advantage: not metabolised by CYP2D6; disadvantage: elimination depends on the kidney function. Carvedilol: advantage: elimination does not depend on the kidney function; disadvantage: is metabolised (to a lesser extent than metoprolol) by CYP2D6. OTHER INDICATIONS: atenolol or bisoprolol. Neither is metabolised by CYP2D6.

\n", + "id" : 1452104108, + "html" : "

The guideline does not provide a recommendation for metoprolol in normal metabolizers.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302527", - "name" : "Recommendation Annotation PA166302527", + "id" : "PA166302530", + "name" : "Recommendation Annotation PA166302530", "alternateDrugAvailable" : false, "classification" : { "id" : 1448526251, @@ -122921,24 +124212,24 @@ "implications" : [ "The guideline does not provide a description of the impact of a normal metabolizer phenotype on metoprolol." ], - "lookupKey" : {"CYP2D6": "1.5"}, + "lookupKey" : {"CYP2D6": "2.5"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450480", "name" : "metoprolol", - "version" : 15 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104995", "name" : "Annotation of DPWG Guideline for metoprolol and CYP2D6", - "version" : 35 + "version" : 103 }, "text" : { - "id" : 1452104106, + "id" : 1452104109, "html" : "

The guideline does not provide a recommendation for metoprolol in normal metabolizers.

\n", "version" : 0 }, @@ -122970,14 +124261,14 @@ "objCls" : "Chemical", "id" : "PA450480", "name" : "metoprolol", - "version" : 15 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104995", "name" : "Annotation of DPWG Guideline for metoprolol and CYP2D6", - "version" : 35 + "version" : 103 }, "text" : { "id" : 1452104110, @@ -122988,9 +124279,9 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302522", - "name" : "Recommendation Annotation PA166302522", - "alternateDrugAvailable" : false, + "id" : "PA166302532", + "name" : "Recommendation Annotation PA166302532", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -123003,35 +124294,35 @@ }, "dosingInformation" : true, "implications" : [ - "The gene variation reduces the conversion of metoprolol to inactive metabolites. However, the clinical consequences are limited mainly to the occurrence of asymptomatic bradycardia." + "The gene variation increases the conversion of metoprolol to inactive metabolites. This can increase the dose requirement. However, with a target dose of 200 mg/day, there was no effect on the blood pressure and hardly any effect on the reduction of the heart rate." ], - "lookupKey" : {"CYP2D6": "0.25"}, + "lookupKey" : {"CYP2D6": "4.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450480", "name" : "metoprolol", - "version" : 15 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104995", "name" : "Annotation of DPWG Guideline for metoprolol and CYP2D6", - "version" : 35 + "version" : 103 }, "text" : { - "id" : 1452104101, - "html" : "

If a GRADUAL REDUCTION in HEART RATE is desired, or in the event of SYMPTOMATIC BRADYCARDIA:

\n\n

OTHER CASES:

\n\n", + "id" : 1452104111, + "html" : "

Use the maximum dose for the relevant indication as a target dose.

\n

If the effectiveness is still insufficient: increase the dose based on effectiveness and side effects to 2.5 times the standard dose or select an alternative.

\n

Possible alternatives include: HEART FAILURE: bisoprolol or carvedilol. Bisoprolol: advantage: not metabolised by CYP2D6; disadvantage: elimination depends on the kidney function. Carvedilol: advantage: elimination does not depend on the kidney function; disadvantage: is metabolised (to a lesser extent than metoprolol) by CYP2D6. OTHER INDICATIONS: atenolol or bisoprolol. Neither is metabolised by CYP2D6.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302535", - "name" : "Recommendation Annotation PA166302535", + "id" : "PA166302533", + "name" : "Recommendation Annotation PA166302533", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -123047,24 +124338,24 @@ "implications" : [ "The gene variation increases the conversion of metoprolol to inactive metabolites. This can increase the dose requirement. However, with a target dose of 200 mg/day, there was no effect on the blood pressure and hardly any effect on the reduction of the heart rate." ], - "lookupKey" : {"CYP2D6": "≥3.5"}, + "lookupKey" : {"CYP2D6": "≥3.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450480", "name" : "metoprolol", - "version" : 15 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104995", "name" : "Annotation of DPWG Guideline for metoprolol and CYP2D6", - "version" : 35 + "version" : 103 }, "text" : { - "id" : 1452104114, + "id" : 1452104112, "html" : "

Use the maximum dose for the relevant indication as a target dose.

\n

If the effectiveness is still insufficient: increase the dose based on effectiveness and side effects to 2.5 times the standard dose or select an alternative.

\n

Possible alternatives include: HEART FAILURE: bisoprolol or carvedilol. Bisoprolol: advantage: not metabolised by CYP2D6; disadvantage: elimination depends on the kidney function. Carvedilol: advantage: elimination does not depend on the kidney function; disadvantage: is metabolised (to a lesser extent than metoprolol) by CYP2D6. OTHER INDICATIONS: atenolol or bisoprolol. Neither is metabolised by CYP2D6.

\n", "version" : 0 }, @@ -123072,91 +124363,51 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302526", - "name" : "Recommendation Annotation PA166302526", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 1448526251, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on metoprolol." - ], - "lookupKey" : {"CYP2D6": "1.25"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA450480", - "name" : "metoprolol", - "version" : 15 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166104995", - "name" : "Annotation of DPWG Guideline for metoprolol and CYP2D6", - "version" : 35 - }, - "text" : { - "id" : 1452104105, - "html" : "

The guideline does not provide a recommendation for metoprolol in normal metabolizers.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166302530", - "name" : "Recommendation Annotation PA166302530", - "alternateDrugAvailable" : false, + "id" : "PA166302534", + "name" : "Recommendation Annotation PA166302534", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on metoprolol." + "The gene variation increases the conversion of metoprolol to inactive metabolites. This can increase the dose requirement. However, with a target dose of 200 mg/day, there was no effect on the blood pressure and hardly any effect on the reduction of the heart rate." ], - "lookupKey" : {"CYP2D6": "2.5"}, + "lookupKey" : {"CYP2D6": "≥3.25"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450480", "name" : "metoprolol", - "version" : 15 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104995", "name" : "Annotation of DPWG Guideline for metoprolol and CYP2D6", - "version" : 35 + "version" : 103 }, "text" : { - "id" : 1452104109, - "html" : "

The guideline does not provide a recommendation for metoprolol in normal metabolizers.

\n", + "id" : 1452104113, + "html" : "

Use the maximum dose for the relevant indication as a target dose.

\n

If the effectiveness is still insufficient: increase the dose based on effectiveness and side effects to 2.5 times the standard dose or select an alternative.

\n

Possible alternatives include: HEART FAILURE: bisoprolol or carvedilol. Bisoprolol: advantage: not metabolised by CYP2D6; disadvantage: elimination depends on the kidney function. Carvedilol: advantage: elimination does not depend on the kidney function; disadvantage: is metabolised (to a lesser extent than metoprolol) by CYP2D6. OTHER INDICATIONS: atenolol or bisoprolol. Neither is metabolised by CYP2D6.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302521", - "name" : "Recommendation Annotation PA166302521", - "alternateDrugAvailable" : false, + "id" : "PA166302535", + "name" : "Recommendation Annotation PA166302535", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -123169,35 +124420,35 @@ }, "dosingInformation" : true, "implications" : [ - "The gene variation reduces the conversion of metoprolol to inactive metabolites. However, the clinical consequences are limited mainly to the occurrence of asymptomatic bradycardia." + "The gene variation increases the conversion of metoprolol to inactive metabolites. This can increase the dose requirement. However, with a target dose of 200 mg/day, there was no effect on the blood pressure and hardly any effect on the reduction of the heart rate." ], - "lookupKey" : {"CYP2D6": "0.0"}, + "lookupKey" : {"CYP2D6": "≥3.5"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450480", "name" : "metoprolol", - "version" : 15 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104995", "name" : "Annotation of DPWG Guideline for metoprolol and CYP2D6", - "version" : 35 + "version" : 103 }, "text" : { - "id" : 1452104100, - "html" : "

If a GRADUAL REDUCTION in HEART RATE is desired, or in the event of SYMPTOMATIC BRADYCARDIA:

\n\n

OTHER CASES:

\n\n", + "id" : 1452104114, + "html" : "

Use the maximum dose for the relevant indication as a target dose.

\n

If the effectiveness is still insufficient: increase the dose based on effectiveness and side effects to 2.5 times the standard dose or select an alternative.

\n

Possible alternatives include: HEART FAILURE: bisoprolol or carvedilol. Bisoprolol: advantage: not metabolised by CYP2D6; disadvantage: elimination depends on the kidney function. Carvedilol: advantage: elimination does not depend on the kidney function; disadvantage: is metabolised (to a lesser extent than metoprolol) by CYP2D6. OTHER INDICATIONS: atenolol or bisoprolol. Neither is metabolised by CYP2D6.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302534", - "name" : "Recommendation Annotation PA166302534", + "id" : "PA166302536", + "name" : "Recommendation Annotation PA166302536", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -123213,24 +124464,24 @@ "implications" : [ "The gene variation increases the conversion of metoprolol to inactive metabolites. This can increase the dose requirement. However, with a target dose of 200 mg/day, there was no effect on the blood pressure and hardly any effect on the reduction of the heart rate." ], - "lookupKey" : {"CYP2D6": "≥3.25"}, + "lookupKey" : {"CYP2D6": "≥4.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450480", "name" : "metoprolol", - "version" : 15 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104995", "name" : "Annotation of DPWG Guideline for metoprolol and CYP2D6", - "version" : 35 + "version" : 103 }, "text" : { - "id" : 1452104113, + "id" : 1452104115, "html" : "

Use the maximum dose for the relevant indication as a target dose.

\n

If the effectiveness is still insufficient: increase the dose based on effectiveness and side effects to 2.5 times the standard dose or select an alternative.

\n

Possible alternatives include: HEART FAILURE: bisoprolol or carvedilol. Bisoprolol: advantage: not metabolised by CYP2D6; disadvantage: elimination depends on the kidney function. Carvedilol: advantage: elimination does not depend on the kidney function; disadvantage: is metabolised (to a lesser extent than metoprolol) by CYP2D6. OTHER INDICATIONS: atenolol or bisoprolol. Neither is metabolised by CYP2D6.

\n", "version" : 0 }, @@ -123238,9 +124489,9 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302525", - "name" : "Recommendation Annotation PA166302525", - "alternateDrugAvailable" : false, + "id" : "PA166302537", + "name" : "Recommendation Annotation PA166302537", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -123253,27 +124504,27 @@ }, "dosingInformation" : true, "implications" : [ - "The gene variation reduces the conversion of metoprolol to inactive metabolites. However, the clinical consequences are limited mainly to the occurrence of asymptomatic bradycardia." + "The gene variation increases the conversion of metoprolol to inactive metabolites. This can increase the dose requirement. However, with a target dose of 200 mg/day, there was no effect on the blood pressure and hardly any effect on the reduction of the heart rate." ], - "lookupKey" : {"CYP2D6": "1.0"}, + "lookupKey" : {"CYP2D6": "≥5.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450480", "name" : "metoprolol", - "version" : 15 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104995", "name" : "Annotation of DPWG Guideline for metoprolol and CYP2D6", - "version" : 35 + "version" : 103 }, "text" : { - "id" : 1452104104, - "html" : "

If a GRADUAL REDUCTION in HEART RATE is desired, or in the event of SYMPTOMATIC BRADYCARDIA:

\n\n

OTHER CASES:

\n\n", + "id" : 1452104116, + "html" : "

Use the maximum dose for the relevant indication as a target dose.

\n

If the effectiveness is still insufficient: increase the dose based on effectiveness and side effects to 2.5 times the standard dose or select an alternative.

\n

Possible alternatives include: HEART FAILURE: bisoprolol or carvedilol. Bisoprolol: advantage: not metabolised by CYP2D6; disadvantage: elimination depends on the kidney function. Carvedilol: advantage: elimination does not depend on the kidney function; disadvantage: is metabolised (to a lesser extent than metoprolol) by CYP2D6. OTHER INDICATIONS: atenolol or bisoprolol. Neither is metabolised by CYP2D6.

\n", "version" : 0 }, "version" : 0 @@ -123304,14 +124555,14 @@ "objCls" : "Chemical", "id" : "PA450480", "name" : "metoprolol", - "version" : 15 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104995", "name" : "Annotation of DPWG Guideline for metoprolol and CYP2D6", - "version" : 35 + "version" : 103 }, "text" : { "id" : 1452104117, @@ -123319,47 +124570,6 @@ "version" : 0 }, "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166302529", - "name" : "Recommendation Annotation PA166302529", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 1448526251, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on metoprolol." - ], - "lookupKey" : {"CYP2D6": "2.25"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA450480", - "name" : "metoprolol", - "version" : 15 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166104995", - "name" : "Annotation of DPWG Guideline for metoprolol and CYP2D6", - "version" : 35 - }, - "text" : { - "id" : 1452104108, - "html" : "

The guideline does not provide a recommendation for metoprolol in normal metabolizers.

\n", - "version" : 0 - }, - "version" : 0 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166104995" @@ -123631,7 +124841,7 @@ "objCls" : "Chemical", "id" : "PA450657", "name" : "nortriptyline", - "version" : 7 + "version" : 36 } ], "relatedGenes" : [ @@ -123640,30 +124850,30 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "DPWG", "summaryMarkdown" : { "id" : 1447981930, "html" : "

The Dutch Pharmacogenetics Working Group Guideline for nortriptyline recommends a dose reduction for CYP2D6 poor or intermediate metabolizer patients. For CYP2D6 ultrarapid metabolizers, select an alternative drug or use 1.7 times the standard dose. Monitoring of nortriptyline and 10-hydroxynortriptyline plasma concentrations is recommended.

\n", - "version" : 1 + "version" : 2 }, "terms" : [], "textMarkdown" : { "id" : 1447981929, "html" : "

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

\n

November 2018 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for nortriptyline based on CYP2D6 genotype. They recommend a dose increase or use of an alternative antidepressant in CYP2D6 ultrarapid metabolizers (UMs) and a dose reduction in CYP2D6 poor metabolizers (PMs). Monitoring of nortriptyline and Z-10-hydroxynortriptyline plasma concentrations is also recommended.

\n

Wording in table taken from the Dutch guidelines November 2018 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
CYP2D6 UMnortriptylineThe risk of ineffectiveness and cardiotoxic effects may be increased. The gene variation leads to a decrease in the plasma concentration of nortriptyline and an increase in the plasma concentration of the cardiotoxic metabolite Z-10-hydroxynortriptyline.Use 1.7 times the standard dose and monitor the effect and side effects or the plasma concentration of nortriptyline and be alert to an increase in the plasma concentration of the cardiotoxic metabolite Z-10-hydroxynortriptyline. Plasma concentrations of Z-hydroxynortriptyline exceeding 40 ng/mL are considered toxic.
If a dose increase is not wanted due to the cardiotoxic hydroxy metabolite: avoid nortriptyline. Antidepressants that are not metabolised via CYP2D6 - or to a lesser extent - include, for example, citalopram and sertraline.
CYP2D6 IMnortriptylineThe risk of side effects may be increased, because the gene variation leads to an increased plasma concentration of nortriptyline.Use 60% of the standard dose and monitor the effect and side effects or the plasma concentration of nortriptyline in order to set the maintenance dose.
The therapeutic range of nortriptyline is 50-150 ng/mL. Values exceeding 250 ng/mL are considered toxic.
CYP2D6 PMnortriptylineThe risk of side effects may be increased, because the gene variation leads to an increased plasma concentration of nortriptyline.Use 40% of the standard dose and monitor the effect and side effects or the plasma concentration of nortriptyline in order to set the maintenance dose.
The therapeutic range of nortriptyline is 50-150 ng/mL. Values exceeding 250 ng/mL are considered toxic.
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for nortriptyline and CYP2D6:

\n
\n

The Dutch Pharmacogenetics Working Group considers genotyping before starting nortriptyline to be potentially beneficial for the prevention of side effects and for drug efficacy. Genotyping can be considered on an individual patient basis. If, however, the genotype is available, the Dutch Pharmacogenetics Working Group recommends adhering to the gene-drug guideline.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n

2011 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for nortriptyline based on CYP2D6 genotype [Article:21412232]. They recommend reducing the dose for poor and intermediate metabolizer patients and selecting an alternative drug or increasing the dose for ultra metabolizers.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Phenotype (Genotype)Therapeutic Dose RecommendationLevel of EvidenceClinical Relevance
PM (2 inactive alleles)Reduce dose by 60% and monitor nortriptyline + 10-hydroxynortriptyline plasma concentrations.Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Clinical effect (S): long-standing discomfort (48-168 hr) without permanent injury e.g. failure of therapy with tricyclic antidepressants, atypical antipsychotic drugs; extrapyramidal side effects; parkinsonism; ADE resulting from increased bioavailability of tricyclic antidepressants, metoprolol, propafenone (central effects e.g. dizziness); INR 4.5-6.0; neutropenia 1.0-1.5x109/l; leucopenia 2.0-3.0x109/l; thrombocytopenia 50-75x109/l.
IM (2 decreased activity alleles, or 1 active and 1 inactive allele, or 1 decreased activity and 1 inactive allele)Reduce dose by 40% and monitor nortriptyline + 10-hydroxynortriptyline plasma concentrations.Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Clinical effect (S): long-standing discomfort (48-168 hr) without permanent injury e.g. failure of therapy with tricyclic antidepressants, atypical antipsychotic drugs; extrapyramidal side effects; parkinsonism; ADE resulting from increased bioavailability of tricyclic antidepressants, metoprolol, propafenone (central effects e.g. dizziness); INR 4.5-6.0; neutropenia 1.0-1.5x109/l; leucopenia 2.0-3.0x109/l; thrombocytopenia 50-75x109/l.
UM (gene duplication in absence of inactive or decreased activity alleles)Select alternative drug (e.g., citalopram, sertraline) or increase dose by 60% and monitor nortriptyline + 10-hydroxynortriptyline plasma concentrations.Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Clinical effect (S): long-standing discomfort (48-168 hr) without permanent injury e.g. failure of therapy with tricyclic antidepressants, atypical antipsychotic drugs; extrapyramidal side effects; parkinsonism; ADE resulting from increased bioavailability of tricyclic antidepressants, metoprolol, propafenone (central effects e.g. dizziness); INR 4.5-6.0; neutropenia 1.0-1.5x109/l; leucopenia 2.0-3.0x109/l; thrombocytopenia 50-75x109/l.
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele TypeAlleles
active*1, *2, *33, *35
decreased activity*9, *10, *17, *29, *36, *41
inactive*3-*8, *11-*16, *19-*21, *38, *40, *42
\n\n", - "version" : 17 + "version" : 22 }, "userId" : "katrin", - "version" : 35 + "version" : 98 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166302555", - "name" : "Recommendation Annotation PA166302555", - "alternateDrugAvailable" : true, + "id" : "PA166302539", + "name" : "Recommendation Annotation PA166302539", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -123676,77 +124886,78 @@ }, "dosingInformation" : true, "implications" : [ - "The risk of ineffectiveness and cardiotoxic effects may be increased. The gene variation leads to a decrease in the plasma concentration of nortriptyline and an increase in the plasma concentration of the cardiotoxic metabolite Z-10-hydroxynortriptyline." + "The risk of side effects may be increased, because the gene variation leads to an increased plasma concentration of nortriptyline." ], - "lookupKey" : {"CYP2D6": "≥5.0"}, + "lookupKey" : {"CYP2D6": "0.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450657", "name" : "nortriptyline", - "version" : 7 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104961", "name" : "Annotation of DPWG Guideline for nortriptyline and CYP2D6", - "version" : 35 + "version" : 98 }, "text" : { - "id" : 1452104134, - "html" : "

Use 1.7 times the standard dose and monitor the effect and side effects or the plasma concentration of nortriptyline and be alert to an increase in the plasma concentration of the cardiotoxic metabolite Z-10-hydroxynortriptyline. Plasma concentrations of Z-hydroxynortriptyline exceeding 40 ng/mL are considered toxic.

\n

If a dose increase is not wanted due to the cardiotoxic hydroxy metabolite: avoid nortriptyline. Antidepressants that are not metabolised via CYP2D6 - or to a lesser extent - include, for example, citalopram and sertraline.

\n", + "id" : 1452104118, + "html" : "

Use 40% of the standard dose and monitor the effect and side effects or the plasma concentration of nortriptyline in order to set the maintenance dose. The therapeutic range of nortriptyline is 50-150 ng/mL. Values exceeding 250 ng/mL are considered toxic.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302546", - "name" : "Recommendation Annotation PA166302546", + "id" : "PA166302540", + "name" : "Recommendation Annotation PA166302540", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on nortriptyline." + "The risk of side effects may be increased, because the gene variation leads to an increased plasma concentration of nortriptyline." ], - "lookupKey" : {"CYP2D6": "2.0"}, + "lookupKey" : {"CYP2D6": "0.25"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450657", "name" : "nortriptyline", - "version" : 7 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104961", "name" : "Annotation of DPWG Guideline for nortriptyline and CYP2D6", - "version" : 35 + "version" : 98 }, "text" : { - "id" : 1452104125, - "html" : "

The guideline does not provide a recommendation for nortriptyline in normal metabolizers.

\n", + "id" : 1452104119, + "html" : "

Use 60% of the standard dose and monitor the effect and side effects or the plasma concentration of nortriptyline in order to set the maintenance dose. The therapeutic range of nortriptyline is 50-150 ng/mL. Values exceeding 250 ng/mL are considered toxic.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302550", - "name" : "Recommendation Annotation PA166302550", - "alternateDrugAvailable" : true, + "id" : "PA166302541", + "name" : "Recommendation Annotation PA166302541", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -123759,35 +124970,35 @@ }, "dosingInformation" : true, "implications" : [ - "The risk of ineffectiveness and cardiotoxic effects may be increased. The gene variation leads to a decrease in the plasma concentration of nortriptyline and an increase in the plasma concentration of the cardiotoxic metabolite Z-10-hydroxynortriptyline." + "The risk of side effects may be increased, because the gene variation leads to an increased plasma concentration of nortriptyline." ], - "lookupKey" : {"CYP2D6": "4.0"}, + "lookupKey" : {"CYP2D6": "0.5"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450657", "name" : "nortriptyline", - "version" : 7 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104961", "name" : "Annotation of DPWG Guideline for nortriptyline and CYP2D6", - "version" : 35 + "version" : 98 }, "text" : { - "id" : 1452104129, - "html" : "

Use 1.7 times the standard dose and monitor the effect and side effects or the plasma concentration of nortriptyline and be alert to an increase in the plasma concentration of the cardiotoxic metabolite Z-10-hydroxynortriptyline. Plasma concentrations of Z-hydroxynortriptyline exceeding 40 ng/mL are considered toxic.

\n

If a dose increase is not wanted due to the cardiotoxic hydroxy metabolite: avoid nortriptyline. Antidepressants that are not metabolised via CYP2D6 - or to a lesser extent - include, for example, citalopram and sertraline.

\n", + "id" : 1452104120, + "html" : "

Use 60% of the standard dose and monitor the effect and side effects or the plasma concentration of nortriptyline in order to set the maintenance dose. The therapeutic range of nortriptyline is 50-150 ng/mL. Values exceeding 250 ng/mL are considered toxic.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302541", - "name" : "Recommendation Annotation PA166302541", + "id" : "PA166302542", + "name" : "Recommendation Annotation PA166302542", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -123803,24 +125014,24 @@ "implications" : [ "The risk of side effects may be increased, because the gene variation leads to an increased plasma concentration of nortriptyline." ], - "lookupKey" : {"CYP2D6": "0.5"}, + "lookupKey" : {"CYP2D6": "0.75"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450657", "name" : "nortriptyline", - "version" : 7 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104961", "name" : "Annotation of DPWG Guideline for nortriptyline and CYP2D6", - "version" : 35 + "version" : 98 }, "text" : { - "id" : 1452104120, + "id" : 1452104121, "html" : "

Use 60% of the standard dose and monitor the effect and side effects or the plasma concentration of nortriptyline in order to set the maintenance dose. The therapeutic range of nortriptyline is 50-150 ng/mL. Values exceeding 250 ng/mL are considered toxic.

\n", "version" : 0 }, @@ -123828,9 +125039,9 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302554", - "name" : "Recommendation Annotation PA166302554", - "alternateDrugAvailable" : true, + "id" : "PA166302543", + "name" : "Recommendation Annotation PA166302543", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -123843,27 +125054,68 @@ }, "dosingInformation" : true, "implications" : [ - "The risk of ineffectiveness and cardiotoxic effects may be increased. The gene variation leads to a decrease in the plasma concentration of nortriptyline and an increase in the plasma concentration of the cardiotoxic metabolite Z-10-hydroxynortriptyline." + "The risk of side effects may be increased, because the gene variation leads to an increased plasma concentration of nortriptyline." ], - "lookupKey" : {"CYP2D6": "≥4.0"}, + "lookupKey" : {"CYP2D6": "1.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450657", "name" : "nortriptyline", - "version" : 7 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104961", "name" : "Annotation of DPWG Guideline for nortriptyline and CYP2D6", - "version" : 35 + "version" : 98 }, "text" : { - "id" : 1452104133, - "html" : "

Use 1.7 times the standard dose and monitor the effect and side effects or the plasma concentration of nortriptyline and be alert to an increase in the plasma concentration of the cardiotoxic metabolite Z-10-hydroxynortriptyline. Plasma concentrations of Z-hydroxynortriptyline exceeding 40 ng/mL are considered toxic.

\n

If a dose increase is not wanted due to the cardiotoxic hydroxy metabolite: avoid nortriptyline. Antidepressants that are not metabolised via CYP2D6 - or to a lesser extent - include, for example, citalopram and sertraline.

\n", + "id" : 1452104122, + "html" : "

Use 60% of the standard dose and monitor the effect and side effects or the plasma concentration of nortriptyline in order to set the maintenance dose. The therapeutic range of nortriptyline is 50-150 ng/mL. Values exceeding 250 ng/mL are considered toxic.

\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166302544", + "name" : "Recommendation Annotation PA166302544", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 1448526251, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : false, + "implications" : [ + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on nortriptyline." + ], + "lookupKey" : {"CYP2D6": "1.25"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA450657", + "name" : "nortriptyline", + "version" : 36 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104961", + "name" : "Annotation of DPWG Guideline for nortriptyline and CYP2D6", + "version" : 98 + }, + "text" : { + "id" : 1452104123, + "html" : "

The guideline does not provide a recommendation for nortriptyline in normal metabolizers.

\n", "version" : 0 }, "version" : 0 @@ -123893,14 +125145,14 @@ "objCls" : "Chemical", "id" : "PA450657", "name" : "nortriptyline", - "version" : 7 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104961", "name" : "Annotation of DPWG Guideline for nortriptyline and CYP2D6", - "version" : 35 + "version" : 98 }, "text" : { "id" : 1452104124, @@ -123911,134 +125163,90 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302549", - "name" : "Recommendation Annotation PA166302549", - "alternateDrugAvailable" : true, + "id" : "PA166302546", + "name" : "Recommendation Annotation PA166302546", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "The risk of ineffectiveness and cardiotoxic effects may be increased. The gene variation leads to a decrease in the plasma concentration of nortriptyline and an increase in the plasma concentration of the cardiotoxic metabolite Z-10-hydroxynortriptyline." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on nortriptyline." ], - "lookupKey" : {"CYP2D6": "3.0"}, + "lookupKey" : {"CYP2D6": "2.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450657", "name" : "nortriptyline", - "version" : 7 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104961", "name" : "Annotation of DPWG Guideline for nortriptyline and CYP2D6", - "version" : 35 + "version" : 98 }, "text" : { - "id" : 1452104128, - "html" : "

Use 1.7 times the standard dose and monitor the effect and side effects or the plasma concentration of nortriptyline and be alert to an increase in the plasma concentration of the cardiotoxic metabolite Z-10-hydroxynortriptyline. Plasma concentrations of Z-hydroxynortriptyline exceeding 40 ng/mL are considered toxic.

\n

If a dose increase is not wanted due to the cardiotoxic hydroxy metabolite: avoid nortriptyline. Antidepressants that are not metabolised via CYP2D6 - or to a lesser extent - include, for example, citalopram and sertraline.

\n", + "id" : 1452104125, + "html" : "

The guideline does not provide a recommendation for nortriptyline in normal metabolizers.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302540", - "name" : "Recommendation Annotation PA166302540", + "id" : "PA166302547", + "name" : "Recommendation Annotation PA166302547", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 - }, - "dosingInformation" : true, - "implications" : [ - "The risk of side effects may be increased, because the gene variation leads to an increased plasma concentration of nortriptyline." - ], - "lookupKey" : {"CYP2D6": "0.25"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA450657", - "name" : "nortriptyline", - "version" : 7 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166104961", - "name" : "Annotation of DPWG Guideline for nortriptyline and CYP2D6", - "version" : 35 - }, - "text" : { - "id" : 1452104119, - "html" : "

Use 60% of the standard dose and monitor the effect and side effects or the plasma concentration of nortriptyline in order to set the maintenance dose. The therapeutic range of nortriptyline is 50-150 ng/mL. Values exceeding 250 ng/mL are considered toxic.

\n", "version" : 0 }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166302553", - "name" : "Recommendation Annotation PA166302553", - "alternateDrugAvailable" : true, - "classification" : { - "id" : 981501929, - "description" : "Not Applicable", - "parents" : [], - "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", - "valid" : true, - "version" : 1 - }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "The risk of ineffectiveness and cardiotoxic effects may be increased. The gene variation leads to a decrease in the plasma concentration of nortriptyline and an increase in the plasma concentration of the cardiotoxic metabolite Z-10-hydroxynortriptyline." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on nortriptyline." ], - "lookupKey" : {"CYP2D6": "≥3.5"}, + "lookupKey" : {"CYP2D6": "2.25"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450657", "name" : "nortriptyline", - "version" : 7 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104961", "name" : "Annotation of DPWG Guideline for nortriptyline and CYP2D6", - "version" : 35 + "version" : 98 }, "text" : { - "id" : 1452104132, - "html" : "

Use 1.7 times the standard dose and monitor the effect and side effects or the plasma concentration of nortriptyline and be alert to an increase in the plasma concentration of the cardiotoxic metabolite Z-10-hydroxynortriptyline. Plasma concentrations of Z-hydroxynortriptyline exceeding 40 ng/mL are considered toxic.

\n

If a dose increase is not wanted due to the cardiotoxic hydroxy metabolite: avoid nortriptyline. Antidepressants that are not metabolised via CYP2D6 - or to a lesser extent - include, for example, citalopram and sertraline.

\n", + "id" : 1452104126, + "html" : "

The guideline does not provide a recommendation for nortriptyline in normal metabolizers.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302544", - "name" : "Recommendation Annotation PA166302544", + "id" : "PA166302548", + "name" : "Recommendation Annotation PA166302548", "alternateDrugAvailable" : false, "classification" : { "id" : 1448526251, @@ -124053,24 +125261,24 @@ "implications" : [ "The guideline does not provide a description of the impact of a normal metabolizer phenotype on nortriptyline." ], - "lookupKey" : {"CYP2D6": "1.25"}, + "lookupKey" : {"CYP2D6": "2.5"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450657", "name" : "nortriptyline", - "version" : 7 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104961", "name" : "Annotation of DPWG Guideline for nortriptyline and CYP2D6", - "version" : 35 + "version" : 98 }, "text" : { - "id" : 1452104123, + "id" : 1452104127, "html" : "

The guideline does not provide a recommendation for nortriptyline in normal metabolizers.

\n", "version" : 0 }, @@ -124078,50 +125286,51 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302548", - "name" : "Recommendation Annotation PA166302548", - "alternateDrugAvailable" : false, + "id" : "PA166302549", + "name" : "Recommendation Annotation PA166302549", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on nortriptyline." + "The risk of ineffectiveness and cardiotoxic effects may be increased. The gene variation leads to a decrease in the plasma concentration of nortriptyline and an increase in the plasma concentration of the cardiotoxic metabolite Z-10-hydroxynortriptyline." ], - "lookupKey" : {"CYP2D6": "2.5"}, + "lookupKey" : {"CYP2D6": "3.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450657", "name" : "nortriptyline", - "version" : 7 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104961", "name" : "Annotation of DPWG Guideline for nortriptyline and CYP2D6", - "version" : 35 + "version" : 98 }, "text" : { - "id" : 1452104127, - "html" : "

The guideline does not provide a recommendation for nortriptyline in normal metabolizers.

\n", + "id" : 1452104128, + "html" : "

Use 1.7 times the standard dose and monitor the effect and side effects or the plasma concentration of nortriptyline and be alert to an increase in the plasma concentration of the cardiotoxic metabolite Z-10-hydroxynortriptyline. Plasma concentrations of Z-hydroxynortriptyline exceeding 40 ng/mL are considered toxic.

\n

If a dose increase is not wanted due to the cardiotoxic hydroxy metabolite: avoid nortriptyline. Antidepressants that are not metabolised via CYP2D6 - or to a lesser extent - include, for example, citalopram and sertraline.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302539", - "name" : "Recommendation Annotation PA166302539", - "alternateDrugAvailable" : false, + "id" : "PA166302550", + "name" : "Recommendation Annotation PA166302550", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -124134,35 +125343,35 @@ }, "dosingInformation" : true, "implications" : [ - "The risk of side effects may be increased, because the gene variation leads to an increased plasma concentration of nortriptyline." + "The risk of ineffectiveness and cardiotoxic effects may be increased. The gene variation leads to a decrease in the plasma concentration of nortriptyline and an increase in the plasma concentration of the cardiotoxic metabolite Z-10-hydroxynortriptyline." ], - "lookupKey" : {"CYP2D6": "0.0"}, + "lookupKey" : {"CYP2D6": "4.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450657", "name" : "nortriptyline", - "version" : 7 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104961", "name" : "Annotation of DPWG Guideline for nortriptyline and CYP2D6", - "version" : 35 + "version" : 98 }, "text" : { - "id" : 1452104118, - "html" : "

Use 40% of the standard dose and monitor the effect and side effects or the plasma concentration of nortriptyline in order to set the maintenance dose. The therapeutic range of nortriptyline is 50-150 ng/mL. Values exceeding 250 ng/mL are considered toxic.

\n", + "id" : 1452104129, + "html" : "

Use 1.7 times the standard dose and monitor the effect and side effects or the plasma concentration of nortriptyline and be alert to an increase in the plasma concentration of the cardiotoxic metabolite Z-10-hydroxynortriptyline. Plasma concentrations of Z-hydroxynortriptyline exceeding 40 ng/mL are considered toxic.

\n

If a dose increase is not wanted due to the cardiotoxic hydroxy metabolite: avoid nortriptyline. Antidepressants that are not metabolised via CYP2D6 - or to a lesser extent - include, for example, citalopram and sertraline.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302552", - "name" : "Recommendation Annotation PA166302552", + "id" : "PA166302551", + "name" : "Recommendation Annotation PA166302551", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -124178,24 +125387,24 @@ "implications" : [ "The risk of ineffectiveness and cardiotoxic effects may be increased. The gene variation leads to a decrease in the plasma concentration of nortriptyline and an increase in the plasma concentration of the cardiotoxic metabolite Z-10-hydroxynortriptyline." ], - "lookupKey" : {"CYP2D6": "≥3.25"}, + "lookupKey" : {"CYP2D6": "≥3.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450657", "name" : "nortriptyline", - "version" : 7 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104961", "name" : "Annotation of DPWG Guideline for nortriptyline and CYP2D6", - "version" : 35 + "version" : 98 }, "text" : { - "id" : 1452104131, + "id" : 1452104130, "html" : "

Use 1.7 times the standard dose and monitor the effect and side effects or the plasma concentration of nortriptyline and be alert to an increase in the plasma concentration of the cardiotoxic metabolite Z-10-hydroxynortriptyline. Plasma concentrations of Z-hydroxynortriptyline exceeding 40 ng/mL are considered toxic.

\n

If a dose increase is not wanted due to the cardiotoxic hydroxy metabolite: avoid nortriptyline. Antidepressants that are not metabolised via CYP2D6 - or to a lesser extent - include, for example, citalopram and sertraline.

\n", "version" : 0 }, @@ -124203,9 +125412,9 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302543", - "name" : "Recommendation Annotation PA166302543", - "alternateDrugAvailable" : false, + "id" : "PA166302552", + "name" : "Recommendation Annotation PA166302552", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -124218,35 +125427,35 @@ }, "dosingInformation" : true, "implications" : [ - "The risk of side effects may be increased, because the gene variation leads to an increased plasma concentration of nortriptyline." + "The risk of ineffectiveness and cardiotoxic effects may be increased. The gene variation leads to a decrease in the plasma concentration of nortriptyline and an increase in the plasma concentration of the cardiotoxic metabolite Z-10-hydroxynortriptyline." ], - "lookupKey" : {"CYP2D6": "1.0"}, + "lookupKey" : {"CYP2D6": "≥3.25"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450657", "name" : "nortriptyline", - "version" : 7 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104961", "name" : "Annotation of DPWG Guideline for nortriptyline and CYP2D6", - "version" : 35 + "version" : 98 }, "text" : { - "id" : 1452104122, - "html" : "

Use 60% of the standard dose and monitor the effect and side effects or the plasma concentration of nortriptyline in order to set the maintenance dose. The therapeutic range of nortriptyline is 50-150 ng/mL. Values exceeding 250 ng/mL are considered toxic.

\n", + "id" : 1452104131, + "html" : "

Use 1.7 times the standard dose and monitor the effect and side effects or the plasma concentration of nortriptyline and be alert to an increase in the plasma concentration of the cardiotoxic metabolite Z-10-hydroxynortriptyline. Plasma concentrations of Z-hydroxynortriptyline exceeding 40 ng/mL are considered toxic.

\n

If a dose increase is not wanted due to the cardiotoxic hydroxy metabolite: avoid nortriptyline. Antidepressants that are not metabolised via CYP2D6 - or to a lesser extent - include, for example, citalopram and sertraline.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302556", - "name" : "Recommendation Annotation PA166302556", + "id" : "PA166302554", + "name" : "Recommendation Annotation PA166302554", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -124262,24 +125471,24 @@ "implications" : [ "The risk of ineffectiveness and cardiotoxic effects may be increased. The gene variation leads to a decrease in the plasma concentration of nortriptyline and an increase in the plasma concentration of the cardiotoxic metabolite Z-10-hydroxynortriptyline." ], - "lookupKey" : {"CYP2D6": "≥6.0"}, + "lookupKey" : {"CYP2D6": "≥4.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450657", "name" : "nortriptyline", - "version" : 7 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104961", "name" : "Annotation of DPWG Guideline for nortriptyline and CYP2D6", - "version" : 35 + "version" : 98 }, "text" : { - "id" : 1452104135, + "id" : 1452104133, "html" : "

Use 1.7 times the standard dose and monitor the effect and side effects or the plasma concentration of nortriptyline and be alert to an increase in the plasma concentration of the cardiotoxic metabolite Z-10-hydroxynortriptyline. Plasma concentrations of Z-hydroxynortriptyline exceeding 40 ng/mL are considered toxic.

\n

If a dose increase is not wanted due to the cardiotoxic hydroxy metabolite: avoid nortriptyline. Antidepressants that are not metabolised via CYP2D6 - or to a lesser extent - include, for example, citalopram and sertraline.

\n", "version" : 0 }, @@ -124287,49 +125496,50 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302547", - "name" : "Recommendation Annotation PA166302547", - "alternateDrugAvailable" : false, + "id" : "PA166302555", + "name" : "Recommendation Annotation PA166302555", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on nortriptyline." + "The risk of ineffectiveness and cardiotoxic effects may be increased. The gene variation leads to a decrease in the plasma concentration of nortriptyline and an increase in the plasma concentration of the cardiotoxic metabolite Z-10-hydroxynortriptyline." ], - "lookupKey" : {"CYP2D6": "2.25"}, + "lookupKey" : {"CYP2D6": "≥5.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450657", "name" : "nortriptyline", - "version" : 7 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104961", "name" : "Annotation of DPWG Guideline for nortriptyline and CYP2D6", - "version" : 35 + "version" : 98 }, "text" : { - "id" : 1452104126, - "html" : "

The guideline does not provide a recommendation for nortriptyline in normal metabolizers.

\n", + "id" : 1452104134, + "html" : "

Use 1.7 times the standard dose and monitor the effect and side effects or the plasma concentration of nortriptyline and be alert to an increase in the plasma concentration of the cardiotoxic metabolite Z-10-hydroxynortriptyline. Plasma concentrations of Z-hydroxynortriptyline exceeding 40 ng/mL are considered toxic.

\n

If a dose increase is not wanted due to the cardiotoxic hydroxy metabolite: avoid nortriptyline. Antidepressants that are not metabolised via CYP2D6 - or to a lesser extent - include, for example, citalopram and sertraline.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302551", - "name" : "Recommendation Annotation PA166302551", + "id" : "PA166302556", + "name" : "Recommendation Annotation PA166302556", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -124345,24 +125555,24 @@ "implications" : [ "The risk of ineffectiveness and cardiotoxic effects may be increased. The gene variation leads to a decrease in the plasma concentration of nortriptyline and an increase in the plasma concentration of the cardiotoxic metabolite Z-10-hydroxynortriptyline." ], - "lookupKey" : {"CYP2D6": "≥3.0"}, + "lookupKey" : {"CYP2D6": "≥6.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450657", "name" : "nortriptyline", - "version" : 7 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104961", "name" : "Annotation of DPWG Guideline for nortriptyline and CYP2D6", - "version" : 35 + "version" : 98 }, "text" : { - "id" : 1452104130, + "id" : 1452104135, "html" : "

Use 1.7 times the standard dose and monitor the effect and side effects or the plasma concentration of nortriptyline and be alert to an increase in the plasma concentration of the cardiotoxic metabolite Z-10-hydroxynortriptyline. Plasma concentrations of Z-hydroxynortriptyline exceeding 40 ng/mL are considered toxic.

\n

If a dose increase is not wanted due to the cardiotoxic hydroxy metabolite: avoid nortriptyline. Antidepressants that are not metabolised via CYP2D6 - or to a lesser extent - include, for example, citalopram and sertraline.

\n", "version" : 0 }, @@ -124370,9 +125580,9 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302542", - "name" : "Recommendation Annotation PA166302542", - "alternateDrugAvailable" : false, + "id" : "PA166302553", + "name" : "Recommendation Annotation PA166302553", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -124385,30 +125595,30 @@ }, "dosingInformation" : true, "implications" : [ - "The risk of side effects may be increased, because the gene variation leads to an increased plasma concentration of nortriptyline." + "The risk of ineffectiveness and cardiotoxic effects may be increased. The gene variation leads to a decrease in the plasma concentration of nortriptyline and an increase in the plasma concentration of the cardiotoxic metabolite Z-10-hydroxynortriptyline." ], - "lookupKey" : {"CYP2D6": "0.75"}, + "lookupKey" : {"CYP2D6": "≥3.5"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450657", "name" : "nortriptyline", - "version" : 7 + "version" : 36 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104961", "name" : "Annotation of DPWG Guideline for nortriptyline and CYP2D6", - "version" : 35 + "version" : 98 }, "text" : { - "id" : 1452104121, - "html" : "

Use 60% of the standard dose and monitor the effect and side effects or the plasma concentration of nortriptyline in order to set the maintenance dose. The therapeutic range of nortriptyline is 50-150 ng/mL. Values exceeding 250 ng/mL are considered toxic.

\n", + "id" : 1452104132, + "html" : "

Use 1.7 times the standard dose and monitor the effect and side effects or the plasma concentration of nortriptyline and be alert to an increase in the plasma concentration of the cardiotoxic metabolite Z-10-hydroxynortriptyline. Plasma concentrations of Z-hydroxynortriptyline exceeding 40 ng/mL are considered toxic.

\n

If a dose increase is not wanted due to the cardiotoxic hydroxy metabolite: avoid nortriptyline. Antidepressants that are not metabolised via CYP2D6 - or to a lesser extent - include, for example, citalopram and sertraline.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166104961" @@ -124603,7 +125813,7 @@ "objCls" : "Chemical", "id" : "PA450704", "name" : "omeprazole", - "version" : 21 + "version" : 52 } ], "relatedGenes" : [ @@ -124612,29 +125822,70 @@ "id" : "PA124", "symbol" : "CYP2C19", "name" : "cytochrome P450 family 2 subfamily C member 19", - "version" : 7210 + "version" : 7266 } ], "source" : "DPWG", "summaryMarkdown" : { "id" : 1447981902, "html" : "

For CYP2C19 ultrarapid metabolizers who are undergoing H. pylori eradication therapy, use a 3-fold higher dose. For CYP2C19 ultrarapid metabolizers with other indications, be alert to reduced effectiveness and, if necessary, use a 3-fold higher dose.

\n", - "version" : 1 + "version" : 2 }, "terms" : [], "textMarkdown" : { "id" : 1447981901, "html" : "

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

\n

November 2018 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for omeprazole based on CYP2C19 genotype. Patients who are CYP2C19 ultrarapid metabolizers who are undergoing H. pylori eradication therapy should receive a 3-fold higher dose. In CYP2C19 ultrarapid metabolizer patients with other indications, be alert to reduced effectiveness, and, if necessary, use a 3-fold higher dose. Patients should be advised to report persisting symptoms of dyspepsia.

\n

Wording in table taken from the Dutch guidelines November 2018 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
CYP2C19 PMomeprazoleNO action is required for this gene-drug interaction.The higher plasma concentration of omeprazole results in an increase in the therapeutic effectiveness, without an increase in the side effects.
CYP2C19 IMomeprazoleNO action is required for this gene-drug interaction.The higher plasma concentration of omeprazole results in an increase in the therapeutic effectiveness, without an increase in the side effects.
CYP2C19 UMomeprazoleThe genetic variation may lead to a reduced omeprazole plasma concentration and therefore reduced effectiveness.For Helicobacter pylori ERADICATION THERAPY: 1. use a 3-fold higher dose. 2. advise the patient to contact their doctor if symptoms of dyspepsia persist.
OTHER INDICATIONS: 1. be alert to reduced effectiveness. 2. if necessary, use a 3-fold higher dose. 3. advise the patient to report persisting symptoms of dyspepsia.
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for omeprazole and CYP2C19:

\n
\n

The Dutch Pharmacogenetics Working Group considers genotyping before starting omeprazole to be potentially beneficial for drug efficacy. Genotyping can be considered on an individual patient basis. If, however, the genotype is available, the Dutch Pharmacogenetics Working Group recommends adhering to the gene-drug guideline.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n

2011 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for omeprazole based on CYP2C19 genotype [Article:21412232]. For the CYP2C19 UM phenotype, they conclude to be extra alert to insufficient response and recommend to consider dose increase by 100-200%.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Phenotype (Genotype)Therapeutic Dose RecommendationLevel of EvidenceClinical Relevance
CYP2C19 PM (*2/*2, *2/*3, *3/*3)NonePublished controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpointsPositive clinical effects
CYP2C19 IM (*1/*2, *1/*3, *17/*2, *17/*3)NonePublished controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpointsPositive clinical effects
CYP2C19 UM (*17/*17)Helicobacter pylori eradication: increase dose by 100-200%. Be extra alert to insufficient response. Other: be extra alert to insufficient response. Consider dose increase by 100-200%Published controlled studies of moderate quality# relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpointsMinor clinical effect (statistically significant difference): QTc prolongation (<450 ms female, <470 ms male); international normalized ratio increase < 4.5 Kinetic effect (statistically significant difference)
\n\n", - "version" : 17 + "version" : 22 }, "userId" : "katrin", - "version" : 34 + "version" : 69 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166299194", - "name" : "Recommendation PA166299194", + "id" : "PA166299196", + "name" : "Recommendation PA166299196", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 1448526251, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : false, + "implications" : [ + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on omeprazole." + ], + "lookupKey" : {"CYP2C19": "Normal Metabolizer"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA450704", + "name" : "omeprazole", + "version" : 52 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104957", + "name" : "Annotation of DPWG Guideline for omeprazole and CYP2C19", + "version" : 69 + }, + "text" : { + "id" : 1452061559, + "html" : "

The guideline does not provide a recommendation for omeprazole in normal metabolizers.

\n", + "version" : 0 + }, + "version" : 2 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166299195", + "name" : "Recommendation PA166299195", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -124646,32 +125897,32 @@ "valid" : true, "version" : 1 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "The higher plasma concentration of omeprazole results in an increase in the therapeutic effectiveness, without an increase in the side effects." + "The genetic variation may lead to a reduced omeprazole plasma concentration and therefore reduced effectiveness." ], - "lookupKey" : {"CYP2C19": "Intermediate Metabolizer"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"CYP2C19": "Ultrarapid Metabolizer"}, + "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450704", "name" : "omeprazole", - "version" : 21 + "version" : 52 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104957", "name" : "Annotation of DPWG Guideline for omeprazole and CYP2C19", - "version" : 34 + "version" : 69 }, "text" : { - "id" : 1452061557, - "html" : "

NO action is required for this gene-drug interaction.

\n", - "version" : 0 + "id" : 1452061558, + "html" : "

For Helicobacter pylori ERADICATION THERAPY: 1. Use a 3-fold higher dose. 2. Advise the patient to contact their doctor if symptoms of dyspepsia persist.\nOTHER INDICATIONS: 1. Be alert to reduced effectiveness. 2. If necessary, use a 3-fold higher dose. 3. Advise the patient to report persisting symptoms of dyspepsia.

\n", + "version" : 1 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", @@ -124699,67 +125950,26 @@ "objCls" : "Chemical", "id" : "PA450704", "name" : "omeprazole", - "version" : 21 + "version" : 52 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104957", "name" : "Annotation of DPWG Guideline for omeprazole and CYP2C19", - "version" : 34 + "version" : 69 }, "text" : { "id" : 1452061556, "html" : "

NO action is required for this gene-drug interaction.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166299196", - "name" : "Recommendation PA166299196", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 1448526251, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on omeprazole." - ], - "lookupKey" : {"CYP2C19": "Normal Metabolizer"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA450704", - "name" : "omeprazole", - "version" : 21 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166104957", - "name" : "Annotation of DPWG Guideline for omeprazole and CYP2C19", - "version" : 34 - }, - "text" : { - "id" : 1452061559, - "html" : "

The guideline does not provide a recommendation for omeprazole in normal metabolizers.

\n", - "version" : 0 + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299195", - "name" : "Recommendation PA166299195", + "id" : "PA166299194", + "name" : "Recommendation PA166299194", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -124771,38 +125981,94 @@ "valid" : true, "version" : 1 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "The genetic variation may lead to a reduced omeprazole plasma concentration and therefore reduced effectiveness." + "The higher plasma concentration of omeprazole results in an increase in the therapeutic effectiveness, without an increase in the side effects." ], - "lookupKey" : {"CYP2C19": "Ultrarapid Metabolizer"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"CYP2C19": "Intermediate Metabolizer"}, + "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450704", "name" : "omeprazole", - "version" : 21 + "version" : 52 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104957", "name" : "Annotation of DPWG Guideline for omeprazole and CYP2C19", - "version" : 34 + "version" : 69 }, "text" : { - "id" : 1452061558, - "html" : "

For Helicobacter pylori ERADICATION THERAPY: 1. Use a 3-fold higher dose. 2. Advise the patient to contact their doctor if symptoms of dyspepsia persist.\nOTHER INDICATIONS: 1. Be alert to reduced effectiveness. 2. If necessary, use a 3-fold higher dose. 3. Advise the patient to report persisting symptoms of dyspepsia.

\n", - "version" : 0 + "id" : 1452061557, + "html" : "

NO action is required for this gene-drug interaction.

\n", + "version" : 1 }, - "version" : 0 + "version" : 2 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166104957" }, { - "citations" : [], + "citations" : [ + { + "id" : 15156470, + "title" : "Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction of CYP2C9, HLA-A and HLA-B with anti-epileptic drugs.", + "_sameAs" : "https://www.ncbi.nlm.nih.gov/pubmed/38570725", + "authors" : [ + "Manson Lisanne E N", + "Nijenhuis Marga", + "Soree Bianca", + "de Boer-Veger Nienke J", + "Buunk Anne-Marie", + "Houwink Elisa J F", + "Risselada Arne", + "Rongen Gerard A P J M", + "van Schaik Ron H N", + "Swen Jesse J", + "Touw Daan J", + "van Westrhenen Roos", + "Deneer Vera H M", + "Guchelaar Henk-Jan" + ], + "crossReferences" : [ + { + "id" : 1452435716, + "resource" : "PubMed", + "resourceId" : "38570725", + "_url" : "https://www.ncbi.nlm.nih.gov/pubmed/38570725", + "version" : 0 + }, + { + "id" : 1452435717, + "resource" : "DOI", + "resourceId" : "10.1038/s41431-024-01572-4", + "_url" : "http://dx.doi.org/10.1038%2Fs41431-024-01572-4", + "version" : 0 + } + ], + "day" : -1, + "hasKeyword" : true, + "journal" : "European journal of human genetics : EJHG", + "meshDiseases" : [], + "meshTerms" : [], + "month" : 4, + "nonHuman" : false, + "objCls" : "Literature", + "pediatric" : false, + "pgkbPublication" : false, + "pubDate" : "2024-04-01T00:00:00-07:00", + "summary" : "By developing evidence-based pharmacogenetics guidelines to optimize pharmacotherapy, the Dutch Pharmacogenetics Working Group (DPWG) aims to advance the implementation of pharmacogenetics (PGx). This guideline outlines the gene-drug interaction of CYP2C9 and HLA-B with phenytoin, HLA-A and HLA-B with carbamazepine and HLA-B with oxcarbazepine and lamotrigine. A systematic review was performed and pharmacotherapeutic recommendations were developed. For CYP2C9 intermediate and poor metabolisers, the DPWG recommends lowering the daily dose of phenytoin and adjust based on effect and serum concentration after 7-10 days. For HLA-B*15:02 carriers, the risk of severe cutaneous adverse events associated with phenytoin, carbamazepine, oxcarbazepine, and lamotrigine is strongly increased. For carbamazepine, this risk is also increased in HLA-B*15:11 and HLA-A*31:01 carriers. For HLA-B*15:02, HLA-B*15:11 and HLA-A*31:01 positive patients, the DPWG recommends choosing an alternative anti-epileptic drug. If not possible, it is recommended to advise the patient to report any rash while using carbamazepine, lamotrigine, oxcarbazepine or phenytoin immediately. Carbamazepine should not be used in an HLA-B*15:02 positive patient. DPWG considers CYP2C9 genotyping before the start of phenytoin \"essential\" for toxicity prevention. For patients with an ancestry in which the abovementioned HLA-alleles are prevalent, the DPWG considers HLA-B*15:02 genotyping before the start of carbamazepine, phenytoin, oxcarbazepine, and lamotrigine \"beneficial\", as well as genotyping for HLA-B*15:11 and HLA-A*31:01 before initiating carbamazepine.", + "terms" : [ + {"id":1451577480,"resource":"PGx Paper Types","term":"Implementation","termId":"pgxPaperTypes:1451577480"} + ], + "type" : "Literature", + "version" : 4, + "year" : 2024 + } + ], "guideline" : { "objCls" : "Guideline Annotation", "id" : "PA166265201", @@ -124882,9 +126148,18 @@ "description" : "Updated excerpt on testing.", "type" : "Update", "version" : 0 + }, + { + "id" : 1452439741, + "date" : "2024-04-11T06:30:59.601-07:00", + "description" : "Added 2024 publication.", + "type" : "Update", + "version" : 0 } ], - "literature" : [], + "literature" : [ + {"id":15156470,"title":"Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction of CYP2C9, HLA-A and HLA-B with anti-epileptic drugs.","_sameAs":"https://www.ncbi.nlm.nih.gov/pubmed/38570725","crossReferences":[{"id":1452435716,"resource":"PubMed","resourceId":"38570725","_url":"https://www.ncbi.nlm.nih.gov/pubmed/38570725"},{"id":1452435717,"resource":"DOI","resourceId":"10.1038/s41431-024-01572-4","_url":"http://dx.doi.org/10.1038%2Fs41431-024-01572-4"}],"objCls":"Literature","pubDate":"2024-04-01T00:00:00-07:00","terms":[{"id":1451577480,"resource":"PGx Paper Types","term":"Implementation","termId":"pgxPaperTypes:1451577480"}],"type":"Literature"} + ], "otherPrescribingGuidance" : true, "pediatric" : false, "recommendation" : true, @@ -124894,7 +126169,7 @@ "id" : "PA165954769", "symbol" : "HLA-B*15:02", "name" : "*15:02", - "version" : 5 + "version" : 21 } ], "relatedChemicals" : [ @@ -124902,7 +126177,7 @@ "objCls" : "Chemical", "id" : "PA450732", "name" : "oxcarbazepine", - "version" : 9 + "version" : 27 } ], "relatedGenes" : [ @@ -124911,7 +126186,7 @@ "id" : "PA35056", "symbol" : "HLA-B", "name" : "major histocompatibility complex, class I, B", - "version" : 40 + "version" : 2920 } ], "source" : "DPWG", @@ -124924,10 +126199,10 @@ "textMarkdown" : { "id" : 1451697941, "html" : "

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

\n

May 2021

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for oxcarbazepine based on HLA-B*15:02.

\n

Wording in table taken from the Dutch guidelines May 2021 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
HLA-B*1502oxcarbazepineStevens-Johnson syndrome, the severe cutaneous side effect that can potentially result in permanent damage, occurs more often in patients with this genetic variation. The calculated risk of oxcarbazepine-induced SJS in patients with HLA-B*1502 is 0.73%.Carefully weigh the risk of SJS/TEN against the benefits.
avoid oxcarbazepine if an alternative is available. Carbamazepine carries a 10-fold higher risk of SJS/TEN in these patients and is therefore not an alternative. In these patients, phenytoin and lamotrigine carry a similar risk of SJS/TEN as oxcarbazepine, but more severe forms of SJS/TEN (SJS/TEN overlap and TEN) are also observed with these medicines. Therefore, they are also not suitable as alternatives.
if it is not possible to avoid oxcarbazepine, advise the patient to report any rash immediately.
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for oxcarbazepine and HLA:

\n
\n

HLA-B*1502 has not been detected in a sample of 1350 Dutch persons (Allele Frequency Net Database:\nhttp://www.allelefrequencies.net). For this reason, the KNMP Pharmacogenetics Working Group does not consider\ngenotyping of Dutch patients in general before starting oxcarbazepine to be useful.\nHowever, the HLA-B*1502 frequency is high in Asians, except for Japanese and Koreans. In Japanese the HLAB*1502 frequency is very low (< 0.1%). In Korea, it is less than 1% in some populations and more than 1% in other\npopulations, with a mean of approximately 2% according to the SmPC of carbamazepine. The KNMP Pharmacogenetics Working Group considers genotyping of patients of Asian descent other than Japanese descent before starting oxcarbazepine to be beneficial for drug safety. It is advised to consider genotyping these patients before (or\ndirectly after) drug therapy has been initiated to guide drug selection.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n", - "version" : 4 + "version" : 7 }, "userId" : "lgong", - "version" : 8 + "version" : 32 }, "recommendations" : [ { @@ -124956,21 +126231,21 @@ "objCls" : "Chemical", "id" : "PA450732", "name" : "oxcarbazepine", - "version" : 9 + "version" : 27 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166265201", "name" : "Annotation of DPWG Guideline for oxcarbazepine and HLA-B", - "version" : 8 + "version" : 32 }, "text" : { "id" : 1452061481, "html" : "\n", "version" : 0 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166265201" @@ -125158,7 +126433,7 @@ "objCls" : "Chemical", "id" : "PA450774", "name" : "pantoprazole", - "version" : 15 + "version" : 37 } ], "relatedGenes" : [ @@ -125167,7 +126442,7 @@ "id" : "PA124", "symbol" : "CYP2C19", "name" : "cytochrome P450 family 2 subfamily C member 19", - "version" : 7210 + "version" : 7266 } ], "source" : "DPWG", @@ -125180,94 +126455,94 @@ "textMarkdown" : { "id" : 1447981903, "html" : "

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

\n

November 2018 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for pantoprazole based on CYP2C19 genotype. Patients who are CYP2C19 ultrarapid metabolizers who are undergoing H. pylori eradication therapy should receive a 5-fold higher dose. In CYP2C19 ultrarapid metabolizer patients with other indications, be alert to reduced effectiveness, and, if necessary, use a 5-fold higher dose. Patients should be advised to report persisting symptoms of dyspepsia.

\n

Wording in table taken from the Dutch guidelines November 2018 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
CYP2C19 PMpantoprazoleNO action is required for this gene-drug interaction.The higher plasma concentration of pantoprazole results in an increase in the therapeutic effectiveness, without an increase in the side effects.
CYP2C19 IMpantoprazoleNO action is required for this gene-drug interaction.The higher plasma concentration of pantoprazole results in an increase in the therapeutic effectiveness, without an increase in the side effects.
CYP2C19 UMpantoprazoleThe genetic variation may lead to a reduced pantoprazole plasma concentration and therefore reduced pantoprazole effectiveness.For Helicobacter pylori ERADICATION THERAPY: 1. use a 5-fold higher dose. 2. advise the patient to contact their doctor if symptoms of dyspepsia persist.
OTHER INDICATIONS: 1. be alert to reduced effectiveness. 2. if necessary, use a 5-fold higher dose. 3. advise the patient to report persisting symptoms of dyspepsia.
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for pantoprazole and CYP2C19:

\n
\n

The Dutch Pharmacogenetics Working Group considers genotyping before starting pantoprazole to be potentially beneficial for drug efficacy. Genotyping can be considered on an individual patient basis. If, however, the genotype is available, the Dutch Pharmacogenetics Working Group recommends adhering to the gene-drug guideline.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n

2011 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for pantoprazole based on CYP2C19 genotype [Article:21412232]. For the CYP2C19 UM phenotype, they conclude to be extra alert to insufficient response and recommend to consider dose increase by 400%.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Phenotype (Genotype)Therapeutic Dose RecommendationLevel of EvidenceClinical Relevance
CYP2C19 PM (*2/*2, *2/*3, *3/*3)NonePublished controlled studies of moderate quality# relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpointsPositive clinical effects
CYP2C19 IM (*1/*2, *1/*3, *17/*2, *17/*3)NonePublished controlled studies of moderate quality# relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpointsPositive clinical effects
CYP2C19 UM (*17/*17)Helicobacter pylori eradication: increase dose by 400%. Be extra alert to insufficient response. Other: be extra alert to insufficient response. Consider dose increase by 400%Published controlled studies of moderate quality# relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpointsClinical effect (not statistically significant difference); Kinetic effect (not statistically significant difference)
\n\n", - "version" : 17 + "version" : 20 }, "userId" : "katrin", - "version" : 34 + "version" : 67 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166299212", - "name" : "Recommendation PA166299212", + "id" : "PA166299215", + "name" : "Recommendation PA166299215", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, "dosingInformation" : false, "implications" : [ - "The higher plasma concentration of pantoprazole results in an increase in the therapeutic effectiveness, without an increase in the side effects." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on pantoprazole." ], - "lookupKey" : {"CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450774", "name" : "pantoprazole", - "version" : 15 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104958", "name" : "Annotation of DPWG Guideline for pantoprazole and CYP2C19", - "version" : 34 + "version" : 67 }, "text" : { - "id" : 1452061575, - "html" : "

NO action is required for this gene-drug interaction.

\n", + "id" : 1452061578, + "html" : "

The guideline does not provide a recommendation for pantoprazole in normal metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299215", - "name" : "Recommendation PA166299215", + "id" : "PA166299212", + "name" : "Recommendation PA166299212", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, "dosingInformation" : false, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on pantoprazole." + "The higher plasma concentration of pantoprazole results in an increase in the therapeutic effectiveness, without an increase in the side effects." ], - "lookupKey" : {"CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450774", "name" : "pantoprazole", - "version" : 15 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104958", "name" : "Annotation of DPWG Guideline for pantoprazole and CYP2C19", - "version" : 34 + "version" : 67 }, "text" : { - "id" : 1452061578, - "html" : "

The guideline does not provide a recommendation for pantoprazole in normal metabolizers.

\n", - "version" : 0 + "id" : 1452061575, + "html" : "

NO action is required for this gene-drug interaction.

\n", + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", @@ -125295,21 +126570,21 @@ "objCls" : "Chemical", "id" : "PA450774", "name" : "pantoprazole", - "version" : 15 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104958", "name" : "Annotation of DPWG Guideline for pantoprazole and CYP2C19", - "version" : 34 + "version" : 67 }, "text" : { "id" : 1452061576, "html" : "

NO action is required for this gene-drug interaction.

\n", - "version" : 0 + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", @@ -125337,21 +126612,21 @@ "objCls" : "Chemical", "id" : "PA450774", "name" : "pantoprazole", - "version" : 15 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104958", "name" : "Annotation of DPWG Guideline for pantoprazole and CYP2C19", - "version" : 34 + "version" : 67 }, "text" : { "id" : 1452061577, "html" : "

For Helicobacter pylori ERADICATION THERAPY: 1. use a 5-fold higher dose. 2. advise the patient to contact their doctor if symptoms of dyspepsia persist.\nOTHER INDICATIONS: 1. be alert to reduced effectiveness. 2. if necessary, use a 5-fold higher dose. 3. advise the patient to report persisting symptoms of dyspepsia.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166104958" @@ -125709,7 +126984,7 @@ "objCls" : "Chemical", "id" : "PA450801", "name" : "paroxetine", - "version" : 15 + "version" : 47 } ], "relatedGenes" : [ @@ -125718,25 +126993,109 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "DPWG", "summaryMarkdown" : { "id" : 1447982034, "html" : "

Select an alternative drug rather than paroxetine for CYP2D6 ultrarapid metabolizer patients.

\n", - "version" : 1 + "version" : 2 }, "terms" : [], "textMarkdown" : { "id" : 1447982033, "html" : "

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

\n

Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction between CYP2C19 and CYP2D6 and SSRIs. European journal of human genetics (2021)

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group published a paper with the guidelines as per the November 2018 update and further details on the assessed literature [Article:34782755].

\n

November 2018 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for paroxetine based on CYP2D6 genotype. They recommend paroxetine be avoided in patients who are CYP2D6 ultrarapid metabolizers (UMs). There are no recommendations for patients who are CYP2D6 intermediate metabolizers (IMs) or poor metabolizers (PMs).

\n

Wording in table taken from the Dutch guidelines November 2018 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
CYP2D6 UMparoxetineEfficacy will probably be lacking. The genetic variation increases the conversion of paroxetine.It is not possible to offer substantiated advice for dose adjustment based on the literature. Avoid paroxetine. Antidepressants that are not metabolised by CYP2D6, or to a lesser extent, include for example citalopram or sertraline.
CYP2D6 IMparoxetineThe plasma concentration of paroxetine can increase as a result of the reduced activity of CYP2D6. However, studies did not find any clinical effects.NO action is needed for this gene-drug interaction.
CYP2D6 PMparoxetineThe plasma concentration of paroxetine can increase as a result of the reduced activity of CYP2D6. However, studies did not find any clinical effects.NO action is needed for this gene-drug interaction.
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for paroxetine and CYP2D6:

\n
\n

The Dutch Pharmacogenetics Working Group considers genotyping before starting paroxetine to be potentially beneficial for drug efficacy. Genotyping can be considered on an individual patient basis. If, however, the genotype is available, the Dutch Pharmacogenetics Working Group recommends adhering to the gene-drug guideline.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n

2011 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for paroxetine based on CYP2D6 genotype [Article:21412232]. They suggest using an alternative drug for ultra metabolizers.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Phenotype (Genotype)Therapeutic Dose RecommendationLevel of EvidenceClinical Relevance
PM (2 inactive alleles)None.Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Minor clinical effect (S): QTc prolongation (<450 ms men, <470 ms women); INR increase < 4.5. Kinetic effect (S).
IM (2 decreased activity alleles, or 1 active and 1 inactive allele, or 1 decreased activity and 1 inactive allele)None.Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Minor clinical effect (S): QTc prolongation (<450 ms men, <470 ms women); INR increase < 4.5. Kinetic effect (S).
UM (gene duplication in absence of inactive or decreased activity alleles)Insufficient data to allow calculation of dose adjustment. Select alternative drug (e.g., citalopram, sertraline).Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Clinical effect (S): long-standing discomfort (48-168 hr) without permanent injury e.g. failure of therapy with tricyclic antidepressants, atypical antipsychotic drugs; extrapyramidal side effects; parkinsonism; ADE resulting from increased bioavailability of tricyclic antidepressants, metoprolol, propafenone (central effects e.g. dizziness); INR 4.5-6.0; neutropenia 1.0-1.5x109/l; leucopenia 2.0-3.0x109/l; thrombocytopenia 50-75x109/l.
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele TypeAlleles
active*1, *2, *33, *35
decreased activity*9, *10, *17, *29, *36, *41
inactive*3-*8, *11-*16, *19-*21, *38, *40, *42
\n\n", - "version" : 18 + "version" : 22 }, "userId" : "lgong", - "version" : 35 + "version" : 98 }, "recommendations" : [ + { + "objCls" : "Recommendation Annotation", + "id" : "PA166302557", + "name" : "Recommendation Annotation PA166302557", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501929, + "description" : "Not Applicable", + "parents" : [], + "resource" : "Guideline Strength", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", + "valid" : true, + "version" : 1 + }, + "dosingInformation" : false, + "implications" : [ + "The plasma concentration of paroxetine can increase as a result of the reduced activity of CYP2D6. However, studies did not find any clinical effects." + ], + "lookupKey" : {"CYP2D6": "0.0"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA450801", + "name" : "paroxetine", + "version" : 47 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104976", + "name" : "Annotation of DPWG Guideline for paroxetine and CYP2D6", + "version" : 98 + }, + "text" : { + "id" : 1452104136, + "html" : "

NO action is needed for this gene-drug interaction.

\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166302558", + "name" : "Recommendation Annotation PA166302558", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501929, + "description" : "Not Applicable", + "parents" : [], + "resource" : "Guideline Strength", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", + "valid" : true, + "version" : 1 + }, + "dosingInformation" : false, + "implications" : [ + "The plasma concentration of paroxetine can increase as a result of the reduced activity of CYP2D6. However, studies did not find any clinical effects." + ], + "lookupKey" : {"CYP2D6": "0.25"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA450801", + "name" : "paroxetine", + "version" : 47 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104976", + "name" : "Annotation of DPWG Guideline for paroxetine and CYP2D6", + "version" : 98 + }, + "text" : { + "id" : 1452104137, + "html" : "

NO action is needed for this gene-drug interaction.

\n", + "version" : 0 + }, + "version" : 0 + }, { "objCls" : "Recommendation Annotation", "id" : "PA166302559", @@ -125763,14 +127122,14 @@ "objCls" : "Chemical", "id" : "PA450801", "name" : "paroxetine", - "version" : 15 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104976", "name" : "Annotation of DPWG Guideline for paroxetine and CYP2D6", - "version" : 35 + "version" : 98 }, "text" : { "id" : 1452104138, @@ -125781,9 +127140,9 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302581", - "name" : "Recommendation Annotation PA166302581", - "alternateDrugAvailable" : true, + "id" : "PA166302560", + "name" : "Recommendation Annotation PA166302560", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -125796,36 +127155,36 @@ }, "dosingInformation" : false, "implications" : [ - "Efficacy will probably be lacking. The genetic variation increases the conversion of paroxetine." + "The plasma concentration of paroxetine can increase as a result of the reduced activity of CYP2D6. However, studies did not find any clinical effects." ], - "lookupKey" : {"CYP2D6": "3.0"}, + "lookupKey" : {"CYP2D6": "0.75"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450801", "name" : "paroxetine", - "version" : 15 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104976", "name" : "Annotation of DPWG Guideline for paroxetine and CYP2D6", - "version" : 35 + "version" : 98 }, "text" : { - "id" : 1452104180, - "html" : "

It is not possible to offer substantiated advice for dose adjustment based on the literature.

\n

Avoid paroxetine. Antidepressants that are not metabolised by CYP2D6, or to a lesser extent, include for example citalopram or sertraline.

\n", + "id" : 1452104139, + "html" : "

NO action is needed for this gene-drug interaction.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302603", - "name" : "Recommendation Annotation PA166302603", - "alternateDrugAvailable" : true, + "id" : "PA166302561", + "name" : "Recommendation Annotation PA166302561", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -125838,27 +127197,68 @@ }, "dosingInformation" : false, "implications" : [ - "Efficacy will probably be lacking. The genetic variation increases the conversion of paroxetine." + "The plasma concentration of paroxetine can increase as a result of the reduced activity of CYP2D6. However, studies did not find any clinical effects." ], - "lookupKey" : {"CYP2D6": "≥3.5"}, + "lookupKey" : {"CYP2D6": "1.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450801", "name" : "paroxetine", - "version" : 15 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104976", "name" : "Annotation of DPWG Guideline for paroxetine and CYP2D6", - "version" : 35 + "version" : 98 }, "text" : { - "id" : 1452104202, - "html" : "

It is not possible to offer substantiated advice for dose adjustment based on the literature.

\n

Avoid paroxetine. Antidepressants that are not metabolised by CYP2D6, or to a lesser extent, include for example citalopram or sertraline.

\n", + "id" : 1452104140, + "html" : "

NO action is needed for this gene-drug interaction.

\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166302562", + "name" : "Recommendation Annotation PA166302562", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 1448526251, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : false, + "implications" : [ + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on paroxetine" + ], + "lookupKey" : {"CYP2D6": "1.25"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA450801", + "name" : "paroxetine", + "version" : 47 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104976", + "name" : "Annotation of DPWG Guideline for paroxetine and CYP2D6", + "version" : 98 + }, + "text" : { + "id" : 1452104141, + "html" : "

The guideline does not provide a recommendation for paroxetine in normal metabolizers.

\n", "version" : 0 }, "version" : 0 @@ -125888,14 +127288,14 @@ "objCls" : "Chemical", "id" : "PA450801", "name" : "paroxetine", - "version" : 15 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104976", "name" : "Annotation of DPWG Guideline for paroxetine and CYP2D6", - "version" : 35 + "version" : 98 }, "text" : { "id" : 1452104142, @@ -125906,92 +127306,90 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302558", - "name" : "Recommendation Annotation PA166302558", + "id" : "PA166302564", + "name" : "Recommendation Annotation PA166302564", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, "dosingInformation" : false, "implications" : [ - "The plasma concentration of paroxetine can increase as a result of the reduced activity of CYP2D6. However, studies did not find any clinical effects." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on paroxetine." ], - "lookupKey" : {"CYP2D6": "0.25"}, + "lookupKey" : {"CYP2D6": "2.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450801", "name" : "paroxetine", - "version" : 15 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104976", "name" : "Annotation of DPWG Guideline for paroxetine and CYP2D6", - "version" : 35 + "version" : 98 }, "text" : { - "id" : 1452104137, - "html" : "

NO action is needed for this gene-drug interaction.

\n", + "id" : 1452104143, + "html" : "

The guideline does not provide a recommendation for paroxetine in normal metabolizers.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302602", - "name" : "Recommendation Annotation PA166302602", - "alternateDrugAvailable" : true, + "id" : "PA166302566", + "name" : "Recommendation Annotation PA166302566", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, "dosingInformation" : false, "implications" : [ - "Efficacy will probably be lacking. The genetic variation increases the conversion of paroxetine." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on paroxetine." ], - "lookupKey" : {"CYP2D6": "≥3.25"}, + "lookupKey" : {"CYP2D6": "2.5"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450801", "name" : "paroxetine", - "version" : 15 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104976", "name" : "Annotation of DPWG Guideline for paroxetine and CYP2D6", - "version" : 35 + "version" : 98 }, "text" : { - "id" : 1452104201, - "html" : "

It is not possible to offer substantiated advice for dose adjustment based on the literature.

\n

Avoid paroxetine. Antidepressants that are not metabolised by CYP2D6, or to a lesser extent, include for example citalopram or sertraline.

\n", + "id" : 1452104145, + "html" : "

The guideline does not provide a recommendation for paroxetine in normal metabolizers.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302562", - "name" : "Recommendation Annotation PA166302562", + "id" : "PA166302565", + "name" : "Recommendation Annotation PA166302565", "alternateDrugAvailable" : false, "classification" : { "id" : 1448526251, @@ -126004,35 +127402,35 @@ }, "dosingInformation" : false, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on paroxetine" + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on paroxetine." ], - "lookupKey" : {"CYP2D6": "1.25"}, + "lookupKey" : {"CYP2D6": "2.25"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450801", "name" : "paroxetine", - "version" : 15 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104976", "name" : "Annotation of DPWG Guideline for paroxetine and CYP2D6", - "version" : 35 + "version" : 98 }, "text" : { - "id" : 1452104141, + "id" : 1452104144, "html" : "

The guideline does not provide a recommendation for paroxetine in normal metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302606", - "name" : "Recommendation Annotation PA166302606", + "id" : "PA166302581", + "name" : "Recommendation Annotation PA166302581", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -126048,24 +127446,24 @@ "implications" : [ "Efficacy will probably be lacking. The genetic variation increases the conversion of paroxetine." ], - "lookupKey" : {"CYP2D6": "≥6.0"}, + "lookupKey" : {"CYP2D6": "3.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450801", "name" : "paroxetine", - "version" : 15 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104976", "name" : "Annotation of DPWG Guideline for paroxetine and CYP2D6", - "version" : 35 + "version" : 98 }, "text" : { - "id" : 1452104205, + "id" : 1452104180, "html" : "

It is not possible to offer substantiated advice for dose adjustment based on the literature.

\n

Avoid paroxetine. Antidepressants that are not metabolised by CYP2D6, or to a lesser extent, include for example citalopram or sertraline.

\n", "version" : 0 }, @@ -126073,50 +127471,9 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302566", - "name" : "Recommendation Annotation PA166302566", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 1448526251, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on paroxetine." - ], - "lookupKey" : {"CYP2D6": "2.5"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA450801", - "name" : "paroxetine", - "version" : 15 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166104976", - "name" : "Annotation of DPWG Guideline for paroxetine and CYP2D6", - "version" : 35 - }, - "text" : { - "id" : 1452104145, - "html" : "

The guideline does not provide a recommendation for paroxetine in normal metabolizers.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166302557", - "name" : "Recommendation Annotation PA166302557", - "alternateDrugAvailable" : false, + "id" : "PA166302582", + "name" : "Recommendation Annotation PA166302582", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -126129,27 +127486,27 @@ }, "dosingInformation" : false, "implications" : [ - "The plasma concentration of paroxetine can increase as a result of the reduced activity of CYP2D6. However, studies did not find any clinical effects." + "Efficacy will probably be lacking. The genetic variation increases the conversion of paroxetine." ], - "lookupKey" : {"CYP2D6": "0.0"}, + "lookupKey" : {"CYP2D6": "4.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450801", "name" : "paroxetine", - "version" : 15 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104976", "name" : "Annotation of DPWG Guideline for paroxetine and CYP2D6", - "version" : 35 + "version" : 98 }, "text" : { - "id" : 1452104136, - "html" : "

NO action is needed for this gene-drug interaction.

\n", + "id" : 1452104181, + "html" : "

It is not possible to offer substantiated advice for dose adjustment based on the literature.

\n

Avoid paroxetine. Antidepressants that are not metabolised by CYP2D6, or to a lesser extent, include for example citalopram or sertraline.

\n", "version" : 0 }, "version" : 0 @@ -126180,14 +127537,14 @@ "objCls" : "Chemical", "id" : "PA450801", "name" : "paroxetine", - "version" : 15 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104976", "name" : "Annotation of DPWG Guideline for paroxetine and CYP2D6", - "version" : 35 + "version" : 98 }, "text" : { "id" : 1452104200, @@ -126198,9 +127555,9 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302561", - "name" : "Recommendation Annotation PA166302561", - "alternateDrugAvailable" : false, + "id" : "PA166302602", + "name" : "Recommendation Annotation PA166302602", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -126213,35 +127570,35 @@ }, "dosingInformation" : false, "implications" : [ - "The plasma concentration of paroxetine can increase as a result of the reduced activity of CYP2D6. However, studies did not find any clinical effects." + "Efficacy will probably be lacking. The genetic variation increases the conversion of paroxetine." ], - "lookupKey" : {"CYP2D6": "1.0"}, + "lookupKey" : {"CYP2D6": "≥3.25"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450801", "name" : "paroxetine", - "version" : 15 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104976", "name" : "Annotation of DPWG Guideline for paroxetine and CYP2D6", - "version" : 35 + "version" : 98 }, "text" : { - "id" : 1452104140, - "html" : "

NO action is needed for this gene-drug interaction.

\n", + "id" : 1452104201, + "html" : "

It is not possible to offer substantiated advice for dose adjustment based on the literature.

\n

Avoid paroxetine. Antidepressants that are not metabolised by CYP2D6, or to a lesser extent, include for example citalopram or sertraline.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302605", - "name" : "Recommendation Annotation PA166302605", + "id" : "PA166302603", + "name" : "Recommendation Annotation PA166302603", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -126257,24 +127614,24 @@ "implications" : [ "Efficacy will probably be lacking. The genetic variation increases the conversion of paroxetine." ], - "lookupKey" : {"CYP2D6": "≥5.0"}, + "lookupKey" : {"CYP2D6": "≥3.5"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450801", "name" : "paroxetine", - "version" : 15 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104976", "name" : "Annotation of DPWG Guideline for paroxetine and CYP2D6", - "version" : 35 + "version" : 98 }, "text" : { - "id" : 1452104204, + "id" : 1452104202, "html" : "

It is not possible to offer substantiated advice for dose adjustment based on the literature.

\n

Avoid paroxetine. Antidepressants that are not metabolised by CYP2D6, or to a lesser extent, include for example citalopram or sertraline.

\n", "version" : 0 }, @@ -126282,49 +127639,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302565", - "name" : "Recommendation Annotation PA166302565", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 1448526251, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on paroxetine." - ], - "lookupKey" : {"CYP2D6": "2.25"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA450801", - "name" : "paroxetine", - "version" : 15 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166104976", - "name" : "Annotation of DPWG Guideline for paroxetine and CYP2D6", - "version" : 35 - }, - "text" : { - "id" : 1452104144, - "html" : "

The guideline does not provide a recommendation for paroxetine in normal metabolizers.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166302582", - "name" : "Recommendation Annotation PA166302582", + "id" : "PA166302604", + "name" : "Recommendation Annotation PA166302604", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -126340,24 +127656,24 @@ "implications" : [ "Efficacy will probably be lacking. The genetic variation increases the conversion of paroxetine." ], - "lookupKey" : {"CYP2D6": "4.0"}, + "lookupKey" : {"CYP2D6": "≥4.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450801", "name" : "paroxetine", - "version" : 15 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104976", "name" : "Annotation of DPWG Guideline for paroxetine and CYP2D6", - "version" : 35 + "version" : 98 }, "text" : { - "id" : 1452104181, + "id" : 1452104203, "html" : "

It is not possible to offer substantiated advice for dose adjustment based on the literature.

\n

Avoid paroxetine. Antidepressants that are not metabolised by CYP2D6, or to a lesser extent, include for example citalopram or sertraline.

\n", "version" : 0 }, @@ -126365,9 +127681,9 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302560", - "name" : "Recommendation Annotation PA166302560", - "alternateDrugAvailable" : false, + "id" : "PA166302605", + "name" : "Recommendation Annotation PA166302605", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -126380,35 +127696,35 @@ }, "dosingInformation" : false, "implications" : [ - "The plasma concentration of paroxetine can increase as a result of the reduced activity of CYP2D6. However, studies did not find any clinical effects." + "Efficacy will probably be lacking. The genetic variation increases the conversion of paroxetine." ], - "lookupKey" : {"CYP2D6": "0.75"}, + "lookupKey" : {"CYP2D6": "≥5.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450801", "name" : "paroxetine", - "version" : 15 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104976", "name" : "Annotation of DPWG Guideline for paroxetine and CYP2D6", - "version" : 35 + "version" : 98 }, "text" : { - "id" : 1452104139, - "html" : "

NO action is needed for this gene-drug interaction.

\n", + "id" : 1452104204, + "html" : "

It is not possible to offer substantiated advice for dose adjustment based on the literature.

\n

Avoid paroxetine. Antidepressants that are not metabolised by CYP2D6, or to a lesser extent, include for example citalopram or sertraline.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302604", - "name" : "Recommendation Annotation PA166302604", + "id" : "PA166302606", + "name" : "Recommendation Annotation PA166302606", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -126424,69 +127740,28 @@ "implications" : [ "Efficacy will probably be lacking. The genetic variation increases the conversion of paroxetine." ], - "lookupKey" : {"CYP2D6": "≥4.0"}, + "lookupKey" : {"CYP2D6": "≥6.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450801", "name" : "paroxetine", - "version" : 15 + "version" : 47 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104976", "name" : "Annotation of DPWG Guideline for paroxetine and CYP2D6", - "version" : 35 + "version" : 98 }, "text" : { - "id" : 1452104203, + "id" : 1452104205, "html" : "

It is not possible to offer substantiated advice for dose adjustment based on the literature.

\n

Avoid paroxetine. Antidepressants that are not metabolised by CYP2D6, or to a lesser extent, include for example citalopram or sertraline.

\n", "version" : 0 }, "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166302564", - "name" : "Recommendation Annotation PA166302564", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 1448526251, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on paroxetine." - ], - "lookupKey" : {"CYP2D6": "2.0"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA450801", - "name" : "paroxetine", - "version" : 15 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166104976", - "name" : "Annotation of DPWG Guideline for paroxetine and CYP2D6", - "version" : 35 - }, - "text" : { - "id" : 1452104143, - "html" : "

The guideline does not provide a recommendation for paroxetine in normal metabolizers.

\n", - "version" : 0 - }, - "version" : 0 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166104976" @@ -126580,7 +127855,7 @@ "date" : "2019-05-28T00:00:00-07:00", "description" : "Annotation current with November 2018 DPWG Guideline release", "type" : "Update", - "version" : 0 + "version" : 1 }, { "id" : 1450821023, @@ -126601,7 +127876,7 @@ "date" : "2020-02-11T00:00:00-08:00", "description" : "Fixed link to algorithms.", "type" : "Update", - "version" : 0 + "version" : 1 }, { "id" : 1450963760, @@ -126709,7 +127984,7 @@ "id" : "PA166155091", "symbol" : "rs9923231", "name" : "rs9923231", - "version" : 5 + "version" : 10 } ], "relatedChemicals" : [ @@ -126717,7 +127992,7 @@ "objCls" : "Chemical", "id" : "PA450921", "name" : "phenprocoumon", - "version" : 7 + "version" : 27 } ], "relatedGenes" : [ @@ -126726,23 +128001,23 @@ "id" : "PA133787052", "symbol" : "VKORC1", "name" : "vitamin K epoxide reductase complex subunit 1", - "version" : 16 + "version" : 52 } ], "source" : "DPWG", "summaryMarkdown" : { "id" : 1447981860, "html" : "

Patients with the VKORC1 rs9923231 TT genotype (-1639 AA genotype) is recommended to be given 50% of the standard initial dose of phenprocoumon and more frequent monitoring of INR. The genotype-specific initial dose and maintenance dose can be calculated using an algorithm. There is no recommendation for patients with the VKORC1 rs9923231 CT genotype (-1639 AG genotype).

\n", - "version" : 10 + "version" : 14 }, "terms" : [], "textMarkdown" : { "id" : 1447981859, "html" : "

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

\n

November 2018 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group (DPWG) has evaluated therapeutic dose recommendations for phenprocoumon based on VKORC1 genotype. They recommend that patients with the VKORC1 rs9923231 TT genotype (-1639 AA genotype) receive 50% of the standard initial dose and more frequent monitoring of INR. The genotype-specific initial dose and maintenance dose can be calculated using an algorithm. There is no recommendation for patients with the VKORC1 rs9923231 CT genotype (-1639 AG genotype).

\n

Wording in table taken from the Dutch guidelines November 2018 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
VKORC1 -1639 AAphenprocoumonAn INR = 6, resulting in an increased risk of bleeding, occurs in 17% of these patients with standard regulation by the Anticoagulation Clinic. The genetic variation increases the sensitivity to phenprocoumon.1. Monitoring by a ANTICOAGULATION CLINIC: recommend to use 50% of the standard initial dose.
2.NO monitoring by a anticoagulation clinic: recommend to use 50% of the standard initial dose, recommend more frequent monitoring of the INR.
For patients younger than 75 years, the initial dose and the maintenance dose can be calculated using an algorithm as found in EUPACT. However, for patients aged 75 years and older, this algorithm increases the risk of an INR above the therapeutic range compared to an algorithm without gene variations. Therefore, use of this algorithm is not recommended for these patients.
VKORC1 -1639 AGphenprocoumonThe gene variation leads to a lower dose requirement, but regular monitoring of patients ensures that this does not lead to a distinct increase in the risk of bleeding.NO action is needed for this gene-drug interaction
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Download the algorithm used in EU-PACT provided by DPWG this is an excel file retrieved from DPWG on 3/19/2024.

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for phenprocoumon and VKORC1:

\n
\n

The Dutch Pharmacogenetics Working Group considers genotyping before starting phenprocoumon to be to be beneficial for drug safety. It is advised to genotype these patients before (or directly after) drug therapy has been initiated to guide drug and dose selection.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n

2011 Guideline:

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for phenprocoumon based on VKORC1 genotype [Article:21412232]. They found that VKORC1 rs9934438 genotype contributes to dose variability. However, they make no dosing recommendations at this time "because of strict international normalized ratio monitoring by the Dutch Thrombosis Service."

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GenotypeTherapeutic Dose RecommendationLevel of EvidenceClinical Relevance
VKORC1 rs9934438 AGNonePublished controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Minor clinical effect (S): QTc prolongation (<450 ms , <470 ms); INR increase < 4.5 Kinetic effect (S).
VKORC1 rs9934438 AACheck INR more frequently.Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Minor clinical effect (S): QTc prolongation (<450 ms , <470 ms); INR increase < 4.5 Kinetic effect (S).
\n\n", - "version" : 21 + "version" : 28 }, "userId" : "alie", - "version" : 40 + "version" : 82 }, "recommendations" : [ { @@ -126771,14 +128046,14 @@ "objCls" : "Chemical", "id" : "PA450921", "name" : "phenprocoumon", - "version" : 7 + "version" : 27 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104940", "name" : "Annotation of DPWG Guideline for phenprocoumon and VKORC1", - "version" : 40 + "version" : 82 }, "text" : { "id" : 1452061540, @@ -126812,21 +128087,21 @@ "objCls" : "Chemical", "id" : "PA450921", "name" : "phenprocoumon", - "version" : 7 + "version" : 27 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104940", "name" : "Annotation of DPWG Guideline for phenprocoumon and VKORC1", - "version" : 40 + "version" : 82 }, "text" : { "id" : 1452061539, "html" : "

The guideline does not provide a recommendation for phenprocoumon in patients with the VKORC1 rs9923231 CC genotype (-1639 GG genotype).

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -126854,27 +128129,82 @@ "objCls" : "Chemical", "id" : "PA450921", "name" : "phenprocoumon", - "version" : 7 + "version" : 27 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104940", "name" : "Annotation of DPWG Guideline for phenprocoumon and VKORC1", - "version" : 40 + "version" : 82 }, "text" : { "id" : 1452061541, "html" : "

Monitoring by a ANTICOAGULATION CLINIC:

\n\n

NO monitoring by a anticoagulation clinic:

\n\n", "version" : 0 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166104940" }, { "citations" : [ + { + "id" : 15156470, + "title" : "Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction of CYP2C9, HLA-A and HLA-B with anti-epileptic drugs.", + "_sameAs" : "https://www.ncbi.nlm.nih.gov/pubmed/38570725", + "authors" : [ + "Manson Lisanne E N", + "Nijenhuis Marga", + "Soree Bianca", + "de Boer-Veger Nienke J", + "Buunk Anne-Marie", + "Houwink Elisa J F", + "Risselada Arne", + "Rongen Gerard A P J M", + "van Schaik Ron H N", + "Swen Jesse J", + "Touw Daan J", + "van Westrhenen Roos", + "Deneer Vera H M", + "Guchelaar Henk-Jan" + ], + "crossReferences" : [ + { + "id" : 1452435716, + "resource" : "PubMed", + "resourceId" : "38570725", + "_url" : "https://www.ncbi.nlm.nih.gov/pubmed/38570725", + "version" : 0 + }, + { + "id" : 1452435717, + "resource" : "DOI", + "resourceId" : "10.1038/s41431-024-01572-4", + "_url" : "http://dx.doi.org/10.1038%2Fs41431-024-01572-4", + "version" : 0 + } + ], + "day" : -1, + "hasKeyword" : true, + "journal" : "European journal of human genetics : EJHG", + "meshDiseases" : [], + "meshTerms" : [], + "month" : 4, + "nonHuman" : false, + "objCls" : "Literature", + "pediatric" : false, + "pgkbPublication" : false, + "pubDate" : "2024-04-01T00:00:00-07:00", + "summary" : "By developing evidence-based pharmacogenetics guidelines to optimize pharmacotherapy, the Dutch Pharmacogenetics Working Group (DPWG) aims to advance the implementation of pharmacogenetics (PGx). This guideline outlines the gene-drug interaction of CYP2C9 and HLA-B with phenytoin, HLA-A and HLA-B with carbamazepine and HLA-B with oxcarbazepine and lamotrigine. A systematic review was performed and pharmacotherapeutic recommendations were developed. For CYP2C9 intermediate and poor metabolisers, the DPWG recommends lowering the daily dose of phenytoin and adjust based on effect and serum concentration after 7-10 days. For HLA-B*15:02 carriers, the risk of severe cutaneous adverse events associated with phenytoin, carbamazepine, oxcarbazepine, and lamotrigine is strongly increased. For carbamazepine, this risk is also increased in HLA-B*15:11 and HLA-A*31:01 carriers. For HLA-B*15:02, HLA-B*15:11 and HLA-A*31:01 positive patients, the DPWG recommends choosing an alternative anti-epileptic drug. If not possible, it is recommended to advise the patient to report any rash while using carbamazepine, lamotrigine, oxcarbazepine or phenytoin immediately. Carbamazepine should not be used in an HLA-B*15:02 positive patient. DPWG considers CYP2C9 genotyping before the start of phenytoin \"essential\" for toxicity prevention. For patients with an ancestry in which the abovementioned HLA-alleles are prevalent, the DPWG considers HLA-B*15:02 genotyping before the start of carbamazepine, phenytoin, oxcarbazepine, and lamotrigine \"beneficial\", as well as genotyping for HLA-B*15:11 and HLA-A*31:01 before initiating carbamazepine.", + "terms" : [ + {"id":1451577480,"resource":"PGx Paper Types","term":"Implementation","termId":"pgxPaperTypes:1451577480"} + ], + "type" : "Literature", + "version" : 4, + "year" : 2024 + }, { "id" : 7283333, "title" : "Pharmacogenetics: from bench to byte--an update of guidelines.", @@ -127040,9 +128370,17 @@ "description" : "Checked testing box", "type" : "Update", "version" : 0 + }, + { + "id" : 1452439761, + "date" : "2024-04-11T06:32:26.106-07:00", + "description" : "Added 2024 publication.", + "type" : "Update", + "version" : 0 } ], "literature" : [ + {"id":15156470,"title":"Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction of CYP2C9, HLA-A and HLA-B with anti-epileptic drugs.","_sameAs":"https://www.ncbi.nlm.nih.gov/pubmed/38570725","crossReferences":[{"id":1452435716,"resource":"PubMed","resourceId":"38570725","_url":"https://www.ncbi.nlm.nih.gov/pubmed/38570725"},{"id":1452435717,"resource":"DOI","resourceId":"10.1038/s41431-024-01572-4","_url":"http://dx.doi.org/10.1038%2Fs41431-024-01572-4"}],"objCls":"Literature","pubDate":"2024-04-01T00:00:00-07:00","terms":[{"id":1451577480,"resource":"PGx Paper Types","term":"Implementation","termId":"pgxPaperTypes:1451577480"}],"type":"Literature"}, {"id":7283333,"title":"Pharmacogenetics: from bench to byte--an update of guidelines.","_sameAs":"https://www.ncbi.nlm.nih.gov/pubmed/21412232","crossReferences":[{"id":769250885,"resource":"PubMed","resourceId":"21412232","_url":"https://www.ncbi.nlm.nih.gov/pubmed/21412232"},{"id":1449247827,"resource":"DOI","resourceId":"10.1038/clpt.2011.34","_url":"http://dx.doi.org/10.1038%2Fclpt.2011.34"}],"objCls":"Literature","pubDate":"2011-05-01T00:00:00-07:00","terms":[],"type":"Literature"}, {"id":15103288,"title":"Dutch Pharmacogenetics Working Group Guidelines August 2019","_sameAs":"https://api.pharmgkb.org/v1/preview/download/file/attachment/DPWG_August_2019.pdf","crossReferences":[{"id":1450815695,"resource":"URL","resourceId":"https://api.pharmgkb.org/v1/preview/download/file/attachment/DPWG_August_2019.pdf","_url":"https://api.pharmgkb.org/v1/preview/download/file/attachment/DPWG_August_2019.pdf"}],"objCls":"Literature","terms":[],"type":"Literature"}, {"id":15102465,"title":"Dutch Pharmacogenetics Working Group Guidelines November 2018","_sameAs":"https://api.pharmgkb.org/v1/preview/download/file/attachment/DPWG_November_2018.pdf","crossReferences":[{"id":1450415575,"resource":"URL","resourceId":"https://api.pharmgkb.org/v1/preview/download/file/attachment/DPWG_November_2018.pdf","_url":"https://api.pharmgkb.org/v1/preview/download/file/attachment/DPWG_November_2018.pdf"}],"objCls":"Literature","terms":[],"type":"Literature"} @@ -127056,14 +128394,14 @@ "id" : "PA165816543", "symbol" : "CYP2C9*2", "name" : "*2", - "version" : 23 + "version" : 52 }, { "objCls" : "Haplotype", "id" : "PA165816544", "symbol" : "CYP2C9*3", "name" : "*3", - "version" : 25 + "version" : 55 } ], "relatedChemicals" : [ @@ -127071,7 +128409,7 @@ "objCls" : "Chemical", "id" : "PA450947", "name" : "phenytoin", - "version" : 14 + "version" : 49 } ], "relatedGenes" : [ @@ -127080,71 +128418,70 @@ "id" : "PA126", "symbol" : "CYP2C9", "name" : "cytochrome P450 family 2 subfamily C member 9", - "version" : 7877 + "version" : 7952 } ], "source" : "DPWG", "summaryMarkdown" : { "id" : 1447981976, "html" : "

Use the standard starting dose of phenytoin and reduce the maintenance dose based on CYP2C9 genotype; monitor response and serum concentrations and be aware of ADEs.

\n", - "version" : 0 + "version" : 1 }, "terms" : [], "textMarkdown" : { "id" : 1447981975, "html" : "

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

\n

May 2021 update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has made some minor changes to the names of some phenotype groups in this guideline. The table below has been updated to reflect this but the recommendations themselves have not changed.

\n

November 2018 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for phenytoin based on CYP2C9 genotype. They recommend a reduction in the maintenance dose for patients with the CYP2C9*1/*2, *1/*3, *2/*2, *2/*3, *3/*3 or other CYP2C9 genotypes which lead to an intermediate metabolizer (IM) or poor metabolizer (PM) phenotype. Patient response, serum concentrations and potential ADEs should be monitored.

\n

The annotation of the DPWG guideline for phenytoin and HLA-B can be found here.

\n

Wording in table taken from the Dutch guidelines November 2018 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
CYP2C9 IM otheraphenytoinGenetic variation reduces conversion of phenytoin to inactive metabolites. This increases the risk of side effects.1. The loading dose does not need to be adjusted.
2. For the other doses, use 75% of the standard dose and assess the dose based on effect and serum concentration after 7-10 days.
3. Advise the patient to get in touch if side effects (such as ataxia, nystagmus, slurred speech, sedation or rash) occur.
CYP2C9 PM otheraphenytoinGenetic variation reduces conversion of phenytoin to inactive metabolites. This increases the risk of side effects.1. The loading dose does not need to be adjusted.
2. For the other doses, use 40-50% of the standard dose and assess the dose based on effect and serum concentration after 7-10 days.
3. Advise the patient to get in touch if side effects (such as ataxia, nystagmus, slurred speech, sedation or rash) occur.
CYP2C9 *1/*2phenytoinGenetic variation reduces conversion of phenytoin to inactive metabolites. This increases the risk of side effects.1. The loading dose does not need to be adjusted.
2. For the other doses, use 75% of the standard dose and assess the dose based on effect and serum concentration after 7-10 days.
3. Advise the patient to get in touch if side effects (such as ataxia, nystagmus, slurred speech, sedation or rash) occur.
CYP2C9 *1/*3phenytoinGenetic variation reduces conversion of phenytoin to inactive metabolites. This increases the risk of side effects. The life-threatening cutaneous side effects Stevens-Johnson Syndrome and toxic epidermal necrolysis may occur, especially in Asian patients.1. The loading dose does not need to be adjusted.
2. For the other doses, use 75% of the standard dose and assess the dose based on effect and serum concentration after 7-10 days.
3. Advise the patient to get in touch if side effects (such as ataxia, nystagmus, slurred speech, sedation or, especially in Asian patients, rash) occur.
CYP2C9 *2/*2phenytoinGenetic variation reduces conversion of phenytoin to inactive metabolites. This increases the risk of side effects.1. The loading dose does not need to be adjusted.
2. For the other doses, use 50% of the standard dose and assess the dose based on effect and serum concentration after 7-10 days.
3. Advise the patient to get in touch if side effects (such as ataxia, nystagmus, slurred speech, sedation or rash) occur.
CYP2C9 *2/*3phenytoinGenetic variation reduces conversion of phenytoin to inactive metabolites. This increases the risk of side effects.1. The loading dose does not need to be adjusted.
2. For the other doses, use 50% of the standard dose and assess the dose based on effect and serum concentration after 7-10 days.
3. Advise the patient to get in touch if side effects (such as ataxia, nystagmus, slurred speech, sedation or rash) occur.
CYP2C9 *3/*3phenytoinGenetic variation reduces conversion of phenytoin to inactive metabolites. This increases the risk of side effects. The life-threatening cutaneous side effects Stevens-Johnson Syndrome and toxic epidermal necrolysis may occur, especially in Asian patients.1. The loading dose does not need to be adjusted.
2. For the other doses, use 40% of the standard dose and assess the dose based on effect and serum concentration after 7-10 days.
3. Advise the patient to get in touch if side effects (such as ataxia, nystagmus, slurred speech, sedation or, especially in Asian patients, rash) occur.
\n

a These groups are referred to in the DPWG recommendation PDF as 'IM ANDERS' and 'PM ANDERS', which use the Dutch word 'anders'. PharmGKB has translated these as 'IM other' and PM other', respectively.

\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for phenytoin and CYP2C9:

\n
\n

The KNMP Pharmacogenetics Working Group considers genotyping of patients before starting phenytoin\nmaintenance therapy to be essential for drug safety. Genotyping must be performed before maintenance therapy\nhas been initiated to guide dose selection.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n

2011 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for phenytoin based on CYP2C9 genotype [Article:21412232].

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GenotypeTherapeutic Dose RecommendationLevel of EvidenceClinical Relevance
CYP2C9 *1/*2Standard loading dose. Reduce maintenance dose by 25%. Evaluate response and serum concentration after 7-10 days. Be alert to ADEs (e.g., ataxia, nystagmus, dysarthria, sedation)Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Minor clinical effect (S): QTc prolongation (<450 ms females, <470 ms males); INR increase < 4.5Kinetic effect (S)
CYP2C9 *2/*2Standard loading dose. Reduce maintenance dose by 50%. Evaluate response and serum concentration after 7-10 days. Be alert to ADEs (e.g., ataxia, nystagmus, dysarthria, sedation)Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Minor clinical effect (S): QTc prolongation (<450 ms females, <470 ms males); INR increase < 4.5Kinetic effect (S)
CYP2C9 *1/*3Standard loading dose. Reduce maintenance dose by 25%. Evaluate response and serum concentration after 7-10 days. Be alert to ADEs (e.g., ataxia, nystagmus, dysarthria, sedation)Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Clinical effect (S): long-standing discomfort (> 168 hr), permanent symptom or invalidating injury e.g. failure of prophylaxis of atrial fibrillation; venous thromboembolism; decreased effect of clopidogrel on inhibition of platelet aggregation; ADE resulting from increased bioavailability of phenytoin; INR > 6.0; neutropenia 0.5-1.0x109/l; leucopenia 1.0-2.0x109/l; thrombocytopenia 25-50x109/l; severe diarrhea
CYP2C9 *2/*3Standard loading dose. Reduce maintenance dose by 50%. Evaluate response and serum concentration after 7-10 days. Be alert to ADEs (e.g., ataxia, nystagmus, dysarthria, sedation)Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Minor clinical effect (S): QTc prolongation (<450 ms females, <470 ms males); INR increase < 4.5Kinetic effect (S)
CYP2C9 *3/*3Standard loading dose. Reduce maintenance dose by 50%. Evaluate response and serum concentration after 7-10 days. Be alert to ADEs (e.g., ataxia, nystagmus, dysarthria, sedation)Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Clinical effect (S): long-standing discomfort (> 168 hr), permanent symptom or invalidating injury e.g. failure of prophylaxis of atrial fibrillation; venous thromboembolism; decreased effect of clopidogrel on inhibition of platelet aggregation; ADE resulting from increased bioavailability of phenytoin; INR > 6.0; neutropenia 0.5-1.0x109/l; leucopenia 1.0-2.0x109/l; thrombocytopenia 25-50x109/l; severe diarrhea
\n\n", - "version" : 17 + "version" : 21 }, "userId" : "matt", - "version" : 34 + "version" : 81 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166299256", - "name" : "Recommendation PA166299256", + "id" : "PA166299249", + "name" : "Recommendation PA166299249", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "Genetic variation reduces conversion of phenytoin to inactive metabolites. This increases the risk of side effects. The life-threatening cutaneous side effects Stevens-Johnson Syndrome and toxic epidermal necrolysis may occur, especially in Asian patients." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on phenytoin." ], - "lookupKey" : {"CYP2C9": {"*3": 2}}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"CYP2C9": "Normal Metabolizer"}, + "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450947", "name" : "phenytoin", - "version" : 14 + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104984", "name" : "Annotation of DPWG Guideline for phenytoin and CYP2C9", - "version" : 34 + "version" : 81 }, "text" : { - "id" : 1452061619, - "html" : "
    \n
  1. The loading dose does not need to be adjusted.
    2. \n
  2. For the other doses, use 40% of the standard dose and assess the dose based on effect and serum concentration after 7-10 days.
    3. \n
  3. Advise the patient to get in touch if side effects (such as ataxia, nystagmus, slurred speech, sedation or, especially in Asian patients, rash) occur.
    4. \n
\n", + "id" : 1452061612, + "html" : "

The guideline does not provide a recommendation for phenytoin in normal metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299252", - "name" : "Recommendation PA166299252", + "id" : "PA166299253", + "name" : "Recommendation PA166299253", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -127158,35 +128495,35 @@ }, "dosingInformation" : true, "implications" : [ - "Genetic variation reduces conversion of phenytoin to inactive metabolites. This increases the risk of side effects. The life-threatening cutaneous side effects Stevens-Johnson Syndrome and toxic epidermal necrolysis may occur, especially in Asian patients." + "Genetic variation reduces conversion of phenytoin to inactive metabolites. This increases the risk of side effects." ], - "lookupKey" : {"CYP2C9": {"*1": 1, "*3": 1}}, + "lookupKey" : {"CYP2C9": "Poor Metabolizer"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450947", "name" : "phenytoin", - "version" : 14 + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104984", "name" : "Annotation of DPWG Guideline for phenytoin and CYP2C9", - "version" : 34 + "version" : 81 }, "text" : { - "id" : 1452061615, - "html" : "
    \n
  1. The loading dose does not need to be adjusted.
    2. \n
  2. For the other doses, use 75% of the standard dose and assess the dose based on effect and serum concentration after 7-10 days.
    3. \n
  3. Advise the patient to get in touch if side effects (such as ataxia, nystagmus, slurred speech, sedation or, especially in Asian patients, rash) occur.
    4. \n
\n", + "id" : 1452061616, + "html" : "
    \n
  1. The loading dose does not need to be adjusted.
    2. \n
  2. For the other doses, use 40-50% of the standard dose and assess the dose based on effect and serum concentration after 7-10 days.
    3. \n
  3. Advise the patient to get in touch if side effects (such as ataxia, nystagmus, slurred speech, sedation or rash) occur.
    4. \n
\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299255", - "name" : "Recommendation PA166299255", + "id" : "PA166299250", + "name" : "Recommendation PA166299250", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -127202,33 +128539,33 @@ "implications" : [ "Genetic variation reduces conversion of phenytoin to inactive metabolites. This increases the risk of side effects." ], - "lookupKey" : {"CYP2C9": {"*2": 1, "*3": 1}}, + "lookupKey" : {"CYP2C9": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450947", "name" : "phenytoin", - "version" : 14 + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104984", "name" : "Annotation of DPWG Guideline for phenytoin and CYP2C9", - "version" : 34 + "version" : 81 }, "text" : { - "id" : 1452061618, - "html" : "
    \n
  1. The loading dose does not need to be adjusted.
    2. \n
  2. For the other doses, use 50% of the standard dose and assess the dose based on effect and serum concentration after 7-10 days.
    3. \n
  3. Advise the patient to get in touch if side effects (such as ataxia, nystagmus, slurred speech, sedation or rash) occur.
    4. \n
\n", + "id" : 1452061613, + "html" : "
    \n
  1. The loading dose does not need to be adjusted.
    2. \n
  2. For the other doses, use 75% of the standard dose and assess the dose based on effect and serum concentration after 7-10 days.
    3. \n
  3. Advise the patient to get in touch if side effects (such as ataxia, nystagmus, slurred speech, sedation or rash) occur.
    4. \n
\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299251", - "name" : "Recommendation PA166299251", + "id" : "PA166299256", + "name" : "Recommendation PA166299256", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -127242,71 +128579,72 @@ }, "dosingInformation" : true, "implications" : [ - "Genetic variation reduces conversion of phenytoin to inactive metabolites. This increases the risk of side effects." + "Genetic variation reduces conversion of phenytoin to inactive metabolites. This increases the risk of side effects. The life-threatening cutaneous side effects Stevens-Johnson Syndrome and toxic epidermal necrolysis may occur, especially in Asian patients." ], - "lookupKey" : {"CYP2C9": {"*1": 1, "*2": 1}}, + "lookupKey" : {"CYP2C9": {"*3": 2}}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450947", "name" : "phenytoin", - "version" : 14 + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104984", "name" : "Annotation of DPWG Guideline for phenytoin and CYP2C9", - "version" : 34 + "version" : 81 }, "text" : { - "id" : 1452061614, - "html" : "
    \n
  1. The loading dose does not need to be adjusted.
    2. \n
  2. For the other doses, use 75% of the standard dose and assess the dose based on effect and serum concentration after 7-10 days.
    3. \n
  3. Advise the patient to get in touch if side effects (such as ataxia, nystagmus, slurred speech, sedation or rash) occur.
    4. \n
\n", + "id" : 1452061619, + "html" : "
    \n
  1. The loading dose does not need to be adjusted.
    2. \n
  2. For the other doses, use 40% of the standard dose and assess the dose based on effect and serum concentration after 7-10 days.
    3. \n
  3. Advise the patient to get in touch if side effects (such as ataxia, nystagmus, slurred speech, sedation or, especially in Asian patients, rash) occur.
    4. \n
\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299249", - "name" : "Recommendation PA166299249", + "id" : "PA166299255", + "name" : "Recommendation PA166299255", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on phenytoin." + "Genetic variation reduces conversion of phenytoin to inactive metabolites. This increases the risk of side effects." ], - "lookupKey" : {"CYP2C9": "Normal Metabolizer"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"CYP2C9": {"*2": 1, "*3": 1}}, + "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450947", "name" : "phenytoin", - "version" : 14 + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104984", "name" : "Annotation of DPWG Guideline for phenytoin and CYP2C9", - "version" : 34 + "version" : 81 }, "text" : { - "id" : 1452061612, - "html" : "

The guideline does not provide a recommendation for phenytoin in normal metabolizers.

\n", + "id" : 1452061618, + "html" : "
    \n
  1. The loading dose does not need to be adjusted.
    2. \n
  2. For the other doses, use 50% of the standard dose and assess the dose based on effect and serum concentration after 7-10 days.
    3. \n
  3. Advise the patient to get in touch if side effects (such as ataxia, nystagmus, slurred speech, sedation or rash) occur.
    4. \n
\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -127334,26 +128672,26 @@ "objCls" : "Chemical", "id" : "PA450947", "name" : "phenytoin", - "version" : 14 + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104984", "name" : "Annotation of DPWG Guideline for phenytoin and CYP2C9", - "version" : 34 + "version" : 81 }, "text" : { "id" : 1452061617, "html" : "
    \n
  1. The loading dose does not need to be adjusted.
    2. \n
  2. For the other doses, use 50% of the standard dose and assess the dose based on effect and serum concentration after 7-10 days.
    3. \n
  3. Advise the patient to get in touch if side effects (such as ataxia, nystagmus, slurred speech, sedation or rash) occur.
    4. \n
\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299250", - "name" : "Recommendation PA166299250", + "id" : "PA166299252", + "name" : "Recommendation PA166299252", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -127367,35 +128705,35 @@ }, "dosingInformation" : true, "implications" : [ - "Genetic variation reduces conversion of phenytoin to inactive metabolites. This increases the risk of side effects." + "Genetic variation reduces conversion of phenytoin to inactive metabolites. This increases the risk of side effects. The life-threatening cutaneous side effects Stevens-Johnson Syndrome and toxic epidermal necrolysis may occur, especially in Asian patients." ], - "lookupKey" : {"CYP2C9": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2C9": {"*1": 1, "*3": 1}}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450947", "name" : "phenytoin", - "version" : 14 + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104984", "name" : "Annotation of DPWG Guideline for phenytoin and CYP2C9", - "version" : 34 + "version" : 81 }, "text" : { - "id" : 1452061613, - "html" : "
    \n
  1. The loading dose does not need to be adjusted.
    2. \n
  2. For the other doses, use 75% of the standard dose and assess the dose based on effect and serum concentration after 7-10 days.
    3. \n
  3. Advise the patient to get in touch if side effects (such as ataxia, nystagmus, slurred speech, sedation or rash) occur.
    4. \n
\n", + "id" : 1452061615, + "html" : "
    \n
  1. The loading dose does not need to be adjusted.
    2. \n
  2. For the other doses, use 75% of the standard dose and assess the dose based on effect and serum concentration after 7-10 days.
    3. \n
  3. Advise the patient to get in touch if side effects (such as ataxia, nystagmus, slurred speech, sedation or, especially in Asian patients, rash) occur.
    4. \n
\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299253", - "name" : "Recommendation PA166299253", + "id" : "PA166299251", + "name" : "Recommendation PA166299251", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -127411,34 +128749,90 @@ "implications" : [ "Genetic variation reduces conversion of phenytoin to inactive metabolites. This increases the risk of side effects." ], - "lookupKey" : {"CYP2C9": "Poor Metabolizer"}, + "lookupKey" : {"CYP2C9": {"*1": 1, "*2": 1}}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450947", "name" : "phenytoin", - "version" : 14 + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104984", "name" : "Annotation of DPWG Guideline for phenytoin and CYP2C9", - "version" : 34 + "version" : 81 }, "text" : { - "id" : 1452061616, - "html" : "
    \n
  1. The loading dose does not need to be adjusted.
    2. \n
  2. For the other doses, use 40-50% of the standard dose and assess the dose based on effect and serum concentration after 7-10 days.
    3. \n
  3. Advise the patient to get in touch if side effects (such as ataxia, nystagmus, slurred speech, sedation or rash) occur.
    4. \n
\n", + "id" : 1452061614, + "html" : "
    \n
  1. The loading dose does not need to be adjusted.
    2. \n
  2. For the other doses, use 75% of the standard dose and assess the dose based on effect and serum concentration after 7-10 days.
    3. \n
  3. Advise the patient to get in touch if side effects (such as ataxia, nystagmus, slurred speech, sedation or rash) occur.
    4. \n
\n", "version" : 0 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166104984" }, { - "citations" : [], + "citations" : [ + { + "id" : 15156470, + "title" : "Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction of CYP2C9, HLA-A and HLA-B with anti-epileptic drugs.", + "_sameAs" : "https://www.ncbi.nlm.nih.gov/pubmed/38570725", + "authors" : [ + "Manson Lisanne E N", + "Nijenhuis Marga", + "Soree Bianca", + "de Boer-Veger Nienke J", + "Buunk Anne-Marie", + "Houwink Elisa J F", + "Risselada Arne", + "Rongen Gerard A P J M", + "van Schaik Ron H N", + "Swen Jesse J", + "Touw Daan J", + "van Westrhenen Roos", + "Deneer Vera H M", + "Guchelaar Henk-Jan" + ], + "crossReferences" : [ + { + "id" : 1452435716, + "resource" : "PubMed", + "resourceId" : "38570725", + "_url" : "https://www.ncbi.nlm.nih.gov/pubmed/38570725", + "version" : 0 + }, + { + "id" : 1452435717, + "resource" : "DOI", + "resourceId" : "10.1038/s41431-024-01572-4", + "_url" : "http://dx.doi.org/10.1038%2Fs41431-024-01572-4", + "version" : 0 + } + ], + "day" : -1, + "hasKeyword" : true, + "journal" : "European journal of human genetics : EJHG", + "meshDiseases" : [], + "meshTerms" : [], + "month" : 4, + "nonHuman" : false, + "objCls" : "Literature", + "pediatric" : false, + "pgkbPublication" : false, + "pubDate" : "2024-04-01T00:00:00-07:00", + "summary" : "By developing evidence-based pharmacogenetics guidelines to optimize pharmacotherapy, the Dutch Pharmacogenetics Working Group (DPWG) aims to advance the implementation of pharmacogenetics (PGx). This guideline outlines the gene-drug interaction of CYP2C9 and HLA-B with phenytoin, HLA-A and HLA-B with carbamazepine and HLA-B with oxcarbazepine and lamotrigine. A systematic review was performed and pharmacotherapeutic recommendations were developed. For CYP2C9 intermediate and poor metabolisers, the DPWG recommends lowering the daily dose of phenytoin and adjust based on effect and serum concentration after 7-10 days. For HLA-B*15:02 carriers, the risk of severe cutaneous adverse events associated with phenytoin, carbamazepine, oxcarbazepine, and lamotrigine is strongly increased. For carbamazepine, this risk is also increased in HLA-B*15:11 and HLA-A*31:01 carriers. For HLA-B*15:02, HLA-B*15:11 and HLA-A*31:01 positive patients, the DPWG recommends choosing an alternative anti-epileptic drug. If not possible, it is recommended to advise the patient to report any rash while using carbamazepine, lamotrigine, oxcarbazepine or phenytoin immediately. Carbamazepine should not be used in an HLA-B*15:02 positive patient. DPWG considers CYP2C9 genotyping before the start of phenytoin \"essential\" for toxicity prevention. For patients with an ancestry in which the abovementioned HLA-alleles are prevalent, the DPWG considers HLA-B*15:02 genotyping before the start of carbamazepine, phenytoin, oxcarbazepine, and lamotrigine \"beneficial\", as well as genotyping for HLA-B*15:11 and HLA-A*31:01 before initiating carbamazepine.", + "terms" : [ + {"id":1451577480,"resource":"PGx Paper Types","term":"Implementation","termId":"pgxPaperTypes:1451577480"} + ], + "type" : "Literature", + "version" : 4, + "year" : 2024 + } + ], "guideline" : { "objCls" : "Guideline Annotation", "id" : "PA166264881", @@ -127510,9 +128904,18 @@ "description" : "Updated links for risk analysis pdf and preemptive testing page.", "type" : "Update", "version" : 0 + }, + { + "id" : 1452439762, + "date" : "2024-04-11T06:32:53.872-07:00", + "description" : "Added 2024 publication.", + "type" : "Update", + "version" : 0 } ], - "literature" : [], + "literature" : [ + {"id":15156470,"title":"Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction of CYP2C9, HLA-A and HLA-B with anti-epileptic drugs.","_sameAs":"https://www.ncbi.nlm.nih.gov/pubmed/38570725","crossReferences":[{"id":1452435716,"resource":"PubMed","resourceId":"38570725","_url":"https://www.ncbi.nlm.nih.gov/pubmed/38570725"},{"id":1452435717,"resource":"DOI","resourceId":"10.1038/s41431-024-01572-4","_url":"http://dx.doi.org/10.1038%2Fs41431-024-01572-4"}],"objCls":"Literature","pubDate":"2024-04-01T00:00:00-07:00","terms":[{"id":1451577480,"resource":"PGx Paper Types","term":"Implementation","termId":"pgxPaperTypes:1451577480"}],"type":"Literature"} + ], "otherPrescribingGuidance" : true, "pediatric" : false, "recommendation" : true, @@ -127522,7 +128925,7 @@ "id" : "PA165954769", "symbol" : "HLA-B*15:02", "name" : "*15:02", - "version" : 5 + "version" : 21 } ], "relatedChemicals" : [ @@ -127530,7 +128933,7 @@ "objCls" : "Chemical", "id" : "PA450947", "name" : "phenytoin", - "version" : 14 + "version" : 49 } ], "relatedGenes" : [ @@ -127539,7 +128942,7 @@ "id" : "PA35056", "symbol" : "HLA-B", "name" : "major histocompatibility complex, class I, B", - "version" : 40 + "version" : 2920 } ], "source" : "DPWG", @@ -127552,10 +128955,10 @@ "textMarkdown" : { "id" : 1451695781, "html" : "

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

\n

May 2021

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for phenytoin based on HLA-B*15:02.

\n

The annotation of the DPWG guideline for phenytoin and CYP2C9 can be found here

\n

Wording in table taken from the Dutch guidelines May 2021 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
HLA-B*1502phenytoinThe life-threatening cutaneous side effect Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) occurs more frequently in patients with this genetic variation. The calculated risk of phenytoin-induced SJS/TEN in patients with HLA-B*1502 is 0.65%.Carefully weigh the risk of SJS/TEN against the benefits.
Avoid phenytoin if an alternative is possible. Carbamazepine carries a 10-fold higher risk of SJS/TEN for these patients and is therefore not an alternative. A comparable risk has been reported for lamotrigine as for phenytoin. The same applies for oxcarbazepine, but the most severe forms (SJS/TEN overlap and TEN) are not observed with oxcarbazepine.
If it is not possible to avoid this medication, then advise the patient to report any skin rash immediately
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for phenytoin and HLA:

\n
\n

HLA-B*1502 has not been detected in a sample of 1350 Dutch persons (Allele Frequency Net Database: http://www.allelefrequencies.net). For this reason, the Dutch Pharmacogenetics Working Group does not consider genotyping of Dutch patients in general before starting phenytoin to be useful.\nHowever, the HLA-B*1502 frequency is high in Asians, except for Japanese and Koreans. The Dutch Pharmacogenetics Working Group considers genotyping of patients of Asian descent other than Japanese or Korean descent before starting phenytoin to be beneficial for drug safety. It is advised to genotype these patients before (or directly after) drug therapy has been initiated to guide drug and dose selection.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n", - "version" : 5 + "version" : 7 }, "userId" : "rachel", - "version" : 9 + "version" : 32 }, "recommendations" : [ { @@ -127584,21 +128987,21 @@ "objCls" : "Chemical", "id" : "PA450947", "name" : "phenytoin", - "version" : 14 + "version" : 49 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166264881", "name" : "Annotation of DPWG Guideline for phenytoin and HLA-B", - "version" : 9 + "version" : 32 }, "text" : { "id" : 1452061468, "html" : "\n", "version" : 0 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166264881" @@ -127705,7 +129108,7 @@ "id" : 1450415022, "date" : "2019-05-23T00:00:00-07:00", "type" : "Create", - "version" : 0 + "version" : 1 }, { "id" : 1450821025, @@ -127909,7 +129312,7 @@ "objCls" : "Chemical", "id" : "PA450965", "name" : "pimozide", - "version" : 12 + "version" : 33 } ], "relatedGenes" : [ @@ -127918,7 +129321,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "DPWG", @@ -127931,16 +129334,16 @@ "textMarkdown" : { "id" : 1450415021, "html" : "

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

\n

Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction between CYP2D6, CYP3A4 and CYP1A2 and antipsychotics. European journal of human genetics (2023)

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group published a paper with the guidelines for pimozide and CYP2D6 as per the February 2022 guidelines and further details on the assessed literature [Article:37002327]. Wording in the poor and intermediate metabolizer recommendation changed from "standard" to "normal" and is reflected in the table below.

\n

February 2022 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has updated their therapeutic dose recommendations for pimozide based on CYP2D6 genotype. They now give more detailed dosing instructions by age.

\n

Wording in table taken from the Dutch guidelines February 2022 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
CYP2D6 UMpimozideThis gene variation can result in lower pimozide concentrations. However, there is no evidence of reduced effectiveness.NO action is required for this gene-drug interaction.
CYP2D6 IMpimozideThe risk of QT-prolongation – and thereby also the risk of torsade de points – is theoretically increased, because the genetic variation results in an increase in the plasma concentration of pimozide. The elevated plasma concentration and associated theoretical increased risk of QT elongation can be negated by following the dose recommendations provided below.Use no more than the following doses (80% of the normal maximum dose):
12 years and older: 16 mg/day
younger than 12 years: 0.08 mg/kg per day to a maximum of 3 mg/day
CYP2D6 PMpimozideThe risk of QT-prolongation – and thereby also the risk of torsade de points – is theoretically increased, because the genetic variation results in an increase in the plasma concentration of pimozide. The elevated plasma concentration and associated theoretical increased risk of QT elongation can be negated by following the dose recommendations provided below.Use no more than the following doses (50% of the normal maximum dose):
12 years and older: 10 mg/day
younger than 12 years: 0.05 mg/kg per day to a maximum of 2 mg/day
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for pimozide and CYP2D6:

\n
\n

The Dutch Pharmacogenetics Working Group considers genotyping before starting pimozide to be potentially beneficial for the prevention of adverse events. Genotyping can be considered on an individual patient basis. If, however, the genotype is available, the Dutch Pharmacogenetics Working Group recommends adhering to the gene-drug guideline

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n

November 2018 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for pimozide based on CYP2D6 genotype. They recommend a dose reduction for patients who are CYP2D6 intermediate metabolizers (IMs) or poor metabolizers (PMs). There are no recommendations for patients who are CYP2D6 ultrarapid metabolizers (UMs).

\n

Wording in table taken from the Dutch guidelines November 2018 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
CYP2D6 UMpimozideThis gene variation can result in lower pimozide concentrations. However, there is no evidence of reduced effectiveness.NO action is required for this gene-drug interaction.
CYP2D6 IMpimozideThe risk of QT-prolongation – and thereby also the risk of torsade de points – is theoretically increased, because the genetic variation results in an increase in the plasma concentration of pimozide. The risk of an excessively high plasma concentration can be negated by following the dose recommendations provided.Use no more than the following doses (80% of the standard maximum dose):
adults 16 mg/day
children 0.08 mg/kg per day to a maximum of 3 mg/day
CYP2D6 PMpimozideThe risk of QT-prolongation – and thereby also the risk of torsade de points – is theoretically increased, because the genetic variation results in an increase in the plasma concentration of pimozide. The risk of an excessively high plasma concentration can be negated by following the dose recommendations provided.Use no more than the following doses (50% of the standard maximum dose):
adults 10 mg/day
children 0.05 mg/kg per day to a maximum of 2 mg/day
\n", - "version" : 7 + "version" : 11 }, "userId" : "rachel", - "version" : 19 + "version" : 80 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166302643", - "name" : "Recommendation Annotation PA166302643", + "id" : "PA166302621", + "name" : "Recommendation Annotation PA166302621", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -127954,35 +129357,35 @@ }, "dosingInformation" : true, "implications" : [ - "The risk of QT-prolongation – and thereby also the risk of torsade de points – is theoretically increased, because the genetic variation results in an increase in the plasma concentration of pimozide. The elevated plasma concentration and associated theoretical increased risk of QT elongation can be negated by following the dose recommendations provided below." + "The risk of QT-prolongation – and thereby also the risk of torsade de points – is theoretically increased, because the genetic variation results in an increase in the plasmaconcentration of pimozide. The elevated plasma concentration and associated theoretical increased risk of QT elongation can be negated by following the doserecommendations provided below." ], - "lookupKey" : {"CYP2D6": "0.75"}, + "lookupKey" : {"CYP2D6": "0.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450965", "name" : "pimozide", - "version" : 12 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182819", "name" : "Annotation of DPWG Guideline for pimozide and CYP2D6", - "version" : 19 + "version" : 80 }, "text" : { - "id" : 1452104242, - "html" : "

Use no more than the following doses (80% of the normal maximum dose):

\n\n", + "id" : 1452104220, + "html" : "

Use no more than the following doses (50% of the normal maximum dose):

\n\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302621", - "name" : "Recommendation Annotation PA166302621", + "id" : "PA166302641", + "name" : "Recommendation Annotation PA166302641", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -127996,76 +129399,77 @@ }, "dosingInformation" : true, "implications" : [ - "The risk of QT-prolongation – and thereby also the risk of torsade de points – is theoretically increased, because the genetic variation results in an increase in the plasmaconcentration of pimozide. The elevated plasma concentration and associated theoretical increased risk of QT elongation can be negated by following the doserecommendations provided below." + "The risk of QT-prolongation – and thereby also the risk of torsade de points – is theoretically increased, because the genetic variation results in an increase in the plasma concentration of pimozide. The elevated plasma concentration and associated theoretical increased risk of QT elongation can be negated by following the dose recommendations provided below." ], - "lookupKey" : {"CYP2D6": "0.0"}, + "lookupKey" : {"CYP2D6": "0.25"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450965", "name" : "pimozide", - "version" : 12 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182819", "name" : "Annotation of DPWG Guideline for pimozide and CYP2D6", - "version" : 19 + "version" : 80 }, "text" : { - "id" : 1452104220, - "html" : "

Use no more than the following doses (50% of the normal maximum dose):

\n\n", + "id" : 1452104240, + "html" : "

Use no more than the following doses (80% of the normal maximum dose):

\n\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302647", - "name" : "Recommendation Annotation PA166302647", + "id" : "PA166302642", + "name" : "Recommendation Annotation PA166302642", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on pimozide." + "The risk of QT-prolongation – and thereby also the risk of torsade de points – is theoretically increased, because the genetic variation results in an increase in the plasma concentration of pimozide. The elevated plasma concentration and associated theoretical increased risk of QT elongation can be negated by following the dose recommendations provided below." ], - "lookupKey" : {"CYP2D6": "2.0"}, + "lookupKey" : {"CYP2D6": "0.5"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450965", "name" : "pimozide", - "version" : 12 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182819", "name" : "Annotation of DPWG Guideline for pimozide and CYP2D6", - "version" : 19 + "version" : 80 }, "text" : { - "id" : 1452104246, - "html" : "

The guideline does not provide a recommendation for pimozide in normal metabolizers.

\n", + "id" : 1452104241, + "html" : "

Use no more than the following doses (80% of the normal maximum dose):

\n\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302682", - "name" : "Recommendation Annotation PA166302682", + "id" : "PA166302643", + "name" : "Recommendation Annotation PA166302643", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -128077,37 +129481,37 @@ "valid" : true, "version" : 1 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "This gene variation can result in lower pimozide concentrations. However, there is no evidence of reduced effectiveness." + "The risk of QT-prolongation – and thereby also the risk of torsade de points – is theoretically increased, because the genetic variation results in an increase in the plasma concentration of pimozide. The elevated plasma concentration and associated theoretical increased risk of QT elongation can be negated by following the dose recommendations provided below." ], - "lookupKey" : {"CYP2D6": "3.0"}, + "lookupKey" : {"CYP2D6": "0.75"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450965", "name" : "pimozide", - "version" : 12 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182819", "name" : "Annotation of DPWG Guideline for pimozide and CYP2D6", - "version" : 19 + "version" : 80 }, "text" : { - "id" : 1452104281, - "html" : "

NO action is required for this gene-drug interaction.

\n", + "id" : 1452104242, + "html" : "

Use no more than the following doses (80% of the normal maximum dose):

\n\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302686", - "name" : "Recommendation Annotation PA166302686", + "id" : "PA166302644", + "name" : "Recommendation Annotation PA166302644", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -128119,121 +129523,160 @@ "valid" : true, "version" : 1 }, + "dosingInformation" : true, + "implications" : [ + "The risk of QT-prolongation – and thereby also the risk of torsade de points – is theoretically increased, because the genetic variation results in an increase in the plasma concentration of pimozide. The elevated plasma concentration and associated theoretical increased risk of QT elongation can be negated by following the dose recommendations provided below." + ], + "lookupKey" : {"CYP2D6": "1.0"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA450965", + "name" : "pimozide", + "version" : 33 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166182819", + "name" : "Annotation of DPWG Guideline for pimozide and CYP2D6", + "version" : 80 + }, + "text" : { + "id" : 1452104243, + "html" : "

Use no more than the following doses (80% of the normal maximum dose):

\n\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166302645", + "name" : "Recommendation Annotation PA166302645", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 1448526251, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", + "valid" : true, + "version" : 0 + }, "dosingInformation" : false, "implications" : [ - "This gene variation can result in lower pimozide concentrations. However, there is no evidence of reduced effectiveness." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on pimozide." ], - "lookupKey" : {"CYP2D6": "≥3.5"}, + "lookupKey" : {"CYP2D6": "1.25"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450965", "name" : "pimozide", - "version" : 12 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182819", "name" : "Annotation of DPWG Guideline for pimozide and CYP2D6", - "version" : 19 + "version" : 80 }, "text" : { - "id" : 1452104285, - "html" : "

NO action is required for this gene-drug interaction.

\n", + "id" : 1452104244, + "html" : "

The guideline does not provide a recommendation for pimozide in normal metabolizers.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302642", - "name" : "Recommendation Annotation PA166302642", + "id" : "PA166302646", + "name" : "Recommendation Annotation PA166302646", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "The risk of QT-prolongation – and thereby also the risk of torsade de points – is theoretically increased, because the genetic variation results in an increase in the plasma concentration of pimozide. The elevated plasma concentration and associated theoretical increased risk of QT elongation can be negated by following the dose recommendations provided below." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on pimozide." ], - "lookupKey" : {"CYP2D6": "0.5"}, + "lookupKey" : {"CYP2D6": "1.5"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450965", "name" : "pimozide", - "version" : 12 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182819", "name" : "Annotation of DPWG Guideline for pimozide and CYP2D6", - "version" : 19 + "version" : 80 }, "text" : { - "id" : 1452104241, - "html" : "

Use no more than the following doses (80% of the normal maximum dose):

\n\n", + "id" : 1452104245, + "html" : "

The guideline does not provide a recommendation for pimozide in normal metabolizers.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302685", - "name" : "Recommendation Annotation PA166302685", + "id" : "PA166302647", + "name" : "Recommendation Annotation PA166302647", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, "dosingInformation" : false, "implications" : [ - "This gene variation can result in lower pimozide concentrations. However, there is no evidence of reduced effectiveness." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on pimozide." ], - "lookupKey" : {"CYP2D6": "≥3.25"}, + "lookupKey" : {"CYP2D6": "2.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450965", "name" : "pimozide", - "version" : 12 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182819", "name" : "Annotation of DPWG Guideline for pimozide and CYP2D6", - "version" : 19 + "version" : 80 }, "text" : { - "id" : 1452104284, - "html" : "

NO action is required for this gene-drug interaction.

\n", + "id" : 1452104246, + "html" : "

The guideline does not provide a recommendation for pimozide in normal metabolizers.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302646", - "name" : "Recommendation Annotation PA166302646", + "id" : "PA166302661", + "name" : "Recommendation Annotation PA166302661", "alternateDrugAvailable" : false, "classification" : { "id" : 1448526251, @@ -128248,24 +129691,24 @@ "implications" : [ "The guideline does not provide a description of the impact of a normal metabolizer phenotype on pimozide." ], - "lookupKey" : {"CYP2D6": "1.5"}, + "lookupKey" : {"CYP2D6": "2.25"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450965", "name" : "pimozide", - "version" : 12 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182819", "name" : "Annotation of DPWG Guideline for pimozide and CYP2D6", - "version" : 19 + "version" : 80 }, "text" : { - "id" : 1452104245, + "id" : 1452104260, "html" : "

The guideline does not provide a recommendation for pimozide in normal metabolizers.

\n", "version" : 0 }, @@ -128296,14 +129739,14 @@ "objCls" : "Chemical", "id" : "PA450965", "name" : "pimozide", - "version" : 12 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182819", "name" : "Annotation of DPWG Guideline for pimozide and CYP2D6", - "version" : 19 + "version" : 80 }, "text" : { "id" : 1452104280, @@ -128314,8 +129757,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302689", - "name" : "Recommendation Annotation PA166302689", + "id" : "PA166302682", + "name" : "Recommendation Annotation PA166302682", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -128331,24 +129774,24 @@ "implications" : [ "This gene variation can result in lower pimozide concentrations. However, there is no evidence of reduced effectiveness." ], - "lookupKey" : {"CYP2D6": "≥6.0"}, + "lookupKey" : {"CYP2D6": "3.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450965", "name" : "pimozide", - "version" : 12 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182819", "name" : "Annotation of DPWG Guideline for pimozide and CYP2D6", - "version" : 19 + "version" : 80 }, "text" : { - "id" : 1452104288, + "id" : 1452104281, "html" : "

NO action is required for this gene-drug interaction.

\n", "version" : 0 }, @@ -128356,8 +129799,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302641", - "name" : "Recommendation Annotation PA166302641", + "id" : "PA166302683", + "name" : "Recommendation Annotation PA166302683", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -128369,78 +129812,163 @@ "valid" : true, "version" : 1 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "The risk of QT-prolongation – and thereby also the risk of torsade de points – is theoretically increased, because the genetic variation results in an increase in the plasma concentration of pimozide. The elevated plasma concentration and associated theoretical increased risk of QT elongation can be negated by following the dose recommendations provided below." + "This gene variation can result in lower pimozide concentrations. However, there is no evidence of reduced effectiveness." ], - "lookupKey" : {"CYP2D6": "0.25"}, + "lookupKey" : {"CYP2D6": "4.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450965", "name" : "pimozide", - "version" : 12 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182819", "name" : "Annotation of DPWG Guideline for pimozide and CYP2D6", - "version" : 19 + "version" : 80 }, "text" : { - "id" : 1452104240, - "html" : "

Use no more than the following doses (80% of the normal maximum dose):

\n\n", + "id" : 1452104282, + "html" : "

NO action is required for this gene-drug interaction.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302645", - "name" : "Recommendation Annotation PA166302645", + "id" : "PA166302684", + "name" : "Recommendation Annotation PA166302684", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", + "valid" : true, + "version" : 1 + }, + "dosingInformation" : false, + "implications" : [ + "This gene variation can result in lower pimozide concentrations. However, there is no evidence of reduced effectiveness." + ], + "lookupKey" : {"CYP2D6": "≥3.0"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA450965", + "name" : "pimozide", + "version" : 33 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166182819", + "name" : "Annotation of DPWG Guideline for pimozide and CYP2D6", + "version" : 80 + }, + "text" : { + "id" : 1452104283, + "html" : "

NO action is required for this gene-drug interaction.

\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166302685", + "name" : "Recommendation Annotation PA166302685", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501929, + "description" : "Not Applicable", + "parents" : [], + "resource" : "Guideline Strength", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, + "version" : 1 + }, + "dosingInformation" : false, + "implications" : [ + "This gene variation can result in lower pimozide concentrations. However, there is no evidence of reduced effectiveness." + ], + "lookupKey" : {"CYP2D6": "≥3.25"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA450965", + "name" : "pimozide", + "version" : 33 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166182819", + "name" : "Annotation of DPWG Guideline for pimozide and CYP2D6", + "version" : 80 + }, + "text" : { + "id" : 1452104284, + "html" : "

NO action is required for this gene-drug interaction.

\n", "version" : 0 }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166302686", + "name" : "Recommendation Annotation PA166302686", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501929, + "description" : "Not Applicable", + "parents" : [], + "resource" : "Guideline Strength", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", + "valid" : true, + "version" : 1 + }, "dosingInformation" : false, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on pimozide." + "This gene variation can result in lower pimozide concentrations. However, there is no evidence of reduced effectiveness." ], - "lookupKey" : {"CYP2D6": "1.25"}, + "lookupKey" : {"CYP2D6": "≥3.5"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450965", "name" : "pimozide", - "version" : 12 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182819", "name" : "Annotation of DPWG Guideline for pimozide and CYP2D6", - "version" : 19 + "version" : 80 }, "text" : { - "id" : 1452104244, - "html" : "

The guideline does not provide a recommendation for pimozide in normal metabolizers.

\n", + "id" : 1452104285, + "html" : "

NO action is required for this gene-drug interaction.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302684", - "name" : "Recommendation Annotation PA166302684", + "id" : "PA166302687", + "name" : "Recommendation Annotation PA166302687", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -128456,24 +129984,24 @@ "implications" : [ "This gene variation can result in lower pimozide concentrations. However, there is no evidence of reduced effectiveness." ], - "lookupKey" : {"CYP2D6": "≥3.0"}, + "lookupKey" : {"CYP2D6": "≥4.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450965", "name" : "pimozide", - "version" : 12 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182819", "name" : "Annotation of DPWG Guideline for pimozide and CYP2D6", - "version" : 19 + "version" : 80 }, "text" : { - "id" : 1452104283, + "id" : 1452104286, "html" : "

NO action is required for this gene-drug interaction.

\n", "version" : 0 }, @@ -128505,14 +130033,14 @@ "objCls" : "Chemical", "id" : "PA450965", "name" : "pimozide", - "version" : 12 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182819", "name" : "Annotation of DPWG Guideline for pimozide and CYP2D6", - "version" : 19 + "version" : 80 }, "text" : { "id" : 1452104287, @@ -128523,133 +130051,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302644", - "name" : "Recommendation Annotation PA166302644", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 981501929, - "description" : "Not Applicable", - "parents" : [], - "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", - "valid" : true, - "version" : 1 - }, - "dosingInformation" : true, - "implications" : [ - "The risk of QT-prolongation – and thereby also the risk of torsade de points – is theoretically increased, because the genetic variation results in an increase in the plasma concentration of pimozide. The elevated plasma concentration and associated theoretical increased risk of QT elongation can be negated by following the dose recommendations provided below." - ], - "lookupKey" : {"CYP2D6": "1.0"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA450965", - "name" : "pimozide", - "version" : 12 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166182819", - "name" : "Annotation of DPWG Guideline for pimozide and CYP2D6", - "version" : 19 - }, - "text" : { - "id" : 1452104243, - "html" : "

Use no more than the following doses (80% of the normal maximum dose):

\n\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166302683", - "name" : "Recommendation Annotation PA166302683", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 981501929, - "description" : "Not Applicable", - "parents" : [], - "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", - "valid" : true, - "version" : 1 - }, - "dosingInformation" : false, - "implications" : [ - "This gene variation can result in lower pimozide concentrations. However, there is no evidence of reduced effectiveness." - ], - "lookupKey" : {"CYP2D6": "4.0"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA450965", - "name" : "pimozide", - "version" : 12 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166182819", - "name" : "Annotation of DPWG Guideline for pimozide and CYP2D6", - "version" : 19 - }, - "text" : { - "id" : 1452104282, - "html" : "

NO action is required for this gene-drug interaction.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166302661", - "name" : "Recommendation Annotation PA166302661", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 1448526251, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on pimozide." - ], - "lookupKey" : {"CYP2D6": "2.25"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA450965", - "name" : "pimozide", - "version" : 12 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166182819", - "name" : "Annotation of DPWG Guideline for pimozide and CYP2D6", - "version" : 19 - }, - "text" : { - "id" : 1452104260, - "html" : "

The guideline does not provide a recommendation for pimozide in normal metabolizers.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166302687", - "name" : "Recommendation Annotation PA166302687", + "id" : "PA166302689", + "name" : "Recommendation Annotation PA166302689", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -128665,24 +130068,24 @@ "implications" : [ "This gene variation can result in lower pimozide concentrations. However, there is no evidence of reduced effectiveness." ], - "lookupKey" : {"CYP2D6": "≥4.0"}, + "lookupKey" : {"CYP2D6": "≥6.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450965", "name" : "pimozide", - "version" : 12 + "version" : 33 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182819", "name" : "Annotation of DPWG Guideline for pimozide and CYP2D6", - "version" : 19 + "version" : 80 }, "text" : { - "id" : 1452104286, + "id" : 1452104288, "html" : "

NO action is required for this gene-drug interaction.

\n", "version" : 0 }, @@ -128951,7 +130354,7 @@ "objCls" : "Chemical", "id" : "PA451131", "name" : "propafenone", - "version" : 11 + "version" : 28 } ], "relatedGenes" : [ @@ -128960,30 +130363,30 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "DPWG", "summaryMarkdown" : { "id" : 1447981932, "html" : "

Reduce the dose of propafenone by 70% for CYP2D6 poor metabolizers, and monitor propafenone plasma concentrations or use an alternative drug for CYP2D6 intermediate and ultrarapid metabolizers.

\n", - "version" : 2 + "version" : 3 }, "terms" : [], "textMarkdown" : { "id" : 1447981931, "html" : "

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

\n

November 2018 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for propafenone based on CYP2D6 genotype. They recommend monitoring plasma concentrations and performing an ECG or selecting an alternative antiarrhythmic drug for CYP2D6 ultrarapid metabolizers (UMs) and intermeidate metabolizers (IMs). They also recommend that patients who are CYP2D6 poor metabolizers (PMs) receive 30% of a standard dose of propafenone.

\n

Wording in table taken from the Dutch guidelines November 2018 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
CYP2D6 UMpropafenoneGenetic variation decreases the sum of the plasma concentrations of propafenone and the active metabolite 5-hydroxypropafenone. This increases the risk of reduced or no efficacyIt is not possible to offer adequately substantiated recommendations for dose adjustment based on the literature.
1. Either monitor plasma concentrations, perform an ECG and be alert to reduced efficacy of the therapy.
2. Or choose an alternative. Antiarrhythmic drugs that are hardly if at all metabolised by CYP2D6 include, for example, sotalol, disopyramide, quinidine and amiodarone.
CYP2D6 IMpropafenoneGenetic variation increases the sum of the plasma concentrations of propafenone and the active metabolite 5-hydroxypropafenone. This may increase the risk of side effects.It is not possible to offer adequately substantiated recommendations for dose adjustment based on the literature.
1. Either guide the dose by therapeutic drug monitoring, perform an ECG and be alert to side effects
2. Or choose an alternative. Antiarrhythmic drugs that are hardly if at all metabolised by CYP2D6 include, for example, sotalol, disopyramide, quinidine and amiodarone.
CYP2D6 PMpropafenoneGenetic variation increases the sum of the plasma concentrations of propafenone and the active metabolite 5-hydroxypropafenone. This increases the risk of side effects.Reduce the dose to 30% of the standard dose, perform an ECG and monitor plasma concentrations.
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for propafenone and CYP2D6:

\n
\n

The KNMP Pharmacogenetics Working Group considers genotyping before starting propafenone to be potentially\nbeneficial for the prevention of side effects and drug effectiveness. Genotyping can be considered on an individual\npatient basis. If, however, the genotype is available, the KNMP Pharmacogenetics Working Group recommends\nadhering to the gene-drug guideline.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n

2011 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for propafenone based on CYP2D6 genotype [Article:21412232]. They suggest a reduced dose for poor metabolizers, and adjusting dose according to plasma concentrations or using an alternative drug for intermediate and ultrarapid metabolizers.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Phenotype (Genotype)Therapeutic Dose RecommendationLevel of EvidenceClinical Relevance
PM (2 inactive alleles)Reduce dose by 70%, record ECG, monitor plasma concentrationPublished controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Clinical effect (S): long-standing discomfort (48-168 hr) without permanent injury e.g. failure of therapy with tricyclic antidepressants, atypical antipsychotic drugs; extrapyramidal side effects; parkinsonism; ADE resulting from increased bioavailability of tricyclic antidepressants, metoprolol, propafenone (central effects e.g. dizziness); INR 4.5-6.0; neutropenia 1.0-1.5x10 9/l; leucopenia 2.0-3.0x10 9/l; thrombocytopenia 50-75x10 9/l
IM (2 decreased activity alleles, or 1 active and 1 inactive allele, or 1 decreased activity and 1 inactive allele)Insufficient data to allow calculation of dose adjustment. Adjust dose in response to plasma concentration and record ECG or select alternative drug (e.g., sotalol, disopyramide, quinidine, amiodarone)Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Minor clinical effect (S): QTc prolongation (<450 ms male, <470 ms female); INR increase < 4.5, Kinetic effect (S)
UM (gene duplication in absence of inactive or decreased activity alleles)Insufficient data to allow calculation of dose adjustment. Adjust dose in response to plasma concentration and record ECG or select alternative drug (e.g., sotalol, disopyramide, quinidine, amiodarone)Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Clinical effect (S): long-standing discomfort (> 168 hr), permanent symptom or invalidating injury e.g. failure of prophylaxis of atrial fibrillation; venous thromboembolism; decreased effect of clopidogrel on inhibition of platelet aggregation; ADE resulting from increased bioavailability of phenytoin; INR > 6.0; neutropenia 0.5-1.0x10 9/l; leucopenia 1.0-2.0x10 9/l; thrombocytopenia 25-50x10 9/l; severe diarrhea
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele TypeAlleles
active*1, *2, *33, *35
decreased activity*9, *10, *17, *29, *36, *41
inactive*3-*8, *11-*16, *19-*21, *38, *40, *42
\n\n", - "version" : 15 + "version" : 20 }, "userId" : "cfthorn", - "version" : 33 + "version" : 93 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166302705", - "name" : "Recommendation Annotation PA166302705", - "alternateDrugAvailable" : true, + "id" : "PA166302690", + "name" : "Recommendation Annotation PA166302690", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -128994,121 +130397,160 @@ "valid" : true, "version" : 1 }, + "dosingInformation" : true, + "implications" : [ + "Genetic variation increases the sum of the plasma concentrations of propafenone and the active metabolite 5-hydroxypropafenone. This increases the risk of side effects." + ], + "lookupKey" : {"CYP2D6": "0.0"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA451131", + "name" : "propafenone", + "version" : 28 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104962", + "name" : "Annotation of DPWG Guideline for propafenone and CYP2D6", + "version" : 93 + }, + "text" : { + "id" : 1452104289, + "html" : "

Reduce the dose to 30% of the standard dose, perform an ECG and monitor plasma concentrations.

\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166302695", + "name" : "Recommendation Annotation PA166302695", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 1448526251, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", + "valid" : true, + "version" : 0 + }, "dosingInformation" : false, "implications" : [ - "Genetic variation decreases the sum of the plasma concentrations of propafenone and the active metabolite 5-hydroxypropafenone. This increases the risk of reduced or no efficacy." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on propafenone." ], - "lookupKey" : {"CYP2D6": "≥4.0"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"CYP2D6": "1.25"}, + "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451131", "name" : "propafenone", - "version" : 11 + "version" : 28 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104962", "name" : "Annotation of DPWG Guideline for propafenone and CYP2D6", - "version" : 33 + "version" : 93 }, "text" : { - "id" : 1452104304, - "html" : "

It is not possible to offer adequately substantiated recommendations for dose adjustment based on the literature.

\n\n", + "id" : 1452104294, + "html" : "

The guideline does not provide a recommendation for propafenone in normal metabolizers.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302691", - "name" : "Recommendation Annotation PA166302691", - "alternateDrugAvailable" : true, + "id" : "PA166302696", + "name" : "Recommendation Annotation PA166302696", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, "dosingInformation" : false, "implications" : [ - "Genetic variation increases the sum of the plasma concentrations of propafenone and the active metabolite 5-hydroxypropafenone. This may increase the risk of side effects." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on propafenone." ], - "lookupKey" : {"CYP2D6": "0.25"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"CYP2D6": "1.5"}, + "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451131", "name" : "propafenone", - "version" : 11 + "version" : 28 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104962", "name" : "Annotation of DPWG Guideline for propafenone and CYP2D6", - "version" : 33 + "version" : 93 }, "text" : { - "id" : 1452104290, - "html" : "

It is not possible to offer adequately substantiated recommendations for dose adjustment based on the literature.

\n\n", + "id" : 1452104295, + "html" : "

The guideline does not provide a recommendation for propafenone in normal metabolizers.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302700", - "name" : "Recommendation Annotation PA166302700", - "alternateDrugAvailable" : true, + "id" : "PA166302697", + "name" : "Recommendation Annotation PA166302697", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, "dosingInformation" : false, "implications" : [ - "Genetic variation decreases the sum of the plasma concentrations of propafenone and the active metabolite 5-hydroxypropafenone. This increases the risk of reduced or no efficacy." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on propafenone." ], - "lookupKey" : {"CYP2D6": "3.0"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"CYP2D6": "2.0"}, + "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451131", "name" : "propafenone", - "version" : 11 + "version" : 28 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104962", "name" : "Annotation of DPWG Guideline for propafenone and CYP2D6", - "version" : 33 + "version" : 93 }, "text" : { - "id" : 1452104299, - "html" : "

It is not possible to offer adequately substantiated recommendations for dose adjustment based on the literature.

\n\n", + "id" : 1452104296, + "html" : "

The guideline does not provide a recommendation for propafenone in normal metabolizers.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302695", - "name" : "Recommendation Annotation PA166302695", + "id" : "PA166302698", + "name" : "Recommendation Annotation PA166302698", "alternateDrugAvailable" : false, "classification" : { "id" : 1448526251, @@ -129123,24 +130565,24 @@ "implications" : [ "The guideline does not provide a description of the impact of a normal metabolizer phenotype on propafenone." ], - "lookupKey" : {"CYP2D6": "1.25"}, + "lookupKey" : {"CYP2D6": "2.25"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451131", "name" : "propafenone", - "version" : 11 + "version" : 28 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104962", "name" : "Annotation of DPWG Guideline for propafenone and CYP2D6", - "version" : 33 + "version" : 93 }, "text" : { - "id" : 1452104294, + "id" : 1452104297, "html" : "

The guideline does not provide a recommendation for propafenone in normal metabolizers.

\n", "version" : 0 }, @@ -129171,14 +130613,14 @@ "objCls" : "Chemical", "id" : "PA451131", "name" : "propafenone", - "version" : 11 + "version" : 28 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104962", "name" : "Annotation of DPWG Guideline for propafenone and CYP2D6", - "version" : 33 + "version" : 93 }, "text" : { "id" : 1452104298, @@ -129189,8 +130631,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302704", - "name" : "Recommendation Annotation PA166302704", + "id" : "PA166302700", + "name" : "Recommendation Annotation PA166302700", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -129206,24 +130648,24 @@ "implications" : [ "Genetic variation decreases the sum of the plasma concentrations of propafenone and the active metabolite 5-hydroxypropafenone. This increases the risk of reduced or no efficacy." ], - "lookupKey" : {"CYP2D6": "≥3.5"}, + "lookupKey" : {"CYP2D6": "3.0"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451131", "name" : "propafenone", - "version" : 11 + "version" : 28 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104962", "name" : "Annotation of DPWG Guideline for propafenone and CYP2D6", - "version" : 33 + "version" : 93 }, "text" : { - "id" : 1452104303, + "id" : 1452104299, "html" : "

It is not possible to offer adequately substantiated recommendations for dose adjustment based on the literature.

\n\n", "version" : 0 }, @@ -129231,9 +130673,9 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302690", - "name" : "Recommendation Annotation PA166302690", - "alternateDrugAvailable" : false, + "id" : "PA166302701", + "name" : "Recommendation Annotation PA166302701", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -129244,37 +130686,37 @@ "valid" : true, "version" : 1 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "Genetic variation increases the sum of the plasma concentrations of propafenone and the active metabolite 5-hydroxypropafenone. This increases the risk of side effects." + "Genetic variation decreases the sum of the plasma concentrations of propafenone and the active metabolite 5-hydroxypropafenone. This increases the risk of reduced or no efficacy." ], - "lookupKey" : {"CYP2D6": "0.0"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"CYP2D6": "4.0"}, + "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451131", "name" : "propafenone", - "version" : 11 + "version" : 28 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104962", "name" : "Annotation of DPWG Guideline for propafenone and CYP2D6", - "version" : 33 + "version" : 93 }, "text" : { - "id" : 1452104289, - "html" : "

Reduce the dose to 30% of the standard dose, perform an ECG and monitor plasma concentrations.

\n", + "id" : 1452104300, + "html" : "

It is not possible to offer adequately substantiated recommendations for dose adjustment based on the literature.

\n\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302694", - "name" : "Recommendation Annotation PA166302694", + "id" : "PA166302702", + "name" : "Recommendation Annotation PA166302702", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -129288,27 +130730,27 @@ }, "dosingInformation" : false, "implications" : [ - "Genetic variation increases the sum of the plasma concentrations of propafenone and the active metabolite 5-hydroxypropafenone. This may increase the risk of side effects." + "Genetic variation decreases the sum of the plasma concentrations of propafenone and the active metabolite 5-hydroxypropafenone. This increases the risk of reduced or no efficacy." ], - "lookupKey" : {"CYP2D6": "1.0"}, + "lookupKey" : {"CYP2D6": "≥3.0"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451131", "name" : "propafenone", - "version" : 11 + "version" : 28 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104962", "name" : "Annotation of DPWG Guideline for propafenone and CYP2D6", - "version" : 33 + "version" : 93 }, "text" : { - "id" : 1452104293, - "html" : "

It is not possible to offer adequately substantiated recommendations for dose adjustment based on the literature.

\n\n", + "id" : 1452104301, + "html" : "

It is not possible to offer adequately substantiated recommendations for dose adjustment based on the literature.

\n\n", "version" : 0 }, "version" : 0 @@ -129339,14 +130781,14 @@ "objCls" : "Chemical", "id" : "PA451131", "name" : "propafenone", - "version" : 11 + "version" : 28 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104962", "name" : "Annotation of DPWG Guideline for propafenone and CYP2D6", - "version" : 33 + "version" : 93 }, "text" : { "id" : 1452104302, @@ -129357,49 +130799,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302698", - "name" : "Recommendation Annotation PA166302698", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 1448526251, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on propafenone." - ], - "lookupKey" : {"CYP2D6": "2.25"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA451131", - "name" : "propafenone", - "version" : 11 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166104962", - "name" : "Annotation of DPWG Guideline for propafenone and CYP2D6", - "version" : 33 - }, - "text" : { - "id" : 1452104297, - "html" : "

The guideline does not provide a recommendation for propafenone in normal metabolizers.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166302707", - "name" : "Recommendation Annotation PA166302707", + "id" : "PA166302704", + "name" : "Recommendation Annotation PA166302704", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -129415,24 +130816,24 @@ "implications" : [ "Genetic variation decreases the sum of the plasma concentrations of propafenone and the active metabolite 5-hydroxypropafenone. This increases the risk of reduced or no efficacy." ], - "lookupKey" : {"CYP2D6": "≥6.0"}, + "lookupKey" : {"CYP2D6": "≥3.5"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451131", "name" : "propafenone", - "version" : 11 + "version" : 28 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104962", "name" : "Annotation of DPWG Guideline for propafenone and CYP2D6", - "version" : 33 + "version" : 93 }, "text" : { - "id" : 1452104306, + "id" : 1452104303, "html" : "

It is not possible to offer adequately substantiated recommendations for dose adjustment based on the literature.

\n\n", "version" : 0 }, @@ -129440,8 +130841,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302693", - "name" : "Recommendation Annotation PA166302693", + "id" : "PA166302705", + "name" : "Recommendation Annotation PA166302705", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -129455,35 +130856,35 @@ }, "dosingInformation" : false, "implications" : [ - "Genetic variation increases the sum of the plasma concentrations of propafenone and the active metabolite 5-hydroxypropafenone. This may increase the risk of side effects." + "Genetic variation decreases the sum of the plasma concentrations of propafenone and the active metabolite 5-hydroxypropafenone. This increases the risk of reduced or no efficacy." ], - "lookupKey" : {"CYP2D6": "0.75"}, + "lookupKey" : {"CYP2D6": "≥4.0"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451131", "name" : "propafenone", - "version" : 11 + "version" : 28 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104962", "name" : "Annotation of DPWG Guideline for propafenone and CYP2D6", - "version" : 33 + "version" : 93 }, "text" : { - "id" : 1452104292, - "html" : "

It is not possible to offer adequately substantiated recommendations for dose adjustment based on the literature.

\n\n", + "id" : 1452104304, + "html" : "

It is not possible to offer adequately substantiated recommendations for dose adjustment based on the literature.

\n\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302702", - "name" : "Recommendation Annotation PA166302702", + "id" : "PA166302706", + "name" : "Recommendation Annotation PA166302706", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -129499,24 +130900,24 @@ "implications" : [ "Genetic variation decreases the sum of the plasma concentrations of propafenone and the active metabolite 5-hydroxypropafenone. This increases the risk of reduced or no efficacy." ], - "lookupKey" : {"CYP2D6": "≥3.0"}, + "lookupKey" : {"CYP2D6": "≥5.0"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451131", "name" : "propafenone", - "version" : 11 + "version" : 28 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104962", "name" : "Annotation of DPWG Guideline for propafenone and CYP2D6", - "version" : 33 + "version" : 93 }, "text" : { - "id" : 1452104301, + "id" : 1452104305, "html" : "

It is not possible to offer adequately substantiated recommendations for dose adjustment based on the literature.

\n\n", "version" : 0 }, @@ -129524,90 +130925,92 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302696", - "name" : "Recommendation Annotation PA166302696", - "alternateDrugAvailable" : false, + "id" : "PA166302707", + "name" : "Recommendation Annotation PA166302707", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, "dosingInformation" : false, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on propafenone." + "Genetic variation decreases the sum of the plasma concentrations of propafenone and the active metabolite 5-hydroxypropafenone. This increases the risk of reduced or no efficacy." ], - "lookupKey" : {"CYP2D6": "1.5"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"CYP2D6": "≥6.0"}, + "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451131", "name" : "propafenone", - "version" : 11 + "version" : 28 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104962", "name" : "Annotation of DPWG Guideline for propafenone and CYP2D6", - "version" : 33 + "version" : 93 }, "text" : { - "id" : 1452104295, - "html" : "

The guideline does not provide a recommendation for propafenone in normal metabolizers.

\n", + "id" : 1452104306, + "html" : "

It is not possible to offer adequately substantiated recommendations for dose adjustment based on the literature.

\n\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302697", - "name" : "Recommendation Annotation PA166302697", - "alternateDrugAvailable" : false, + "id" : "PA166302694", + "name" : "Recommendation Annotation PA166302694", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, "dosingInformation" : false, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on propafenone." + "Genetic variation increases the sum of the plasma concentrations of propafenone and the active metabolite 5-hydroxypropafenone. This may increase the risk of side effects." ], - "lookupKey" : {"CYP2D6": "2.0"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"CYP2D6": "1.0"}, + "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451131", "name" : "propafenone", - "version" : 11 + "version" : 28 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104962", "name" : "Annotation of DPWG Guideline for propafenone and CYP2D6", - "version" : 33 + "version" : 93 }, "text" : { - "id" : 1452104296, - "html" : "

The guideline does not provide a recommendation for propafenone in normal metabolizers.

\n", + "id" : 1452104293, + "html" : "

It is not possible to offer adequately substantiated recommendations for dose adjustment based on the literature.

\n\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302706", - "name" : "Recommendation Annotation PA166302706", + "id" : "PA166302693", + "name" : "Recommendation Annotation PA166302693", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -129621,30 +131024,30 @@ }, "dosingInformation" : false, "implications" : [ - "Genetic variation decreases the sum of the plasma concentrations of propafenone and the active metabolite 5-hydroxypropafenone. This increases the risk of reduced or no efficacy." + "Genetic variation increases the sum of the plasma concentrations of propafenone and the active metabolite 5-hydroxypropafenone. This may increase the risk of side effects." ], - "lookupKey" : {"CYP2D6": "≥5.0"}, + "lookupKey" : {"CYP2D6": "0.75"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451131", "name" : "propafenone", - "version" : 11 + "version" : 28 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104962", "name" : "Annotation of DPWG Guideline for propafenone and CYP2D6", - "version" : 33 + "version" : 93 }, "text" : { - "id" : 1452104305, - "html" : "

It is not possible to offer adequately substantiated recommendations for dose adjustment based on the literature.

\n\n", + "id" : 1452104292, + "html" : "

It is not possible to offer adequately substantiated recommendations for dose adjustment based on the literature.

\n\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -129672,26 +131075,26 @@ "objCls" : "Chemical", "id" : "PA451131", "name" : "propafenone", - "version" : 11 + "version" : 28 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104962", "name" : "Annotation of DPWG Guideline for propafenone and CYP2D6", - "version" : 33 + "version" : 93 }, "text" : { "id" : 1452104291, "html" : "

It is not possible to offer adequately substantiated recommendations for dose adjustment based on the literature.

\n\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302701", - "name" : "Recommendation Annotation PA166302701", + "id" : "PA166302691", + "name" : "Recommendation Annotation PA166302691", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -129705,30 +131108,30 @@ }, "dosingInformation" : false, "implications" : [ - "Genetic variation decreases the sum of the plasma concentrations of propafenone and the active metabolite 5-hydroxypropafenone. This increases the risk of reduced or no efficacy." + "Genetic variation increases the sum of the plasma concentrations of propafenone and the active metabolite 5-hydroxypropafenone. This may increase the risk of side effects." ], - "lookupKey" : {"CYP2D6": "4.0"}, + "lookupKey" : {"CYP2D6": "0.25"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451131", "name" : "propafenone", - "version" : 11 + "version" : 28 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104962", "name" : "Annotation of DPWG Guideline for propafenone and CYP2D6", - "version" : 33 + "version" : 93 }, "text" : { - "id" : 1452104300, - "html" : "

It is not possible to offer adequately substantiated recommendations for dose adjustment based on the literature.

\n\n", + "id" : 1452104290, + "html" : "

It is not possible to offer adequately substantiated recommendations for dose adjustment based on the literature.

\n\n", "version" : 0 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166104962" @@ -129850,7 +131253,7 @@ "date" : "2022-03-28T00:00:00-07:00", "description" : "Updated link to testing guidance page", "type" : "Update", - "version" : 0 + "version" : 1 }, { "id" : 1451732895, @@ -129928,84 +131331,84 @@ "id" : "PA165819201", "symbol" : "CYP3A4*1", "name" : "*1", - "version" : 18 + "version" : 49 }, { "objCls" : "Haplotype", "id" : "PA165819229", "symbol" : "CYP3A4*11", "name" : "*11", - "version" : 18 + "version" : 52 }, { "objCls" : "Haplotype", "id" : "PA165819230", "symbol" : "CYP3A4*12", "name" : "*12", - "version" : 18 + "version" : 51 }, { "objCls" : "Haplotype", "id" : "PA165819231", "symbol" : "CYP3A4*13", "name" : "*13", - "version" : 18 + "version" : 51 }, { "objCls" : "Haplotype", "id" : "PA165819236", "symbol" : "CYP3A4*16", "name" : "*16", - "version" : 17 + "version" : 50 }, { "objCls" : "Haplotype", "id" : "PA165819239", "symbol" : "CYP3A4*17", "name" : "*17", - "version" : 18 + "version" : 51 }, { "objCls" : "Haplotype", "id" : "PA165819240", "symbol" : "CYP3A4*18", "name" : "*18", - "version" : 17 + "version" : 50 }, { "objCls" : "Haplotype", "id" : "PA165819244", "symbol" : "CYP3A4*20", "name" : "*20", - "version" : 19 + "version" : 53 }, { "objCls" : "Haplotype", "id" : "PA166048680", "symbol" : "CYP3A4*22", "name" : "*22", - "version" : 15 + "version" : 46 }, { "objCls" : "Haplotype", "id" : "PA166245583", "symbol" : "CYP3A4*26", "name" : "*26", - "version" : 8 + "version" : 20 }, { "objCls" : "Haplotype", "id" : "PA165819224", "symbol" : "CYP3A4*6", "name" : "*6", - "version" : 18 + "version" : 51 }, { "objCls" : "Haplotype", "id" : "PA165819226", "symbol" : "CYP3A4*8", "name" : "*8", - "version" : 18 + "version" : 52 } ], "relatedChemicals" : [ @@ -130013,7 +131416,7 @@ "objCls" : "Chemical", "id" : "PA451201", "name" : "quetiapine", - "version" : 7 + "version" : 43 } ], "relatedGenes" : [ @@ -130022,7 +131425,7 @@ "id" : "PA130", "symbol" : "CYP3A4", "name" : "cytochrome P450 family 3 subfamily A member 4", - "version" : 8039 + "version" : 8144 } ], "source" : "DPWG", @@ -130035,17 +131438,17 @@ "textMarkdown" : { "id" : 1451698941, "html" : "

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

\n

The CYP3A4 gene information document from DPWG includes CYP3A4*1A, *1B, and *1G, but these alleles are not included in the genotype selection picker above. CYP3A4*1A and *1B have assigned as sub alleles under the CYP3A4*1 core allele by PharmVar. CYP3A4*1G has been retired by PharmVar. See the CYP3A4 Read me document for details.

\n

Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction between CYP2D6, CYP3A4 and CYP1A2 and antipsychotics. European journal of human genetics (2023)

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group published a paper with the guidelines for quetiapine and CYP3A4 as per the February 2022 guidelines and further details on the assessed literature [Article:37002327]. Wording in the poor metabolizer recommendation changed from "standard" to "normal" and is reflected in the table below.

\n

February 2022 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has updated their therapeutic dose recommendations for quetiapine based on CYP3A4 genotypes. They now recommend an alternative drug for patients who are CYP3A4 poor metabolizers (PMs) who are being treated for depression. A dose reduction is recommended for patients who are CYP3A4 PMs and being treated for other indications.

\n

Wording in table taken from the Dutch guidelines February 2022 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
CYP3A4 IMquetiapineThis gene variation reduces the conversion of quetiapine to inactive metabolites and a metabolite with anti-depressant effect. However, the effect on the plasma concentration of quetiapine is limited (20% increase) and it is not known whether this has any clinical consequences. The relationship between the plasma concentration and clinical effect is weak for quetiapine.NO action is needed for this gene-drug interaction.
CYP3A4 PMquetiapineThe plasma concentration of quetiapine is 3.2-fold higher in these patients. In addition, the formation of the active metabolite N-desalkylquetiapine, which is probably responsible for the antidepressant effect, should be reduced. The gene variation results in reduced activity of the enzyme CYP3A4, which converts quetiapine to N-desalkylquetiapine and an inactive metabolite.Indication DEPRESSION: choose an alternative.
Aripiprazole appears to be less dependent on CYP3A4 for metabolism. Olanzapine is not metabolised by CYP3A4.
OTHER INDICATIONS: use 30% of the normal dose.
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for quetiapine and CYP3A4:

\n
\n

The KNMP Pharmacogenetics Working Group considers genotyping before starting quetiapine to be potentially beneficial for prevention of adverse events and for effectiveness. Genotyping can be considered on an individual patient basis. If, however, the genotype is available, the KNMP Pharmacogenetics Working Group recommends adhering to the gene-drug guideline.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n

May 2021 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for quetiapine based on CYP3A4 genotypes. They conclude that this is not a gene-drug interaction (see Dutch guidelines May 2021 update).

\n", - "version" : 7 + "version" : 9 }, "userId" : "cfthorn", - "version" : 15 + "version" : 77 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166299124", - "name" : "Recommendation PA166299124", - "alternateDrugAvailable" : true, + "id" : "PA166299123", + "name" : "Recommendation PA166299123", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -130056,115 +131459,115 @@ "valid" : true, "version" : 1 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "The plasma concentration of quetiapine is 3.2-fold higher in these patients. In addition, the formation of the active metabolite N-desalkylquetiapine, which is probably\nresponsible for the antidepressant effect, should be reduced. The gene variation results in reduced activity of the enzyme CYP3A4, which converts quetiapine to N-desalkylquetiapine\nand an inactive metabolite." + "This gene variation reduces the conversion of quetiapine to inactive metabolites and a metabolite with anti-depressant effect. However, the effect on the plasma concentration\nof quetiapine is limited (20% increase) and it is not known whether this has any clinical consequences. The relationship between the plasma concentration and clinical effect is\nweak for quetiapine." ], - "lookupKey" : {"CYP3A4": "Poor Metabolizer"}, + "lookupKey" : {"CYP3A4": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451201", "name" : "quetiapine", - "version" : 7 + "version" : 43 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166265421", "name" : "Annotation of DPWG Guideline for quetiapine and CYP3A4", - "version" : 15 + "version" : 77 }, "text" : { - "id" : 1452061487, - "html" : "

Indication DEPRESSION: Choose an alternative. Aripiprazole appears to be less dependent of CYP3A4 for metabolism. Olanzapine is not metabolised by CYP3A4.
\n 
\nOTHER INDICATIONS: Use 30% of the normal dose.

\n", + "id" : 1452061486, + "html" : "

NO action is needed for this gene-drug interaction.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299123", - "name" : "Recommendation PA166299123", + "id" : "PA166299125", + "name" : "Recommendation PA166299125", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, "dosingInformation" : false, "implications" : [ - "This gene variation reduces the conversion of quetiapine to inactive metabolites and a metabolite with anti-depressant effect. However, the effect on the plasma concentration\nof quetiapine is limited (20% increase) and it is not known whether this has any clinical consequences. The relationship between the plasma concentration and clinical effect is\nweak for quetiapine." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on quetiapine." ], - "lookupKey" : {"CYP3A4": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP3A4": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451201", "name" : "quetiapine", - "version" : 7 + "version" : 43 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166265421", "name" : "Annotation of DPWG Guideline for quetiapine and CYP3A4", - "version" : 15 + "version" : 77 }, "text" : { - "id" : 1452061486, - "html" : "

NO action is needed for this gene-drug interaction.

\n", + "id" : 1452061488, + "html" : "

The guideline does not provide a recommendation for quetiapine in normal metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299125", - "name" : "Recommendation PA166299125", - "alternateDrugAvailable" : false, + "id" : "PA166299124", + "name" : "Recommendation PA166299124", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on quetiapine." + "The plasma concentration of quetiapine is 3.2-fold higher in these patients. In addition, the formation of the active metabolite N-desalkylquetiapine, which is probably\nresponsible for the antidepressant effect, should be reduced. The gene variation results in reduced activity of the enzyme CYP3A4, which converts quetiapine to N-desalkylquetiapine\nand an inactive metabolite." ], - "lookupKey" : {"CYP3A4": "Normal Metabolizer"}, + "lookupKey" : {"CYP3A4": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451201", "name" : "quetiapine", - "version" : 7 + "version" : 43 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166265421", "name" : "Annotation of DPWG Guideline for quetiapine and CYP3A4", - "version" : 15 + "version" : 77 }, "text" : { - "id" : 1452061488, - "html" : "

The guideline does not provide a recommendation for quetiapine in normal metabolizers.

\n", + "id" : 1452061487, + "html" : "

Indication DEPRESSION: Choose an alternative. Aripiprazole appears to be less dependent of CYP3A4 for metabolism. Olanzapine is not metabolised by CYP3A4.
\n 
\nOTHER INDICATIONS: Use 30% of the normal dose.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166265421" @@ -130343,7 +131746,7 @@ "date" : "2019-05-28T00:00:00-07:00", "description" : "Annotation current with November 2018 DPWG Guideline release", "type" : "Update", - "version" : 0 + "version" : 2 }, { "id" : 1450821030, @@ -130556,7 +131959,7 @@ "objCls" : "Chemical", "id" : "PA451257", "name" : "risperidone", - "version" : 7 + "version" : 43 } ], "relatedGenes" : [ @@ -130565,30 +131968,30 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "DPWG", "summaryMarkdown" : { "id" : 1447981874, "html" : "

The Dutch Pharmacogenetics Working Group Guideline for risperidone recommends decreasing the dose for CYP2D6 poor metabolizers and using an alternative drug or titrate the dose according to the maximum dose for the active metabolite for CYP2D6 ultrarapid metabolizers.

\n", - "version" : 2 + "version" : 3 }, "terms" : [], "textMarkdown" : { "id" : 1447981873, "html" : "

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

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Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction between CYP2D6, CYP3A4 and CYP1A2 and antipsychotics. European journal of human genetics (2023)

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group published a paper with the guidelines for risperidone and CYP2D6 as per the May 2020 guidelines and further details on the assessed literature [Article:37002327]. Wording in the poor metabolizer recommendation changed from "standard" to "normal" and is reflected in the table below.

\n

May 2020 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for risperidone based on CYP2D6 genotype. They recommend decreasing the dose for CYP2D6 poor metabolizers and using an alternative drug or titrate the dose according to the maximum dose for the active metabolite for CYP2D6 ultrarapid metabolizers.

\n

Wording in table taken from the Dutch guidelines May 2020 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
CYP2D6 UMrisperidoneThe percentage of patients with therapy failure increases from 16% to 37%. The gene variation leads to a high ratio of the active metabolite (9-hydroxyrisperidone (paliperidone)) compared to risperidone, which crosses the blood-brain barrier more effectively.Choose an alternative or titrate the dose according to the maximum dose for the active metabolite (paliperidone) (oral 12 mg/day for adults and children from 15 years of age weighing at least 51 kg and 6 mg/day for children from 15 years of age weighing less than 51 kg; intramuscular 75 mg per 2 weeks).
CYP2D6 IMrisperidoneThere is little evidence to support an increase in side effects caused by the gene variation. The gene variation may lead to a decrease in the required maintenance dose. However, as the effect on the dose is smaller than that of the normal biological variation, action is not useful.NO action is needed for this gene-drug interaction.
CYP2D6 PMrisperidoneThe percentage of patients with therapy failure increased from 16% to 26%. The gene variation increases the plasma concentration of risperidone plus the active metabolite and increases the proportion of risperidone in this ratio, which is more effective at crossing the blood-brain barrier.Use 67% of the normal dose. If problematic side effects originating in the central nervous system occur despite this reduced dose, then reduce the dose further to 50% of the normal dose.
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for risperidone and CYP2D6:

\n
\n

The KNMP Pharmacogenetics Working Group considers genotyping before starting risperidone to be potentially beneficial for the prevention of side effects and for drug effectiveness. Genotyping can be considered on an individual patient basis. If, however, the genotype is available, the KNMP Pharmacogenetics Working Group recommends adhering to the gene-drug guideline.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n

November 2018 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for risperidone based on CYP2D6 genotype. They recommend NO action is needed for this gene-drug interaction.

\n

Wording in table taken from the Dutch guidelines November 2018 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
CYP2D6 IMrisperidoneThere is little evidence to support an increase in side effects caused by the genetic variation. The genetic variation may lead to a decrease in the required maintenance dose. However, as the effect on the dose is smaller than that of the normal biological variation, action is not useful.NO action is needed for this gene-drug interaction.
CYP2D6 PMrisperidoneThe genetic variation can result in both an increase in side effects and a stronger decrease in schizophrenia symptoms. In addition to this, the genetic variation may lead to a decrease in the required maintenance dose. However, as the effect on the dose is smaller than that of the normal biological variation, action is not useful.NO action is needed for this gene-drug interaction.
CYP2D6 UMrisperidoneGenetic variation may lead to an increase in the required maintenance dose. However, as the effect is smaller than that of the normal biological variation, action is not useful.NO action is needed for this gene-drug interaction.
\n

2011 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for risperidone based on CYP2D6 genotypes [Article:21412232]. For patients who are CYP2D6 poor metabolizers, intermediate metabolizers, or ultrarapid metabolizers, they recommend selecting an alternative drug or being extra alert to Adverse Drug Events and adjusting dose to clinical response.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Phenotype (Genotype)Therapeutic Dose RecommendationLevel of EvidenceClinical Relevance
PM (two inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) alleles)Insufficient data to allow calculation of dose adjustment. Select alternative drug (e.g., quetiapine,olanzapine, clozapine) or be extra alert to ADEs and adjust dose to clinical response.Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Clinical effect (S): long-standing discomfort (> 168 hr), permanent symptom or invalidating injury e.g. failure of prophylaxis of atrial fibrillation; venous thromboembolism; decreased effect of clopidogrel on inhibition of platelet aggregation; ADE resulting from increased bioavailability of phenytoin; INR > 6.0; neutropenia 0.5-1.0x109/l; leucopenia 1.0-2.0x109/l; thrombocytopenia 25-50x109/l; severe diarrhea.
IM (two decreased-activity (*9, *10, *17, *29, *36, *41) alleles or carrying one active (*1, *2, *33, *35) and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele, or carrying one decreased-activity (*9, *10, *17, *29, *36, *41) allele and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele)Insufficient data to allow calculation of dose adjustment. Select alternative drug (e.g., quetiapine, olanzapine, clozapine) or be extra alert to ADEs and adjust dose to clinical response.Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Clinical effect (S): long-standing discomfort (48-168 hr) without permanent injury e.g. failure of therapy with tricyclic antidepressants, atypical antipsychotic drugs; extrapyramidal side effects; parkinsonism; ADE resulting from increased bioavailability of tricyclic antidepressants, metoprolol, propafenone (central effects e.g. dizziness); INR 4.5-6.0; neutropenia 1.0-1.5x109/l; leucopenia 2.0-3.0x109/l; thrombocytopenia 50-75x109/l.
UM (a gene duplication in absence of inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) or decreased-activity (*9, *10, *17, *29, *36, *41) alleles)Insufficient data to allow calculation of dose adjustment. Select alternative drug (e.g., quetiapine, olanzapine, clozapine) or be extra alert to ADEs and adjust dose to clinical response.Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Clinical effect (S): long-standing discomfort (48-168 hr) without permanent injury e.g. failure of therapy with tricyclic antidepressants, atypical antipsychotic drugs; extrapyramidal side effects; parkinsonism; ADE resulting from increased bioavailability of tricyclic antidepressants, metoprolol, propafenone (central effects e.g. dizziness); INR 4.5-6.0; neutropenia 1.0-1.5x109/l; leucopenia 2.0-3.0x109/l; thrombocytopenia 50-75x109/l.
\n\n", - "version" : 20 + "version" : 28 }, "userId" : "alie", - "version" : 39 + "version" : 113 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166302718", - "name" : "Recommendation Annotation PA166302718", - "alternateDrugAvailable" : true, + "id" : "PA166302708", + "name" : "Recommendation Annotation PA166302708", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -130601,27 +132004,27 @@ }, "dosingInformation" : true, "implications" : [ - "The percentage of patients with therapy failure increases from 16% to 37%. The gene variation leads to a high ratio of the active metabolite (9-hydroxyrisperidone (paliperidone)) compared to risperidone, which crosses the blood-brain barrier more effectively." + "The percentage of patients with therapy failure increased from 16% to 26%. The gene variation increases the plasma concentration of risperidone plus the active metabolite and increases the proportion of risperidone in this ratio, which is more effective at crossing the blood-brain barrier." ], - "lookupKey" : {"CYP2D6": "3.0"}, + "lookupKey" : {"CYP2D6": "0.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451257", "name" : "risperidone", - "version" : 7 + "version" : 43 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104943", "name" : "Annotation of DPWG Guideline for risperidone and CYP2D6", - "version" : 39 + "version" : 113 }, "text" : { - "id" : 1452104317, - "html" : "

Choose an alternative or titrate the dose according to the maximum dose for the active metabolite (paliperidone) (oral 12 mg/day for adults and children from 15 years of age weighing at least 51 kg and 6 mg/day for children from 15 years of age weighing less than 51 kg; intramuscular 75 mg per 2 weeks).

\n", + "id" : 1452104307, + "html" : "

Use 67% of the normal dose. If problematic side effects originating in the central nervous system occur despite this reduced dose, then reduce the dose further to 50% of the normal dose.

\n", "version" : 0 }, "version" : 0 @@ -130652,14 +132055,14 @@ "objCls" : "Chemical", "id" : "PA451257", "name" : "risperidone", - "version" : 7 + "version" : 43 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104943", "name" : "Annotation of DPWG Guideline for risperidone and CYP2D6", - "version" : 39 + "version" : 113 }, "text" : { "id" : 1452104308, @@ -130670,9 +132073,9 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302722", - "name" : "Recommendation Annotation PA166302722", - "alternateDrugAvailable" : true, + "id" : "PA166302710", + "name" : "Recommendation Annotation PA166302710", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -130683,119 +132086,79 @@ "valid" : true, "version" : 1 }, - "dosingInformation" : true, - "implications" : [ - "The percentage of patients with therapy failure increases from 16% to 37%. The gene variation leads to a high ratio of the active metabolite (9-hydroxyrisperidone (paliperidone)) compared to risperidone, which crosses the blood-brain barrier more effectively." - ], - "lookupKey" : {"CYP2D6": "≥3.5"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA451257", - "name" : "risperidone", - "version" : 7 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166104943", - "name" : "Annotation of DPWG Guideline for risperidone and CYP2D6", - "version" : 39 - }, - "text" : { - "id" : 1452104321, - "html" : "

Choose an alternative or titrate the dose according to the maximum dose for the active metabolite (paliperidone) (oral 12 mg/day for adults and children from 15 years of age weighing at least 51 kg and 6 mg/day for children from 15 years of age weighing less than 51 kg; intramuscular 75 mg per 2 weeks).

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166302713", - "name" : "Recommendation Annotation PA166302713", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 1448526251, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", - "valid" : true, - "version" : 0 - }, "dosingInformation" : false, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on risperidone." + "There is little evidence to support an increase in side effects caused by the gene variation. The gene variation may lead to a decrease in the required maintenance dose. However, as the effect on the dose is smaller than that of the normal biological variation, action is not useful." ], - "lookupKey" : {"CYP2D6": "1.25"}, + "lookupKey" : {"CYP2D6": "0.5"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451257", "name" : "risperidone", - "version" : 7 + "version" : 43 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104943", "name" : "Annotation of DPWG Guideline for risperidone and CYP2D6", - "version" : 39 + "version" : 113 }, "text" : { - "id" : 1452104312, - "html" : "

The guideline does not provide a recommendation for risperidone in normal metabolizers.

\n", + "id" : 1452104309, + "html" : "

NO action is needed for this gene-drug interaction.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302717", - "name" : "Recommendation Annotation PA166302717", + "id" : "PA166302711", + "name" : "Recommendation Annotation PA166302711", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, "dosingInformation" : false, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on risperidone." + "There is little evidence to support an increase in side effects caused by the gene variation. The gene variation may lead to a decrease in the required maintenance dose. However, as the effect on the dose is smaller than that of the normal biological variation, action is not useful." ], - "lookupKey" : {"CYP2D6": "2.5"}, + "lookupKey" : {"CYP2D6": "0.75"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451257", "name" : "risperidone", - "version" : 7 + "version" : 43 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104943", "name" : "Annotation of DPWG Guideline for risperidone and CYP2D6", - "version" : 39 + "version" : 113 }, "text" : { - "id" : 1452104316, - "html" : "

The guideline does not provide a recommendation for risperidone in normal metabolizers.

\n", + "id" : 1452104310, + "html" : "

NO action is needed for this gene-drug interaction.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302708", - "name" : "Recommendation Annotation PA166302708", + "id" : "PA166302712", + "name" : "Recommendation Annotation PA166302712", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -130807,155 +132170,152 @@ "valid" : true, "version" : 1 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "The percentage of patients with therapy failure increased from 16% to 26%. The gene variation increases the plasma concentration of risperidone plus the active metabolite and increases the proportion of risperidone in this ratio, which is more effective at crossing the blood-brain barrier." + "There is little evidence to support an increase in side effects caused by the gene variation. The gene variation may lead to a decrease in the required maintenance dose. However, as the effect on the dose is smaller than that of the normal biological variation, action is not useful." ], - "lookupKey" : {"CYP2D6": "0.0"}, + "lookupKey" : {"CYP2D6": "1.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451257", "name" : "risperidone", - "version" : 7 + "version" : 43 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104943", "name" : "Annotation of DPWG Guideline for risperidone and CYP2D6", - "version" : 39 + "version" : 113 }, "text" : { - "id" : 1452104307, - "html" : "

Use 67% of the normal dose. If problematic side effects originating in the central nervous system occur despite this reduced dose, then reduce the dose further to 50% of the normal dose.

\n", + "id" : 1452104311, + "html" : "

NO action is needed for this gene-drug interaction.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302721", - "name" : "Recommendation Annotation PA166302721", - "alternateDrugAvailable" : true, + "id" : "PA166302713", + "name" : "Recommendation Annotation PA166302713", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "The percentage of patients with therapy failure increases from 16% to 37%. The gene variation leads to a high ratio of the active metabolite (9-hydroxyrisperidone (paliperidone)) compared to risperidone, which crosses the blood-brain barrier more effectively." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on risperidone." ], - "lookupKey" : {"CYP2D6": "≥3.25"}, + "lookupKey" : {"CYP2D6": "1.25"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451257", "name" : "risperidone", - "version" : 7 + "version" : 43 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104943", "name" : "Annotation of DPWG Guideline for risperidone and CYP2D6", - "version" : 39 + "version" : 113 }, "text" : { - "id" : 1452104320, - "html" : "

Choose an alternative or titrate the dose according to the maximum dose for the active metabolite (paliperidone) (oral 12 mg/day for adults and children from 15 years of age weighing at least 51 kg and 6 mg/day for children from 15 years of age weighing less than 51 kg; intramuscular 75 mg per 2 weeks).

\n", + "id" : 1452104312, + "html" : "

The guideline does not provide a recommendation for risperidone in normal metabolizers.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302712", - "name" : "Recommendation Annotation PA166302712", + "id" : "PA166302714", + "name" : "Recommendation Annotation PA166302714", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, "dosingInformation" : false, "implications" : [ - "There is little evidence to support an increase in side effects caused by the gene variation. The gene variation may lead to a decrease in the required maintenance dose. However, as the effect on the dose is smaller than that of the normal biological variation, action is not useful." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on risperidone." ], - "lookupKey" : {"CYP2D6": "1.0"}, + "lookupKey" : {"CYP2D6": "1.5"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451257", "name" : "risperidone", - "version" : 7 + "version" : 43 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104943", "name" : "Annotation of DPWG Guideline for risperidone and CYP2D6", - "version" : 39 + "version" : 113 }, "text" : { - "id" : 1452104311, - "html" : "

NO action is needed for this gene-drug interaction.

\n", + "id" : 1452104313, + "html" : "

The guideline does not provide a recommendation for risperidone in normal metabolizers.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302725", - "name" : "Recommendation Annotation PA166302725", - "alternateDrugAvailable" : true, + "id" : "PA166302715", + "name" : "Recommendation Annotation PA166302715", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "The percentage of patients with therapy failure increases from 16% to 37%. The gene variation leads to a high ratio of the active metabolite (9-hydroxyrisperidone (paliperidone)) compared to risperidone, which crosses the blood-brain barrier more effectively." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on risperidone." ], - "lookupKey" : {"CYP2D6": "≥6.0"}, + "lookupKey" : {"CYP2D6": "2.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451257", "name" : "risperidone", - "version" : 7 + "version" : 43 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104943", "name" : "Annotation of DPWG Guideline for risperidone and CYP2D6", - "version" : 39 + "version" : 113 }, "text" : { - "id" : 1452104324, - "html" : "

Choose an alternative or titrate the dose according to the maximum dose for the active metabolite (paliperidone) (oral 12 mg/day for adults and children from 15 years of age weighing at least 51 kg and 6 mg/day for children from 15 years of age weighing less than 51 kg; intramuscular 75 mg per 2 weeks).

\n", + "id" : 1452104314, + "html" : "

The guideline does not provide a recommendation for risperidone in normal metabolizers.

\n", "version" : 0 }, "version" : 0 @@ -130985,14 +132345,14 @@ "objCls" : "Chemical", "id" : "PA451257", "name" : "risperidone", - "version" : 7 + "version" : 43 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104943", "name" : "Annotation of DPWG Guideline for risperidone and CYP2D6", - "version" : 39 + "version" : 113 }, "text" : { "id" : 1452104315, @@ -131003,92 +132363,49 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302720", - "name" : "Recommendation Annotation PA166302720", - "alternateDrugAvailable" : true, - "classification" : { - "id" : 981501929, - "description" : "Not Applicable", - "parents" : [], - "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", - "valid" : true, - "version" : 1 - }, - "dosingInformation" : true, - "implications" : [ - "The percentage of patients with therapy failure increases from 16% to 37%. The gene variation leads to a high ratio of the active metabolite (9-hydroxyrisperidone (paliperidone)) compared to risperidone, which crosses the blood-brain barrier more effectively." - ], - "lookupKey" : {"CYP2D6": "≥3.0"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA451257", - "name" : "risperidone", - "version" : 7 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166104943", - "name" : "Annotation of DPWG Guideline for risperidone and CYP2D6", - "version" : 39 - }, - "text" : { - "id" : 1452104319, - "html" : "

Choose an alternative or titrate the dose according to the maximum dose for the active metabolite (paliperidone) (oral 12 mg/day for adults and children from 15 years of age weighing at least 51 kg and 6 mg/day for children from 15 years of age weighing less than 51 kg; intramuscular 75 mg per 2 weeks).

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166302711", - "name" : "Recommendation Annotation PA166302711", + "id" : "PA166302717", + "name" : "Recommendation Annotation PA166302717", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, "dosingInformation" : false, "implications" : [ - "There is little evidence to support an increase in side effects caused by the gene variation. The gene variation may lead to a decrease in the required maintenance dose. However, as the effect on the dose is smaller than that of the normal biological variation, action is not useful." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on risperidone." ], - "lookupKey" : {"CYP2D6": "0.75"}, + "lookupKey" : {"CYP2D6": "2.5"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451257", "name" : "risperidone", - "version" : 7 + "version" : 43 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104943", "name" : "Annotation of DPWG Guideline for risperidone and CYP2D6", - "version" : 39 + "version" : 113 }, "text" : { - "id" : 1452104310, - "html" : "

NO action is needed for this gene-drug interaction.

\n", + "id" : 1452104316, + "html" : "

The guideline does not provide a recommendation for risperidone in normal metabolizers.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302724", - "name" : "Recommendation Annotation PA166302724", + "id" : "PA166302718", + "name" : "Recommendation Annotation PA166302718", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -131104,70 +132421,29 @@ "implications" : [ "The percentage of patients with therapy failure increases from 16% to 37%. The gene variation leads to a high ratio of the active metabolite (9-hydroxyrisperidone (paliperidone)) compared to risperidone, which crosses the blood-brain barrier more effectively." ], - "lookupKey" : {"CYP2D6": "≥5.0"}, + "lookupKey" : {"CYP2D6": "3.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451257", "name" : "risperidone", - "version" : 7 + "version" : 43 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104943", "name" : "Annotation of DPWG Guideline for risperidone and CYP2D6", - "version" : 39 + "version" : 113 }, "text" : { - "id" : 1452104323, + "id" : 1452104317, "html" : "

Choose an alternative or titrate the dose according to the maximum dose for the active metabolite (paliperidone) (oral 12 mg/day for adults and children from 15 years of age weighing at least 51 kg and 6 mg/day for children from 15 years of age weighing less than 51 kg; intramuscular 75 mg per 2 weeks).

\n", "version" : 0 }, "version" : 0 }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166302715", - "name" : "Recommendation Annotation PA166302715", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 1448526251, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on risperidone." - ], - "lookupKey" : {"CYP2D6": "2.0"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA451257", - "name" : "risperidone", - "version" : 7 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166104943", - "name" : "Annotation of DPWG Guideline for risperidone and CYP2D6", - "version" : 39 - }, - "text" : { - "id" : 1452104314, - "html" : "

The guideline does not provide a recommendation for risperidone in normal metabolizers.

\n", - "version" : 0 - }, - "version" : 0 - }, { "objCls" : "Recommendation Annotation", "id" : "PA166302719", @@ -131194,14 +132470,14 @@ "objCls" : "Chemical", "id" : "PA451257", "name" : "risperidone", - "version" : 7 + "version" : 43 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104943", "name" : "Annotation of DPWG Guideline for risperidone and CYP2D6", - "version" : 39 + "version" : 113 }, "text" : { "id" : 1452104318, @@ -131212,9 +132488,9 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302710", - "name" : "Recommendation Annotation PA166302710", - "alternateDrugAvailable" : false, + "id" : "PA166302720", + "name" : "Recommendation Annotation PA166302720", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -131225,29 +132501,113 @@ "valid" : true, "version" : 1 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "There is little evidence to support an increase in side effects caused by the gene variation. The gene variation may lead to a decrease in the required maintenance dose. However, as the effect on the dose is smaller than that of the normal biological variation, action is not useful." + "The percentage of patients with therapy failure increases from 16% to 37%. The gene variation leads to a high ratio of the active metabolite (9-hydroxyrisperidone (paliperidone)) compared to risperidone, which crosses the blood-brain barrier more effectively." ], - "lookupKey" : {"CYP2D6": "0.5"}, + "lookupKey" : {"CYP2D6": "≥3.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451257", "name" : "risperidone", - "version" : 7 + "version" : 43 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104943", "name" : "Annotation of DPWG Guideline for risperidone and CYP2D6", - "version" : 39 + "version" : 113 }, "text" : { - "id" : 1452104309, - "html" : "

NO action is needed for this gene-drug interaction.

\n", + "id" : 1452104319, + "html" : "

Choose an alternative or titrate the dose according to the maximum dose for the active metabolite (paliperidone) (oral 12 mg/day for adults and children from 15 years of age weighing at least 51 kg and 6 mg/day for children from 15 years of age weighing less than 51 kg; intramuscular 75 mg per 2 weeks).

\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166302721", + "name" : "Recommendation Annotation PA166302721", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981501929, + "description" : "Not Applicable", + "parents" : [], + "resource" : "Guideline Strength", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", + "valid" : true, + "version" : 1 + }, + "dosingInformation" : true, + "implications" : [ + "The percentage of patients with therapy failure increases from 16% to 37%. The gene variation leads to a high ratio of the active metabolite (9-hydroxyrisperidone (paliperidone)) compared to risperidone, which crosses the blood-brain barrier more effectively." + ], + "lookupKey" : {"CYP2D6": "≥3.25"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA451257", + "name" : "risperidone", + "version" : 43 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104943", + "name" : "Annotation of DPWG Guideline for risperidone and CYP2D6", + "version" : 113 + }, + "text" : { + "id" : 1452104320, + "html" : "

Choose an alternative or titrate the dose according to the maximum dose for the active metabolite (paliperidone) (oral 12 mg/day for adults and children from 15 years of age weighing at least 51 kg and 6 mg/day for children from 15 years of age weighing less than 51 kg; intramuscular 75 mg per 2 weeks).

\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166302722", + "name" : "Recommendation Annotation PA166302722", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981501929, + "description" : "Not Applicable", + "parents" : [], + "resource" : "Guideline Strength", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", + "valid" : true, + "version" : 1 + }, + "dosingInformation" : true, + "implications" : [ + "The percentage of patients with therapy failure increases from 16% to 37%. The gene variation leads to a high ratio of the active metabolite (9-hydroxyrisperidone (paliperidone)) compared to risperidone, which crosses the blood-brain barrier more effectively." + ], + "lookupKey" : {"CYP2D6": "≥3.5"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA451257", + "name" : "risperidone", + "version" : 43 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104943", + "name" : "Annotation of DPWG Guideline for risperidone and CYP2D6", + "version" : 113 + }, + "text" : { + "id" : 1452104321, + "html" : "

Choose an alternative or titrate the dose according to the maximum dose for the active metabolite (paliperidone) (oral 12 mg/day for adults and children from 15 years of age weighing at least 51 kg and 6 mg/day for children from 15 years of age weighing less than 51 kg; intramuscular 75 mg per 2 weeks).

\n", "version" : 0 }, "version" : 0 @@ -131278,14 +132638,14 @@ "objCls" : "Chemical", "id" : "PA451257", "name" : "risperidone", - "version" : 7 + "version" : 43 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104943", "name" : "Annotation of DPWG Guideline for risperidone and CYP2D6", - "version" : 39 + "version" : 113 }, "text" : { "id" : 1452104322, @@ -131296,41 +132656,84 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302714", - "name" : "Recommendation Annotation PA166302714", - "alternateDrugAvailable" : false, + "id" : "PA166302724", + "name" : "Recommendation Annotation PA166302724", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, + "version" : 1 + }, + "dosingInformation" : true, + "implications" : [ + "The percentage of patients with therapy failure increases from 16% to 37%. The gene variation leads to a high ratio of the active metabolite (9-hydroxyrisperidone (paliperidone)) compared to risperidone, which crosses the blood-brain barrier more effectively." + ], + "lookupKey" : {"CYP2D6": "≥5.0"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA451257", + "name" : "risperidone", + "version" : 43 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104943", + "name" : "Annotation of DPWG Guideline for risperidone and CYP2D6", + "version" : 113 + }, + "text" : { + "id" : 1452104323, + "html" : "

Choose an alternative or titrate the dose according to the maximum dose for the active metabolite (paliperidone) (oral 12 mg/day for adults and children from 15 years of age weighing at least 51 kg and 6 mg/day for children from 15 years of age weighing less than 51 kg; intramuscular 75 mg per 2 weeks).

\n", "version" : 0 }, - "dosingInformation" : false, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166302725", + "name" : "Recommendation Annotation PA166302725", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981501929, + "description" : "Not Applicable", + "parents" : [], + "resource" : "Guideline Strength", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", + "valid" : true, + "version" : 1 + }, + "dosingInformation" : true, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on risperidone." + "The percentage of patients with therapy failure increases from 16% to 37%. The gene variation leads to a high ratio of the active metabolite (9-hydroxyrisperidone (paliperidone)) compared to risperidone, which crosses the blood-brain barrier more effectively." ], - "lookupKey" : {"CYP2D6": "1.5"}, + "lookupKey" : {"CYP2D6": "≥6.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451257", "name" : "risperidone", - "version" : 7 + "version" : 43 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104943", "name" : "Annotation of DPWG Guideline for risperidone and CYP2D6", - "version" : 39 + "version" : 113 }, "text" : { - "id" : 1452104313, - "html" : "

The guideline does not provide a recommendation for risperidone in normal metabolizers.

\n", + "id" : 1452104324, + "html" : "

Choose an alternative or titrate the dose according to the maximum dose for the active metabolite (paliperidone) (oral 12 mg/day for adults and children from 15 years of age weighing at least 51 kg and 6 mg/day for children from 15 years of age weighing less than 51 kg; intramuscular 75 mg per 2 weeks).

\n", "version" : 0 }, "version" : 0 @@ -131607,7 +133010,7 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "relatedGenes" : [ @@ -131616,71 +133019,70 @@ "id" : "PA124", "symbol" : "CYP2C19", "name" : "cytochrome P450 family 2 subfamily C member 19", - "version" : 7210 + "version" : 7266 } ], "source" : "DPWG", "summaryMarkdown" : { "id" : 1447981948, "html" : "

Do not give doses exceeding 75 mg/day in patients with CYP2C19 poor metabolizer genotypes, and guide the dose by response and side effects and/or sertraline plasma concentration.

\n", - "version" : 1 + "version" : 2 }, "terms" : [], "textMarkdown" : { "id" : 1447981947, "html" : "

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

\n

Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction between CYP2C19 and CYP2D6 and SSRIs. European journal of human genetics (2021)

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group published a paper with the guidelines as per the November 2018 update and further details on the assessed literature [Article:34782755].

\n

November 2018 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for sertraline based on CYP2C19 genotype. Patients with CYP2C19 poor metabolizer genotypes should not receive doses exceeding 75 mg/day, and dose should be guided by response and side effects and/or sertraline plasma concentration. No action is recommended for CYP2C19 intermediate or ultrarapid metabolizers.

\n

Wording in table taken from the Dutch guidelines November 2018 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
CYP2C19 PMsertralineThe risk of side effects is increased. The gene variation leads to increased plasma concentrations of sertraline.Do not give doses exceeding 75 mg/day. Guide the dose by response and side effects and/or sertraline plasma concentration.
CYP2C19 IMsertralineNO action is needed for this gene-drug interaction.The gene variation has a minor effect on the sertraline plasma concentration. No effect on side effects was found.
CYP2C19 UMsertralineNO action is needed for this gene-drug interaction.The gene variation has a negligible effect on the plasma concentration of sertraline. Moreover, no significant effect on response and side effects has been found.
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for sertraline and CYP2C19:

\n
\n

The Dutch Pharmacogenetics Working Group considers genotyping before starting sertraline to be potentially beneficial. Genotyping can be considered on an individual patient basis. If, however, the genotype is available, the Dutch Pharmacogenetics Working Group recommends adhering to the gene-drug guideline.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n

2011 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for sertraline based on CYP2C19 genotype [Article:21412232].

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Phenotype (Genotype)Therapeutic Dose RecommendationLevel of EvidenceClinical Relevance
CYP2C19 PM (*2/*2, *2/*3, *3/*3)Reduce dose by 50%.Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpointsClinical effect (statistically significant difference): long-standing discomfort (48-168 hr) without permanent injury e.g. failure of therapy with tricyclic antidepressants, atypical antipsychotic drugs; extrapyramidal side effects; parkinsonism; adverse drug events resulting from increased bioavailability of tricyclic antidepressants, metoprolol, propafenone (central effects e.g. dizziness); international normalized ratio 4.5-6.0; neutropenia 1.0-1.5x109/l; leucopenia 2.0-3.0x109/l; thrombocytopenia 50-75x109/l
CYP2C19 IM (*1/*2, *1/*3, *17/*2, *17/*3)Insufficient data to allow calculation of dose adjustment. Be extra alert to adverse drug events (e.g., nausea, vomiting, diarrhea).Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpointsMinor clinical effect (statistically significant difference): QTc prolongation (<450 ms female, <470 ms male); international normalized ratio increase < 4.5; Kinetic effect (statistically significant difference)
CYP2C19 UM (*17/*17)Noneno data was retrieved with the literature searchno data was retrieved with the literature search
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Do not give doses exceeding 75 mg/day. Guide the dose by response and side effects and/or sertraline plasma concentration.

\n", + "id" : 1452061604, + "html" : "

The guideline does not provide a recommendation for sertraline in normal metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299242", - "name" : "Recommendation PA166299242", + "id" : "PA166299243", + "name" : "Recommendation PA166299243", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -131692,73 +133094,32 @@ "valid" : true, "version" : 1 }, - "dosingInformation" : false, - "implications" : [ - "The gene variation has a minor effect on the sertraline plasma concentration. No effect on side effects was found." - ], - "lookupKey" : {"CYP2C19": "Intermediate Metabolizer"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA451333", - "name" : "sertraline", - "version" : 14 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166104980", - "name" : "Annotation of DPWG Guideline for sertraline and CYP2C19", - "version" : 34 - }, - "text" : { - "id" : 1452061605, - "html" : "

NO action is needed for this gene-drug interaction.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166299241", - "name" : "Recommendation PA166299241", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 1448526251, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on sertraline." + "The risk of side effects is increased. The gene variation leads to increased plasma concentrations of sertraline." ], - "lookupKey" : {"CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104980", "name" : "Annotation of DPWG Guideline for sertraline and CYP2C19", - "version" : 34 + "version" : 70 }, "text" : { - "id" : 1452061604, - "html" : "

The guideline does not provide a recommendation for sertraline in normal metabolizers.

\n", + "id" : 1452061606, + "html" : "

Do not give doses exceeding 75 mg/day. Guide the dose by response and side effects and/or sertraline plasma concentration.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", @@ -131786,21 +133147,63 @@ "objCls" : "Chemical", "id" : "PA451333", "name" : "sertraline", - "version" : 14 + "version" : 44 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104980", "name" : "Annotation of DPWG Guideline for sertraline and CYP2C19", - "version" : 34 + "version" : 70 }, "text" : { "id" : 1452061603, "html" : "

NO action is needed for this gene-drug interaction.

\n", - "version" : 0 + "version" : 1 }, - "version" : 0 + "version" : 2 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166299242", + "name" : "Recommendation PA166299242", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501929, + "description" : "Not Applicable", + "parents" : [], + "resource" : "Guideline Strength", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", + "valid" : true, + "version" : 1 + }, + "dosingInformation" : false, + "implications" : [ + "The gene variation has a minor effect on the sertraline plasma concentration. No effect on side effects was found." + ], + "lookupKey" : {"CYP2C19": "Intermediate Metabolizer"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA451333", + "name" : "sertraline", + "version" : 44 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104980", + "name" : "Annotation of DPWG Guideline for sertraline and CYP2C19", + "version" : 70 + }, + "text" : { + "id" : 1452061605, + "html" : "

NO action is needed for this gene-drug interaction.

\n", + "version" : 1 + }, + "version" : 2 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166104980" @@ -131822,7 +133225,7 @@ "date" : "2019-05-27T00:00:00-07:00", "description" : "Annotation current with November 2018 DPWG Guideline release", "type" : "Update", - "version" : 0 + "version" : 1 }, { "id" : 1450821034, @@ -131920,7 +133323,7 @@ "date" : "2024-03-18T00:00:00-07:00", "description" : "Updated links for risk analysis pdf and preemptive testing page.", "type" : "Update", - "version" : 0 + "version" : 1 } ], "literature" : [ @@ -131945,7 +133348,7 @@ "objCls" : "Chemical", "id" : "PA451363", "name" : "simvastatin", - "version" : 24 + "version" : 87 } ], "relatedGenes" : [ @@ -131954,7 +133357,7 @@ "id" : "PA134865839", "symbol" : "SLCO1B1", "name" : "solute carrier organic anion transporter family member 1B1", - "version" : 49 + "version" : 109 } ], "source" : "DPWG", @@ -131967,10 +133370,10 @@ "textMarkdown" : { "id" : 1450415245, "html" : "

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

\n

August 2020 Guideline update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for simvastatin based on SLCO1B1 genotype. They recommend choosing an alternative for patients with the SLCO1B1 521 CC or TC (rs4149056) genotype and consider any additional risk factors for statin-induced myopathy. If an alternative is not an option for patients with the 521 TC genotype, avoid simvastatin doses exceeding 40 mg/day and advise the patient to contact their doctor in the event of muscle symptoms.

\n

Wording in table taken from the Dutch guidelines November 2020 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
SLCO1B1 521 CCsimvastatinWhen using simvastatin 80 mg/day, the risk of myopathy is increased 30-fold to 18% and the risk of severe myopathy is increased 48-fold to 12%. When using 40 mg/day, this risk is increased 7-fold to 1% and 11-fold to 0.68% respectively. The gene variation leads to reduced simvastatin transport to the liver, which increases the simvastatin plasma concentration and therefore the risk of side effects.1. Choose an alternative.
Consider any additional risk factors for statin-induced myopathy.
Atorvastatin is affected less severely by the SLCO1B1 gene variation, but is also affected by CYP3A4 inhibitors such as amiodarone, verapamil and diltiazem. Use of atorvastatin is not recommended for patients with additional risk factors for statin-induced myopathy.
Rosuvastatin and pravastatin are influenced to a lesser extent by the SLCO1B1 gene variation. They are also not influenced by CYP3A4 inhibitors such as amiodarone, verapamil and diltiazem.
Fluvastatin is not significantly influenced by the SLCO1B1 gene variation or CYP3A4 inhibitors.
SLCO1B1 521 TCsimvastatinWhen using simvastatin 80 mg/day, the risk of myopathy is increased 5-fold to 3% for moderately severe to severe myopathy and 1.3% for severe myopathy. When using 40 mg/day, this risk is increased 2.6-fold to 0.39% and 0.17% respectively. The gene variation may lead to reduced simvastatin transport to the liver, which may increase simvastatin plasma concentrations and therefore the risk of side effects.1. Choose an alternative.
Consider any additional risk factors for statin-induced myopathy.
Atorvastatin is affected less severely by the SLCO1B1 gene variation, but is also affected by CYP3A4 inhibitors such as amiodarone, verapamil and diltiazem. Use of atorvastatin is not recommended for patients with additional risk factors for statin-induced myopathy.
Rosuvastatin and pravastatin are influenced to a lesser extent by the SLCO1B1 gene variation. They are also not influenced by CYP3A4 inhibitors such as amiodarone, verapamil and diltiazem.
Fluvastatin is not significantly influenced by the SLCO1B1 gene variation or CYP3A4 inhibitors.
2. If an alternative is not an option:
1. Avoid simvastatin doses exceeding 40mg/day.
2. Advise the patient to contact their doctor in the event of muscle symptoms.
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for simvastatin and SLCO1B1:

\n
\n

The KNMP Pharmacogenetics Working Group considers genotyping before starting simvastatin 80 mg/day to be essential for drug safety. Genotyping must be performed before drug therapy has been initiated to guide drug selection. The KNMP Pharmacogenetics Working Group considers genotyping before starting simvastatin at a dose of 40 mg/day or lower to be beneficial for drug safety. It is advised to genotype the patient before (or directly after) drug therapy has been initiated to guide drug selection.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n

November 2018 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for simvastatin based on SLCO1B1 genotype. They recommend choosing an alternative for patients with the SLCO1B1 521 CC or TC (rs4149056) genotype and consider any additional risk factors for statin-induced myopathy. If an alternative is not an option for patients with the 521 TC genotype, avoid simvastatin doses exceeding 40 mg/day and advise the patient to contact their doctor in the event of muscle symptoms.

\n

Wording in table taken from the Dutch guidelines November 2018 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
521 CCsimvastatinThe genetic polymorphism leads to reduced simvastatin transport to the liver. This increases simvastatin plasma concentrations and therefore the risk of myopathy.1. Choose an alternative. Consider any additional risk factors for statin-induced myopathy. Rosuvastatin and pravastatin are influenced to a lesser extent by SLCO1B1 polymorphisms. They are also not influenced by CYP3A4 inhibitors such as amiodarone, verapamil and diltiazem. Fluvastatin is not influenced by SLCO1B1 polymorphisms or CYP3A4 inhibitors.
521 TCsimvastatinThe genetic polymorphism may lead to reduced simvastatin transport to the liver. This may increase simvastatin plasma concentrations and therefore the risk of myopathy.1. Choose an alternative. Consider any additional risk factors for statin-induced myopathy. Rosuvastatin and pravastatin are influenced to a lesser extent by SLCO1B1 polymorphisms. They are also not influenced by CYP3A4 inhibitors such as amiodarone, verapamil and diltiazem. Fluvastatin is not influenced by SLCO1B1 polymorphisms or CYP3A4 inhibitors.
2. If an alternative is not an option:
1. Avoid simvastatin doses exceeding 40 mg/day
2. Advise the patient to contact their doctor in the event of muscle symptoms.
\n", - "version" : 9 + "version" : 15 }, "userId" : "lgong", - "version" : 14 + "version" : 40 }, "recommendations" : [ { @@ -131999,21 +133402,21 @@ "objCls" : "Chemical", "id" : "PA451363", "name" : "simvastatin", - "version" : 24 + "version" : 87 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182844", "name" : "Annotation of DPWG Guideline for simvastatin and SLCO1B1", - "version" : 14 + "version" : 40 }, "text" : { "id" : 1452061447, "html" : "
    \n
  1. Choose an alternative.\nConsider any additional risk factors for statin-induced myopathy.\nAtorvastatin is affected less severely by the SLCO1B1 gene variation, but is also affected by CYP3A4 inhibitors such as amiodarone, verapamil and diltiazem. Use of atorvastatin is not recommended for patients with additional risk factors for statin-induced myopathy.\nRosuvastatin and pravastatin are influenced to a lesser extent by the SLCO1B1 gene variation. They are also not influenced by CYP3A4 inhibitors such as amiodarone, verapamil and diltiazem.\nFluvastatin is not significantly influenced by the SLCO1B1 gene variation or CYP3A4 inhibitors.
    2. \n
\n", "version" : 0 }, - "version" : 0 + "version" : 4 }, { "objCls" : "Recommendation Annotation", @@ -132041,21 +133444,21 @@ "objCls" : "Chemical", "id" : "PA451363", "name" : "simvastatin", - "version" : 24 + "version" : 87 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182844", "name" : "Annotation of DPWG Guideline for simvastatin and SLCO1B1", - "version" : 14 + "version" : 40 }, "text" : { "id" : 1452061446, "html" : "
    \n
  1. Choose an alternative.\nConsider any additional risk factors for statin-induced myopathy.\nAtorvastatin is affected less severely by the SLCO1B1 gene variation, but is also affected by CYP3A4 inhibitors such as amiodarone, verapamil and diltiazem. Use of atorvastatin is not recommended for patients with additional risk factors for statin-induced myopathy.\nRosuvastatin and pravastatin are influenced to a lesser extent by the SLCO1B1 gene variation. They are also not influenced by CYP3A4 inhibitors such as amiodarone, verapamil and diltiazem.\nFluvastatin is not significantly influenced by the SLCO1B1 gene variation or CYP3A4 inhibitors.
    2. \n
  2. If an alternative is not an option:\n
      \n
    1. Avoid simvastatin doses exceeding 40mg/day.
      2. \n
    2. Advise the patient to contact their doctor in the event of muscle symptoms.
      3. \n
    \n
    3. \n
\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", @@ -132082,21 +133485,21 @@ "objCls" : "Chemical", "id" : "PA451363", "name" : "simvastatin", - "version" : 24 + "version" : 87 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182844", "name" : "Annotation of DPWG Guideline for simvastatin and SLCO1B1", - "version" : 14 + "version" : 40 }, "text" : { "id" : 1452061448, "html" : "

The guideline does not provide a recommendation for atorvastatin in patients with the SLCO1B1 521 TT genotype.

\n", - "version" : 0 + "version" : 1 }, - "version" : 0 + "version" : 4 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166182844" @@ -132203,14 +133606,14 @@ "id" : "PA165816543", "symbol" : "CYP2C9*2", "name" : "*2", - "version" : 23 + "version" : 52 }, { "objCls" : "Haplotype", "id" : "PA165816544", "symbol" : "CYP2C9*3", "name" : "*3", - "version" : 25 + "version" : 55 } ], "relatedChemicals" : [ @@ -132218,7 +133621,7 @@ "objCls" : "Chemical", "id" : "PA166182736", "name" : "siponimod", - "version" : 7 + "version" : 9 } ], "relatedGenes" : [ @@ -132227,7 +133630,7 @@ "id" : "PA126", "symbol" : "CYP2C9", "name" : "cytochrome P450 family 2 subfamily C member 9", - "version" : 7877 + "version" : 7952 } ], "source" : "DPWG", @@ -132240,16 +133643,16 @@ "textMarkdown" : { "id" : 1451153221, "html" : "

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

\n

May 2021 update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has made some minor changes to the names of some phenotype groups in this guideline. The table below has been updated to reflect this but the recommendations themselves have not changed.

\n

May 2020 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for siponimod based on CYP2C9 genotype. They recommend decreasing the dose for CYP2C9 *1/*3, *2/*3 genotypes and to avoid siponimod for the CYP2C9 *3/*3 genotype.

\n

Wording in table taken from the Dutch guidelines May 2020 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
CYP2C9*1/*2siponimodThe genetic variation can slightly increase the exposure to siponimod. However, the effect is too small to expect any impact on efficacy or adverse effects.NO action is required for this gene-drug interaction.
CYP2C9*1/*3siponimodTheoretically, the risk of adverse effects in increased, as the genetic variation results in higher plasma concentrations of siponimod.Use 50% of the normal maintenance dose. Reconsider the choice and the potential benefit of siponimod if the patient is also using a moderate CYP3A4 inducer, such as modafinil. For this genetic variation, a moderate CYP3A4 inducer results in a reduction in the exposure of siponimod by 49%, according to a pharmacokinetic model.
CYP2C9*2/*2siponimodThe genetic variation can slightly increase the exposure to siponimod. However, the effect is too small to expect any impact on efficacy or adverse effects.NO action is required for this gene-drug interaction.
CYP2C9*2/*3siponimodTheoretically, the risk of adverse effects in increased, as the genetic variation results in higher plasma concentrations of siponimod.Use 50% of the normal maintenance dose. Reconsider the choice and the potential benefit of siponimod if the patient is also using a moderate CYP3A4 inducer, such as modafinil. For this genetic variation, a moderate CYP3A4 inducer results in a reduction in the exposure of siponimod by 49%, according to a pharmacokinetic model.
CYP2C9*3/*3siponimodSiponimod is contraindicated in patients with this genetic variation. Theoretically, the risk of adverse effects is greatly increased, as the genetic variation results in much higher plasma concentrations of siponimod.Avoid siponimod.
CYP2C9 IM otherasiponimodTheoretically, the risk of adverse effects in increased, as the genetic variation results in higher plasma concentrations of siponimod.Use 50% of the normal maintenance dose. Reconsider the choice and the potential benefit of siponimod if the patient is also using a moderate CYP3A4 inducer, such as modafinil. For the comparable genetic variation *1/*3, the moderate CYP3A4 inducer results in a reduction in the exposure of siponimod by 49%, according to a pharmacokinetic model.
CYP2C9 PM other asiponimodSiponimod is contraindicated in patients with the comparable genetic variation *3/*3. Theoretically, the risk of adverse effects is greatly increased, as the genetic variation results in much higher plasma concentrations of siponimod.Avoid siponimod.
\n

a These groups are referred to in the DPWG recommendation PDF as 'IM ANDERS' and 'PM ANDERS', which use the Dutch word 'anders'. PharmGKB has translated these as 'IM other' and PM other', respectively.

\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for siponimod and CYP2C9:

\n
\n

Due to the absence of clinical studies with patients with a CYP2C9 genotype leading to reduced CYP2C9 activity, and thus the absence of evidence of an increase in adverse events code ≥ D (grade ≥ 3) in these patients, the clinical implication of the gene-drug interaction scores only 2 out of the maximum of 10 points (with pre-emptive genotyping considered to be potentially beneficial for scores ranging from 0 to 2 points) [...]. However, because there is not enough evidence to reject the warnings and recommendations in the SmPC either, the KNMP decided to adopt the genotyping recommendation in the SmPC. The SmPC indicates that genotyping must be performed before starting siponimod to guide drug and dose selection. This would amount to genotyping being essential for drug safety according to the nomenclature of the KNMP Pharmacogenetics Working Group.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n", - "version" : 5 + "version" : 7 }, "userId" : "katrin", - "version" : 10 + "version" : 48 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166299159", - "name" : "Recommendation PA166299159", + "id" : "PA166299155", + "name" : "Recommendation PA166299155", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -132263,36 +133666,36 @@ }, "dosingInformation" : false, "implications" : [ - "Siponimod is contraindicated in patients with this genetic variation. Theoretically, the risk of adverse effects is greatly increased, as the genetic variation results in much higher plasma concentrations of siponimod." + "Siponimod is contraindicated in patients with the comparable genetic variation *3/*3. Theoretically, the risk of adverse effects is greatly increased, as the genetic variation results in much higher plasma concentrations of siponimod." ], - "lookupKey" : {"CYP2C9": {"*3": 2}}, + "lookupKey" : {"CYP2C9": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166182736", "name" : "siponimod", - "version" : 7 + "version" : 9 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166211021", "name" : "Annotation of DPWG Guideline for siponimod and CYP2C9", - "version" : 10 + "version" : 48 }, "text" : { - "id" : 1452061522, + "id" : 1452061518, "html" : "

Avoid siponimod.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299155", - "name" : "Recommendation PA166299155", - "alternateDrugAvailable" : true, + "id" : "PA166299157", + "name" : "Recommendation PA166299157", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -132305,36 +133708,36 @@ }, "dosingInformation" : false, "implications" : [ - "Siponimod is contraindicated in patients with the comparable genetic variation *3/*3. Theoretically, the risk of adverse effects is greatly increased, as the genetic variation results in much higher plasma concentrations of siponimod." + "The genetic variation can slightly increase the exposure to siponimod. However, the effect is too small to expect any impact on efficacy or adverse effects." ], - "lookupKey" : {"CYP2C9": "Poor Metabolizer"}, + "lookupKey" : {"CYP2C9": {"*2": 2}}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166182736", "name" : "siponimod", - "version" : 7 + "version" : 9 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166211021", "name" : "Annotation of DPWG Guideline for siponimod and CYP2C9", - "version" : 10 + "version" : 48 }, "text" : { - "id" : 1452061518, - "html" : "

Avoid siponimod.

\n", + "id" : 1452061520, + "html" : "

NO action is required for this gene-drug interaction.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299158", - "name" : "Recommendation PA166299158", - "alternateDrugAvailable" : true, + "id" : "PA166299154", + "name" : "Recommendation PA166299154", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -132345,79 +133748,78 @@ "valid" : true, "version" : 1 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "Theoretically, the risk of adverse effects in increased, as the genetic variation results in higher plasma concentrations of siponimod." + "The genetic variation can slightly increase the exposure to siponimod. However, the effect is too small to expect any impact on efficacy or adverse effects." ], - "lookupKey" : {"CYP2C9": {"*2": 1, "*3": 1}}, + "lookupKey" : {"CYP2C9": {"*1": 1, "*2": 1}}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166182736", "name" : "siponimod", - "version" : 7 + "version" : 9 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166211021", "name" : "Annotation of DPWG Guideline for siponimod and CYP2C9", - "version" : 10 + "version" : 48 }, "text" : { - "id" : 1452061521, - "html" : "

Use 50% of the normal maintenance dose. Reconsider the choice and the potential benefit of siponimod if the patient is also using a moderate CYP3A4 inducer, such as modafinil. For this genetic variation, a moderate CYP3A4 inducer results in a reduction in the exposure of siponimod by 49%, according to a pharmacokinetic model.

\n", + "id" : 1452061517, + "html" : "

NO action is required for this gene-drug interaction.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299153", - "name" : "Recommendation PA166299153", - "alternateDrugAvailable" : true, + "id" : "PA166299152", + "name" : "Recommendation PA166299152", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "Theoretically, the risk of adverse effects in increased, as the genetic variation results in higher plasma concentrations of siponimod." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on siponimod." ], - "lookupKey" : {"CYP2C9": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2C9": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166182736", "name" : "siponimod", - "version" : 7 + "version" : 9 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166211021", "name" : "Annotation of DPWG Guideline for siponimod and CYP2C9", - "version" : 10 + "version" : 48 }, "text" : { - "id" : 1452061516, - "html" : "

Use 50% of the normal maintenance dose. Reconsider the choice and the potential benefit of siponimod if the patient is also using a moderate CYP3A4 inducer, such as modafinil. For the comparable genetic variation *1/*3, the moderate CYP3A4 inducer results in a reduction in the exposure of siponimod by 49%, according to a pharmacokinetic model.

\n", + "id" : 1452061515, + "html" : "

The guideline does not provide a recommendation for siponimod in normal metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299156", - "name" : "Recommendation PA166299156", + "id" : "PA166299159", + "name" : "Recommendation PA166299159", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -132429,79 +133831,80 @@ "valid" : true, "version" : 1 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "Theoretically, the risk of adverse effects in increased, as the genetic variation results in higher plasma concentrations of siponimod." + "Siponimod is contraindicated in patients with this genetic variation. Theoretically, the risk of adverse effects is greatly increased, as the genetic variation results in much higher plasma concentrations of siponimod." ], - "lookupKey" : {"CYP2C9": {"*1": 1, "*3": 1}}, + "lookupKey" : {"CYP2C9": {"*3": 2}}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166182736", "name" : "siponimod", - "version" : 7 + "version" : 9 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166211021", "name" : "Annotation of DPWG Guideline for siponimod and CYP2C9", - "version" : 10 + "version" : 48 }, "text" : { - "id" : 1452061519, - "html" : "

Use 50% of the normal maintenance dose. Reconsider the choice and the potential benefit of siponimod if the patient is also using a moderate CYP3A4 inducer, such as modafinil. For this genetic variation, a moderate CYP3A4 inducer results in a reduction in the exposure of siponimod by 49%, according to a pharmacokinetic model.

\n", + "id" : 1452061522, + "html" : "

Avoid siponimod.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299152", - "name" : "Recommendation PA166299152", - "alternateDrugAvailable" : false, + "id" : "PA166299158", + "name" : "Recommendation PA166299158", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on siponimod." + "Theoretically, the risk of adverse effects in increased, as the genetic variation results in higher plasma concentrations of siponimod." ], - "lookupKey" : {"CYP2C9": "Normal Metabolizer"}, + "lookupKey" : {"CYP2C9": {"*2": 1, "*3": 1}}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166182736", "name" : "siponimod", - "version" : 7 + "version" : 9 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166211021", "name" : "Annotation of DPWG Guideline for siponimod and CYP2C9", - "version" : 10 + "version" : 48 }, "text" : { - "id" : 1452061515, - "html" : "

The guideline does not provide a recommendation for siponimod in normal metabolizers.

\n", + "id" : 1452061521, + "html" : "

Use 50% of the normal maintenance dose. Reconsider the choice and the potential benefit of siponimod if the patient is also using a moderate CYP3A4 inducer, such as modafinil. For this genetic variation, a moderate CYP3A4 inducer results in a reduction in the exposure of siponimod by 49%, according to a pharmacokinetic model.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299157", - "name" : "Recommendation PA166299157", - "alternateDrugAvailable" : false, + "id" : "PA166299153", + "name" : "Recommendation PA166299153", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -132512,38 +133915,38 @@ "valid" : true, "version" : 1 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "The genetic variation can slightly increase the exposure to siponimod. However, the effect is too small to expect any impact on efficacy or adverse effects." + "Theoretically, the risk of adverse effects in increased, as the genetic variation results in higher plasma concentrations of siponimod." ], - "lookupKey" : {"CYP2C9": {"*2": 2}}, + "lookupKey" : {"CYP2C9": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166182736", "name" : "siponimod", - "version" : 7 + "version" : 9 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166211021", "name" : "Annotation of DPWG Guideline for siponimod and CYP2C9", - "version" : 10 + "version" : 48 }, "text" : { - "id" : 1452061520, - "html" : "

NO action is required for this gene-drug interaction.

\n", + "id" : 1452061516, + "html" : "

Use 50% of the normal maintenance dose. Reconsider the choice and the potential benefit of siponimod if the patient is also using a moderate CYP3A4 inducer, such as modafinil. For the comparable genetic variation *1/*3, the moderate CYP3A4 inducer results in a reduction in the exposure of siponimod by 49%, according to a pharmacokinetic model.

\n", "version" : 0 }, "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299154", - "name" : "Recommendation PA166299154", - "alternateDrugAvailable" : false, + "id" : "PA166299156", + "name" : "Recommendation PA166299156", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -132554,29 +133957,29 @@ "valid" : true, "version" : 1 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "The genetic variation can slightly increase the exposure to siponimod. However, the effect is too small to expect any impact on efficacy or adverse effects." + "Theoretically, the risk of adverse effects in increased, as the genetic variation results in higher plasma concentrations of siponimod." ], - "lookupKey" : {"CYP2C9": {"*1": 1, "*2": 1}}, + "lookupKey" : {"CYP2C9": {"*1": 1, "*3": 1}}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166182736", "name" : "siponimod", - "version" : 7 + "version" : 9 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166211021", "name" : "Annotation of DPWG Guideline for siponimod and CYP2C9", - "version" : 10 + "version" : 48 }, "text" : { - "id" : 1452061517, - "html" : "

NO action is required for this gene-drug interaction.

\n", + "id" : 1452061519, + "html" : "

Use 50% of the normal maintenance dose. Reconsider the choice and the potential benefit of siponimod if the patient is also using a moderate CYP3A4 inducer, such as modafinil. For this genetic variation, a moderate CYP3A4 inducer results in a reduction in the exposure of siponimod by 49%, according to a pharmacokinetic model.

\n", "version" : 0 }, "version" : 1 @@ -132789,7 +134192,7 @@ "id" : "PA166128219", "symbol" : "CYP3A5*3", "name" : "*3", - "version" : 13 + "version" : 30 } ], "relatedChemicals" : [ @@ -132797,7 +134200,7 @@ "objCls" : "Chemical", "id" : "PA451578", "name" : "tacrolimus", - "version" : 25 + "version" : 81 } ], "relatedGenes" : [ @@ -132806,66 +134209,65 @@ "id" : "PA131", "symbol" : "CYP3A5", "name" : "cytochrome P450 family 3 subfamily A member 5", - "version" : 7962 + "version" : 8072 } ], "source" : "DPWG", "summaryMarkdown" : { "id" : 1447981954, "html" : "

Increased doses of tacrolimus are recommended for CYP3A5 heterozygous and homozygous expressors and adjusted as needed. Instructions for liver transplantation patients include genotypes of both patient and donor.

\n", - "version" : 2 + "version" : 4 }, "terms" : [], "textMarkdown" : { "id" : 1447981953, "html" : "

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

\n

The CYP3A5 gene information document from DPWG includes CYP3A5*2, *4, and *5, but these alleles are not included in the genotype selection picker above. CYP3A5*2, *4 and *5 have been retired by PharmVar in February 2022 after their core SNVs have been found to be in complete linkage equilibrium with the CYP3A5*3-defining intronic variant c.219-237. See Read me document and the PharmVar CYP3A5 GeneFocus [Article:35202484] for additional details.

\n

May 2021 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has made some minor changes to the text of the CYP3A5-tacrolimus guideline. The table below has been updated to reflect this but the recommendations themselves have not changed

\n

May 2020 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for tacrolimus based on CYP3A5 status and includes recommendations for liver transplantations and other transplantations. They recommend increasing the initial dose followed by adjustment based on therapeutic drug monitoring in both heterozygous and homozygous CYP3A5 expressor.

\n

Wording in table taken from the Dutch guidelines May 2020 update and incorporating text changes from the May 2021 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation Indications OTHER than liver transplantationRecommendation LIVER transplantation
CYP3A5 heterozygote expressortacrolimusAn increase of the initial dose can result in an increased chance of reaching a tacrolimus concentration within the target range before the start of therapeutic drug monitoring. However, there is no direct evidence that this results in improved clinical results. The genetic variation results in increased conversion of tacrolimus to inactive metabolites and therefore in a higher required dose.Use 1.5 times the initial dose that would yield the desired result in non-expressers. Adjustment of the dose should then be based on therapeutic drug monitoring.
For example: A Dutch study found a median trough concentration for tacrolimus of 14.7 ng/mL after 3 days at an initial dose of 0.15 mg/kg twice daily for 29 kidney transplant patients who were heterozygous expressers. Their target value was 10 - 15 ng/mL.		In addition to the patient’s genotype, the metabolism of tacrolimus is also determined by the genotype of the transplanted liver.
LIVER is also of the genotype HETEROZYGOUS EXPRESSOR: Use 1.5 times the normal initial dose. Adjustment of the dose should then be based on therapeutic drug monitoring.
If LIVER has a DIFFERENT genotype: There is insufficient evidence in the literature to support a dose recommendation.
CYP3A5 homozygous expressortacrolimusAn increase of the initial dose can result in an increased chance of reaching a tacrolimus concentration within the target range before the start of therapeutic drug monitoring. However, there is no direct evidence that this results in improved clinical results. The genetic variation results in an increased conversion of tacrolimus to inactive metabolites and therefore a higher required dose.Use 2.5 times the initial dose that would yield the desired result in non-expressers. Adjustment of the dose should then be based on therapeutic drug monitoring.
For example: One Dutch study found a median trough concentration for tacrolimus after three days of 9.4 ng/mL at an initial dose of 0.15 mg/kg twice daily for 5 homozygous kidney transplant patients. Their target value was 10 - 15 ng/mL.		In addition to the patient’s genotype, the metabolism of tacrolimus is also determined by the genotype of the transplanted liver.
LIVER is also of the genotype HOMOZYGOUS EXPRESSOR: Use 2.5 times the normal initial dose. Adjustment of the dose should then be based on therapeutic drug monitoring.
LIVER has a DIFFERENT genotype: There is insufficient evidence in the literature to support a dose recommendation.
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for tacrolimus and CYP3A5:

\n
\n

The KNMP Pharmacogenetics Working Group decided not to give a genotyping recommendation for tacrolimus, because evidence of a clinical effect of CYP3A5 expresser phenotypes in standard clinical practice is lacking. Because of this, indications for a positive effect of determining CYP3A5 phenotype and adjusting therapy according to this phenotype are lacking.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n

November 2018 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for tacrolimus based on CYP3A5 status and includes recommendations for liver transplantations and other transplantations. Genetic variation results in an increased conversion of tacrolimus to inactive metabolites and as a result a higher dose is required. Adjustment of the initial dose results in an increased chance of reaching a tacrolimus concentration within the target range before the start of therapeutic drug monitoring on day three. However, there is no direct evidence that this results in improved clinical results.

\n

Wording in table taken from the Dutch guidelines November 2018 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugRecommendation Indications OTHER than liver transplantationRecommendation LIVER transplantation
CYP3A5 heterozygote expressortacrolimusStart with 1.75 times of the standard initial dose that would yield the desired result in non-expressors. Adjustment of the dose should then be based on therapeutic drug monitoring.In addition to the patient’s genotype, the metabolism of tacrolimus is also determined by the genotype of the transplanted liver.
LIVER is also of the genotype HETEROZYGOUS EXPRESSOR: Start with 1.75 times the standard initial dose Adjustment of the dose should then be based on therapeutic drug monitoring.
If LIVER has a DIFFERENT genotype: There is insufficient evidence in the literature to support a dose recommendation.
CYP3A5 homozygous expressortacrolimusStart with 2.5 times the standard initial dose that would yield the desired result in non-expressors Adjustment of the dose should then be based on therapeutic drug monitoring.In addition to the patient’s genotype, the metabolism of tacrolimus is also determined by the genotype of the transplanted liver.
LIVER is also of the genotype HOMOZYGOUS EXPRESSOR: Start with 2.5 times the standard initial dose Adjustment of the dose should then be based on therapeutic drug monitoring.
LIVER has a DIFFERENT genotype: There is insufficient evidence in the literature to support a dose recommendation.
\n

2011 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for tacrolimus based on CYP3A5 genotype [Article:21412232]. They found evidence to support an interaction between tacrolimus and CYP3A5. However, they make no dosing recommendations at this time, due to fact that "in Dutch transplantation hospitals the tacrolimus dose is titrated in response to therapeutic drug monitoring."

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
GenotypeTherapeutic Dose RecommendationLevel of EvidenceClinical Relevance
CYP3A5 *1/*1NonePublished controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Clinical effect (S): short-lived discomfort (< 48 hr) without permanent injury: e.g. reduced decrease in resting heart rate; reduction in exercise tachycardia; decreased pain relief from oxycodone; ADE resulting from increased bioavailability of atomoxetine (decreased appetite, insomnia, sleep disturbance etc); neutropenia > 1.5x109/l; leucopenia > 3.0x109/l; thrombocytopenia > 75x109/l; moderate diarrhea not affecting daily activities; reduced glucose increase following oral glucose tolerance test.
CYP3A5 *1/*3NonePublished controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Clinical effect (S): long-standing discomfort (> 168 hr), permanent symptom or invalidating injury e.g. failure of prophylaxis of atrial fibrillation; venous thromboembolism; decreased effect of clopidogrel on inhibition of platelet aggregation; ADE resulting from increased bioavailability of phenytoin; INR > 6.0; neutropenia 0.5-1.0x109/l; leucopenia 1.0-2.0x109/l; thrombocytopenia 25-50x109/l; severe diarrhea.
\n\n", - "version" : 20 + "version" : 31 }, "userId" : "mariealus", - "version" : 34 + "version" : 103 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166299247", - "name" : "Recommendation PA166299247", + "id" : "PA166299248", + "name" : "Recommendation PA166299248", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "An increase of the initial dose can result in an increased chance of reaching a tacrolimus concentration within the target range before the start of therapeutic drug monitoring. However, there is no direct evidence that this results in improved clinical results. The genetic variation results in increased conversion of tacrolimus to inactive metabolites and therefore in a higher required dose." + "The guideline does not provide a description of the impact of a non-expressor phenotype on tacrolimus." ], - "lookupKey" : {"CYP3A5": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP3A5": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451578", "name" : "tacrolimus", - "version" : 25 + "version" : 81 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104983", "name" : "Annotation of DPWG Guideline for tacrolimus and CYP3A5", - "version" : 34 + "version" : 103 }, "text" : { - "id" : 1452061610, - "html" : "

RECOMMENDATION LIVER TRANSPLANTATION\nIn addition to the patient’s genotype, the metabolism of tacrolimus is also determined by the genotype of the transplanted liver.\nLIVER is also of the genotype HETEROZYGOUS EXPRESSOR: Use 1.5 times the normal initial dose. Adjustment of the dose should then be based on therapeutic drug monitoring.
\nIf LIVER has a DIFFERENT genotype: There is insufficient evidence in the literature to support a dose recommendation.
\nRECOMMENDATION INDICATIONS OTHER THAN LIVER TRANSPLANTATION\nUse 1.5 times the initial dose that would yield the desired result in non-expressers. Adjustment of the dose should then be based on therapeutic drug monitoring. Adjustment of the dose should then be based on therapeutic drug monitoring.\nFor example: A Dutch study found a median trough concentration for tacrolimus of 14.7 ng/mL after 3 days at an initial dose of 0.15 mg/kg twice daily for 29 kidney transplant patients who were heterozygous expressers. Their target value was 10 - 15 ng/mL.

\n", + "id" : 1452061611, + "html" : "

The guideline does not provide a recommendation for tacrolimus in CYP3A5 non-expressers.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", @@ -132893,62 +134295,63 @@ "objCls" : "Chemical", "id" : "PA451578", "name" : "tacrolimus", - "version" : 25 + "version" : 81 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104983", "name" : "Annotation of DPWG Guideline for tacrolimus and CYP3A5", - "version" : 34 + "version" : 103 }, "text" : { "id" : 1452061609, "html" : "

LIVER TRANSPLANTATION\nIn addition to the patient’s genotype, the metabolism of tacrolimus is also determined by the genotype of the transplanted liver.\nLIVER is also of the genotype HOMOZYGOUS EXPRESSOR: Use 2.5 times the normal initial dose. Adjustment of the dose should then be based on therapeutic drug monitoring.\nLIVER has a DIFFERENT genotype: There is insufficient evidence in the literature to support a dose recommendation.

\n

OTHER TRANSPLANTATION\nUse 2.5 times the initial dose that would yield the desired result in non-expressers. Adjustment of the dose should then be based on therapeutic drug monitoring. For example: One Dutch study found a median trough concentration for tacrolimus after three days of 9.4 ng/mL at an initial dose of 0.15 mg/kg twice daily for 5 homozygous kidney transplant patients. Their target value was 10 - 15 ng/mL.

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299248", - "name" : "Recommendation PA166299248", + "id" : "PA166299247", + "name" : "Recommendation PA166299247", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "The guideline does not provide a description of the impact of a non-expressor phenotype on tacrolimus." + "An increase of the initial dose can result in an increased chance of reaching a tacrolimus concentration within the target range before the start of therapeutic drug monitoring. However, there is no direct evidence that this results in improved clinical results. The genetic variation results in increased conversion of tacrolimus to inactive metabolites and therefore in a higher required dose." ], - "lookupKey" : {"CYP3A5": "Poor Metabolizer"}, + "lookupKey" : {"CYP3A5": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451578", "name" : "tacrolimus", - "version" : 25 + "version" : 81 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104983", "name" : "Annotation of DPWG Guideline for tacrolimus and CYP3A5", - "version" : 34 + "version" : 103 }, "text" : { - "id" : 1452061611, - "html" : "

The guideline does not provide a recommendation for tacrolimus in CYP3A5 non-expressers.

\n", + "id" : 1452061610, + "html" : "

RECOMMENDATION LIVER TRANSPLANTATION\nIn addition to the patient’s genotype, the metabolism of tacrolimus is also determined by the genotype of the transplanted liver.\nLIVER is also of the genotype HETEROZYGOUS EXPRESSOR: Use 1.5 times the normal initial dose. Adjustment of the dose should then be based on therapeutic drug monitoring.
\nIf LIVER has a DIFFERENT genotype: There is insufficient evidence in the literature to support a dose recommendation.
\nRECOMMENDATION INDICATIONS OTHER THAN LIVER TRANSPLANTATION\nUse 1.5 times the initial dose that would yield the desired result in non-expressers. Adjustment of the dose should then be based on therapeutic drug monitoring. Adjustment of the dose should then be based on therapeutic drug monitoring.\nFor example: A Dutch study found a median trough concentration for tacrolimus of 14.7 ng/mL after 3 days at an initial dose of 0.15 mg/kg twice daily for 29 kidney transplant patients who were heterozygous expressers. Their target value was 10 - 15 ng/mL.

\n", "version" : 0 }, - "version" : 0 + "version" : 3 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166104983" @@ -133212,7 +134615,7 @@ "objCls" : "Chemical", "id" : "PA451581", "name" : "tamoxifen", - "version" : 23 + "version" : 82 } ], "relatedGenes" : [ @@ -133221,71 +134624,72 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "DPWG", "summaryMarkdown" : { "id" : 1447981920, "html" : "

For CYP2D6 poor and intermediate metabolizers, consider an alternative medication or a dose increase. For intermediate metabolizers, avoid concomitant CYP2D6 inhibitor use.

\n", - "version" : 1 + "version" : 2 }, "terms" : [], "textMarkdown" : { "id" : 1447981919, "html" : "

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

\n

November 2018 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for tamoxifen based on CYP2D6 genotype. They recommend that alternative medication be considered for patients who are CYP2D6 intermediate metabolizers (IMs) or poor metabolizers (PMs). Alternatively, a dose increase can be consider for these patients. Concomitant use of CYP2D6 inhibitors should be avoided in CYP2D6 IMs.

\n

There are no recommendations for CYP2D6 ultrarapid metabolizers (UMs).

\n

Wording in table taken from the Dutch guidelines November 2018 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
CYP2D6 UMtamoxifenAs a result of the genetic variation, the plasma concentration of the active metabolites 4-hydroxytamoxifen and endoxifen can increase. However, there is no evidence that this results in an increase in the side effects.NO action is needed for this gene-drug interaction.
CYP2D6 IMtamoxifenThis gene variation reduces the conversion of tamoxifen to the active metabolite endoxifen. This can result in reduced effectiveness.1. Select an alternative or measure the endoxifen concentration and increase the dose if necessary by a factor of 1.5-2. Aromatase inhibitors are a possible alternative for post-menopausal women.
2. If TAMOXIFEN is selected: avoid co-medication with CYP2D6 inhibitors such as paroxetine and fluoxetine
CYP2D6 PMtamoxifenThis gene variation reduces the conversion of tamoxifen to the active metabolite endoxifen. This can result in reduced effectiveness.Select an alternative or increase the dose to 40 mg/day and monitor the endoxifen concentration. Studies have demonstrated that PM can achieve an adequate endoxifen concentration when the dose is increased to 40-60 mg/day. Aromatase inhibitors are a possible alternative for post-menopausal women.
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for tamoxifen and CYP2D6:

\n
\n

The KNMP Pharmacogenetics Working Group considers genotyping of patients before starting tamoxifen to be beneficial for drug effectiveness. It is advised to consider genotyping the patient before (or directly after) drug\ntherapy has been initiated to guide drug and dose selection

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n

2011 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for tamoxifen based on CYP2D6 genotypes [Article:21412232]. For PM and IM genotypes, they recommend considering using aromatase inhibitors for postmenopausal women due to increased risk for relapse of breast cancer with tamoxifen. For IM genotypes, they recommend avoiding concomitant CYP2D6 inhibitor use.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Phenotype (Genotype)Therapeutic Dose RecommendationLevel of EvidenceClinical Relevance
PM (two inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) alleles)Increased risk for relapse of breast cancer. Consider aromatase inhibitor for postmenopausal women.Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Clinical effect (S): Failure of lifesaving therapy e.g. anticipated myelosuppression; prevention of breast cancer relapse; arrhythmia; neutropenia < 0.5x109/l; leucopenia < 1.0x109/l; thrombocytopenia < 25x109/l; life-threatening complications from diarrhea.
IM (two decreased-activity (*9, *10, *17, *29, *36, *41) alleles or carrying one active (*1, *2, *33, *35) and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele, or carrying one decreased-activity (*9, *10, *17, *29, *36, *41) allele and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele)Increased risk for relapse of breast cancer. Avoid concomitant use of CYP2D6 inhibitors. Consider aromatase inhibitor for postmenopausal women.Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Clinical effect (S): Failure of lifesaving therapy e.g. anticipated myelosuppression; prevention of breast cancer relapse; arrhythmia; neutropenia < 0.5x109/l; leucopenia < 1.0x109/l; thrombocytopenia < 25x109/l; life-threatening complications from diarrhea.
UM (a gene duplication in absence of inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) or decreased-activity (*9, *10, *17, *29, *36, *41) alleles)No.Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Minor clinical effect (S): QTc prolongation (<450 ms female, <470 ms male); INR increase < 4.5. Kinetic effect (S).
\n\n", - "version" : 15 + "version" : 20 }, "userId" : "cfthorn", - "version" : 31 + "version" : 91 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166302762", - "name" : "Recommendation Annotation PA166302762", - "alternateDrugAvailable" : false, + "id" : "PA166302726", + "name" : "Recommendation Annotation PA166302726", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on tamoxifen." + "This gene variation reduces the conversion of tamoxifen to the active metabolite endoxifen. This can result in reduced effectiveness." ], - "lookupKey" : {"CYP2D6": "1.5"}, + "lookupKey" : {"CYP2D6": "0.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451581", "name" : "tamoxifen", - "version" : 23 + "version" : 82 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104966", "name" : "Annotation of DPWG Guideline for tamoxifen and CYP2D6", - "version" : 31 + "version" : 91 }, "text" : { - "id" : 1452104361, - "html" : "

The guideline does not provide a recommendation for tamoxifen in normal metabolizers.

\n", + "id" : 1452104325, + "html" : "

Select an alternative or increase the dose to 40 mg/day and monitor the endoxifen concentration. Studies have demonstrated that PM can achieve an adequate endoxifen concentration when the dose is increased to 40-60 mg/day. Aromatase inhibitors are a possible alternative for post-menopausal women.

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NO action is needed for this gene-drug interaction.

\n", + "id" : 1452104340, + "html" : "\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302842", - "name" : "Recommendation Annotation PA166302842", - "alternateDrugAvailable" : false, + "id" : "PA166302742", + "name" : "Recommendation Annotation PA166302742", + "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -133338,37 +134742,37 @@ "valid" : true, "version" : 1 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "As a result of the genetic variation, the plasma concentration of the active metabolites 4-hydroxytamoxifen and endoxifen can increase. However, there is no evidence that this results in an increase in the side effects." + "This gene variation reduces the conversion of tamoxifen to the active metabolite endoxifen. This can result in reduced effectiveness." ], - "lookupKey" : {"CYP2D6": "≥5.0"}, + "lookupKey" : {"CYP2D6": "0.5"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451581", "name" : "tamoxifen", - "version" : 23 + "version" : 82 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104966", "name" : "Annotation of DPWG Guideline for tamoxifen and CYP2D6", - "version" : 31 + "version" : 91 }, "text" : { - "id" : 1452104441, - "html" : "

NO action is needed for this gene-drug interaction.

\n", + "id" : 1452104341, + "html" : "\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302744", - "name" : "Recommendation Annotation PA166302744", + "id" : "PA166302743", + "name" : "Recommendation Annotation PA166302743", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -133384,24 +134788,24 @@ "implications" : [ "This gene variation reduces the conversion of tamoxifen to the active metabolite endoxifen. This can result in reduced effectiveness." ], - "lookupKey" : {"CYP2D6": "1.0"}, + "lookupKey" : {"CYP2D6": "0.75"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451581", "name" : "tamoxifen", - "version" : 23 + "version" : 82 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104966", "name" : "Annotation of DPWG Guideline for tamoxifen and CYP2D6", - "version" : 31 + "version" : 91 }, "text" : { - "id" : 1452104343, + "id" : 1452104342, "html" : "\n", "version" : 0 }, @@ -133409,8 +134813,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302726", - "name" : "Recommendation Annotation PA166302726", + "id" : "PA166302744", + "name" : "Recommendation Annotation PA166302744", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -133426,25 +134830,25 @@ "implications" : [ "This gene variation reduces the conversion of tamoxifen to the active metabolite endoxifen. This can result in reduced effectiveness." ], - "lookupKey" : {"CYP2D6": "0.0"}, + "lookupKey" : {"CYP2D6": "1.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451581", "name" : "tamoxifen", - "version" : 23 + "version" : 82 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104966", "name" : "Annotation of DPWG Guideline for tamoxifen and CYP2D6", - "version" : 31 + "version" : 91 }, "text" : { - "id" : 1452104325, - "html" : "

Select an alternative or increase the dose to 40 mg/day and monitor the endoxifen concentration. Studies have demonstrated that PM can achieve an adequate endoxifen concentration when the dose is increased to 40-60 mg/day. Aromatase inhibitors are a possible alternative for post-menopausal women.

\n", + "id" : 1452104343, + "html" : "\n", "version" : 0 }, "version" : 0 @@ -133474,14 +134878,14 @@ "objCls" : "Chemical", "id" : "PA451581", "name" : "tamoxifen", - "version" : 23 + "version" : 82 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104966", "name" : "Annotation of DPWG Guideline for tamoxifen and CYP2D6", - "version" : 31 + "version" : 91 }, "text" : { "id" : 1452104360, @@ -133492,50 +134896,49 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302821", - "name" : "Recommendation Annotation PA166302821", + "id" : "PA166302762", + "name" : "Recommendation Annotation PA166302762", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, "dosingInformation" : false, "implications" : [ - "As a result of the genetic variation, the plasma concentration of the active metabolites 4-hydroxytamoxifen and endoxifen can increase. However, there is no evidence that this results in an increase in the side effects." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on tamoxifen." ], - "lookupKey" : {"CYP2D6": "≥3.5"}, + "lookupKey" : {"CYP2D6": "1.5"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451581", "name" : "tamoxifen", - "version" : 23 + "version" : 82 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104966", "name" : "Annotation of DPWG Guideline for tamoxifen and CYP2D6", - "version" : 31 + "version" : 91 }, "text" : { - "id" : 1452104420, - "html" : "

NO action is needed for this gene-drug interaction.

\n", + "id" : 1452104361, + "html" : "

The guideline does not provide a recommendation for tamoxifen in normal metabolizers.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302765", - "name" : "Recommendation Annotation PA166302765", + "id" : "PA166302763", + "name" : "Recommendation Annotation PA166302763", "alternateDrugAvailable" : false, "classification" : { "id" : 1448526251, @@ -133550,24 +134953,24 @@ "implications" : [ "The guideline does not provide a description of the impact of a normal metabolizer phenotype on tamoxifen." ], - "lookupKey" : {"CYP2D6": "2.5"}, + "lookupKey" : {"CYP2D6": "2.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451581", "name" : "tamoxifen", - "version" : 23 + "version" : 82 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104966", "name" : "Annotation of DPWG Guideline for tamoxifen and CYP2D6", - "version" : 31 + "version" : 91 }, "text" : { - "id" : 1452104364, + "id" : 1452104362, "html" : "

The guideline does not provide a recommendation for tamoxifen in normal metabolizers.

\n", "version" : 0 }, @@ -133575,134 +134978,133 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302843", - "name" : "Recommendation Annotation PA166302843", + "id" : "PA166302764", + "name" : "Recommendation Annotation PA166302764", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, "dosingInformation" : false, "implications" : [ - "As a result of the genetic variation, the plasma concentration of the active metabolites 4-hydroxytamoxifen and endoxifen can increase. However, there is no evidence that this results in an increase in the side effects." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on tamoxifen." ], - "lookupKey" : {"CYP2D6": "≥6.0"}, + "lookupKey" : {"CYP2D6": "2.25"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451581", "name" : "tamoxifen", - "version" : 23 + "version" : 82 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104966", "name" : "Annotation of DPWG Guideline for tamoxifen and CYP2D6", - "version" : 31 + "version" : 91 }, "text" : { - "id" : 1452104442, - "html" : "

NO action is needed for this gene-drug interaction.

\n", + "id" : 1452104363, + "html" : "

The guideline does not provide a recommendation for tamoxifen in normal metabolizers.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302743", - "name" : "Recommendation Annotation PA166302743", - "alternateDrugAvailable" : true, + "id" : "PA166302765", + "name" : "Recommendation Annotation PA166302765", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "This gene variation reduces the conversion of tamoxifen to the active metabolite endoxifen. This can result in reduced effectiveness." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on tamoxifen." ], - "lookupKey" : {"CYP2D6": "0.75"}, + "lookupKey" : {"CYP2D6": "2.5"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451581", "name" : "tamoxifen", - "version" : 23 + "version" : 82 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104966", "name" : "Annotation of DPWG Guideline for tamoxifen and CYP2D6", - "version" : 31 + "version" : 91 }, "text" : { - "id" : 1452104342, - "html" : "\n", + "id" : 1452104364, + "html" : "

The guideline does not provide a recommendation for tamoxifen in normal metabolizers.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302764", - "name" : "Recommendation Annotation PA166302764", + "id" : "PA166302766", + "name" : "Recommendation Annotation PA166302766", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, "dosingInformation" : false, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on tamoxifen." + "As a result of the genetic variation, the plasma concentration of the active metabolites 4-hydroxytamoxifen and endoxifen can increase. However, there is no evidence that this results in an increase in the side effects." ], - "lookupKey" : {"CYP2D6": "2.25"}, + "lookupKey" : {"CYP2D6": "3.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451581", "name" : "tamoxifen", - "version" : 23 + "version" : 82 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104966", "name" : "Annotation of DPWG Guideline for tamoxifen and CYP2D6", - "version" : 31 + "version" : 91 }, "text" : { - "id" : 1452104363, - "html" : "

The guideline does not provide a recommendation for tamoxifen in normal metabolizers.

\n", + "id" : 1452104365, + "html" : "

NO action is needed for this gene-drug interaction.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302742", - "name" : "Recommendation Annotation PA166302742", - "alternateDrugAvailable" : true, + "id" : "PA166302767", + "name" : "Recommendation Annotation PA166302767", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -133713,29 +135115,29 @@ "valid" : true, "version" : 1 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "This gene variation reduces the conversion of tamoxifen to the active metabolite endoxifen. This can result in reduced effectiveness." + "As a result of the genetic variation, the plasma concentration of the active metabolites 4-hydroxytamoxifen and endoxifen can increase. However, there is no evidence that this results in an increase in the side effects." ], - "lookupKey" : {"CYP2D6": "0.5"}, + "lookupKey" : {"CYP2D6": "4.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451581", "name" : "tamoxifen", - "version" : 23 + "version" : 82 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104966", "name" : "Annotation of DPWG Guideline for tamoxifen and CYP2D6", - "version" : 31 + "version" : 91 }, "text" : { - "id" : 1452104341, - "html" : "\n", + "id" : 1452104366, + "html" : "

NO action is needed for this gene-drug interaction.

\n", "version" : 0 }, "version" : 0 @@ -133766,14 +135168,14 @@ "objCls" : "Chemical", "id" : "PA451581", "name" : "tamoxifen", - "version" : 23 + "version" : 82 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104966", "name" : "Annotation of DPWG Guideline for tamoxifen and CYP2D6", - "version" : 31 + "version" : 91 }, "text" : { "id" : 1452104380, @@ -133808,14 +135210,14 @@ "objCls" : "Chemical", "id" : "PA451581", "name" : "tamoxifen", - "version" : 23 + "version" : 82 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104966", "name" : "Annotation of DPWG Guideline for tamoxifen and CYP2D6", - "version" : 31 + "version" : 91 }, "text" : { "id" : 1452104400, @@ -133826,50 +135228,51 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302763", - "name" : "Recommendation Annotation PA166302763", + "id" : "PA166302821", + "name" : "Recommendation Annotation PA166302821", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, "dosingInformation" : false, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on tamoxifen." + "As a result of the genetic variation, the plasma concentration of the active metabolites 4-hydroxytamoxifen and endoxifen can increase. However, there is no evidence that this results in an increase in the side effects." ], - "lookupKey" : {"CYP2D6": "2.0"}, + "lookupKey" : {"CYP2D6": "≥3.5"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451581", "name" : "tamoxifen", - "version" : 23 + "version" : 82 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104966", "name" : "Annotation of DPWG Guideline for tamoxifen and CYP2D6", - "version" : 31 + "version" : 91 }, "text" : { - "id" : 1452104362, - "html" : "

The guideline does not provide a recommendation for tamoxifen in normal metabolizers.

\n", + "id" : 1452104420, + "html" : "

NO action is needed for this gene-drug interaction.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302741", - "name" : "Recommendation Annotation PA166302741", - "alternateDrugAvailable" : true, + "id" : "PA166302841", + "name" : "Recommendation Annotation PA166302841", + "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, "description" : "Not Applicable", @@ -133880,37 +135283,37 @@ "valid" : true, "version" : 1 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "This gene variation reduces the conversion of tamoxifen to the active metabolite endoxifen. This can result in reduced effectiveness." + "As a result of the genetic variation, the plasma concentration of the active metabolites 4-hydroxytamoxifen and endoxifen can increase. However, there is no evidence that this results in an increase in the side effects." ], - "lookupKey" : {"CYP2D6": "0.25"}, + "lookupKey" : {"CYP2D6": "≥4.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451581", "name" : "tamoxifen", - "version" : 23 + "version" : 82 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104966", "name" : "Annotation of DPWG Guideline for tamoxifen and CYP2D6", - "version" : 31 + "version" : 91 }, "text" : { - "id" : 1452104340, - "html" : "\n", + "id" : 1452104440, + "html" : "

NO action is needed for this gene-drug interaction.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302767", - "name" : "Recommendation Annotation PA166302767", + "id" : "PA166302842", + "name" : "Recommendation Annotation PA166302842", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -133926,24 +135329,24 @@ "implications" : [ "As a result of the genetic variation, the plasma concentration of the active metabolites 4-hydroxytamoxifen and endoxifen can increase. However, there is no evidence that this results in an increase in the side effects." ], - "lookupKey" : {"CYP2D6": "4.0"}, + "lookupKey" : {"CYP2D6": "≥5.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451581", "name" : "tamoxifen", - "version" : 23 + "version" : 82 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104966", "name" : "Annotation of DPWG Guideline for tamoxifen and CYP2D6", - "version" : 31 + "version" : 91 }, "text" : { - "id" : 1452104366, + "id" : 1452104441, "html" : "

NO action is needed for this gene-drug interaction.

\n", "version" : 0 }, @@ -133951,8 +135354,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302841", - "name" : "Recommendation Annotation PA166302841", + "id" : "PA166302843", + "name" : "Recommendation Annotation PA166302843", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -133968,24 +135371,24 @@ "implications" : [ "As a result of the genetic variation, the plasma concentration of the active metabolites 4-hydroxytamoxifen and endoxifen can increase. However, there is no evidence that this results in an increase in the side effects." ], - "lookupKey" : {"CYP2D6": "≥4.0"}, + "lookupKey" : {"CYP2D6": "≥6.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451581", "name" : "tamoxifen", - "version" : 23 + "version" : 82 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104966", "name" : "Annotation of DPWG Guideline for tamoxifen and CYP2D6", - "version" : 31 + "version" : 91 }, "text" : { - "id" : 1452104440, + "id" : 1452104442, "html" : "

NO action is needed for this gene-drug interaction.

\n", "version" : 0 }, @@ -134234,7 +135637,7 @@ "objCls" : "Chemical", "id" : "PA452620", "name" : "tegafur", - "version" : 26 + "version" : 31 } ], "relatedGenes" : [ @@ -134243,112 +135646,112 @@ "id" : "PA145", "symbol" : "DPYD", "name" : "dihydropyrimidine dehydrogenase", - "version" : 6907 + "version" : 6956 } ], "source" : "DPWG", "summaryMarkdown" : { "id" : 1447981872, "html" : "

Choose an alternative drug to tegafur for patients with DPYD Activity Score of 0. For patients with a DPYD Activity Score of 1 or 1.5, avoid tegafur or start with a low dose and adjust the initial dose based on toxicity and efficacy. Fluorouracil and capecitabine are not alternatives for tegafur, as these are also metabolized by DPD. The DPWG evaluated DPYD genotyping as "essential" and recommend DPYD testing prior to initiating fluoropyrimidines.

\n", - "version" : 4 + "version" : 6 }, "terms" : [], "textMarkdown" : { "id" : 1447981871, "html" : "

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

\n

Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction of DPYD and fluoropyrimidines. European journal of human genetics (2019)

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group published a paper with the guidelines as per the August 2019 update including more details and scoring the clinical implementation PMID: 31745289.

\n

August 2019 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for tegafur based on DPYD genotype. An alternative drug or starting with a lower dose then adjusting the initial dose based on toxicity and efficacy is recommended. Fluorouracil or capecitabine are not an alternatives, as these are also metabolized by DPD.

\n

Wording in table taken from the Dutch guidelines.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
Activity Score 0tegafurThe gene variation increases the risk of severe, possibly fatal toxicity. A reduced conversion of tegafur to inactive metabolites means that the normal dose is an overdose.- avoid tegafur
Fluorouracil and capecitabine are not suitable alternatives, as these are also metabolised by DPD.
- If it is not possible to avoid tegafur: start with a very low dose and adjust the initial dose based on toxicity and efficacy. A substantiated recommendation for dose reduction cannot be made based on the literature.
FENOtegafurThe gene variation increases the risk of severe, possibly fatal toxicity. A reduced conversion of tegafur to inactive metabolites means that the normal dose is an overdose.Avoid tegafur or start with a low dose and adjust the initial dose based on toxicity and efficacy. Fluorouracil and capecitabine are not alternatives, as these are also metabolised by DPD. It is not possible to offer substantiated advice for dose reduction based on the literature.
Activity Score 1tegafurThe gene variation increases the risk of severe, possibly fatal toxicity. A reduced conversion of tegafur into inactive metabolites means that the normal dose is an overdose.Avoid tegafur or start with a low dose and adjust the initial dose based on toxicity and efficacy. Fluorouracil and capecitabine are not alternatives, as these are also metabolised by DPD. It is not possible to offer substantiated advice for dose reduction based on the literature.
Activity Score 1.5tegafurThe gene variation increases the risk of severe, possibly fatal toxicity. A reduced conversion of tegafur into inactive metabolites means that the normal dose is an overdose.Avoid tegafur or start with a low dose and adjust the initial dose based on toxicity and efficacy. Fluorouracil and capecitabine are not alternatives, as these are also metabolised by DPD. It is not possible to offer substantiated advice for dose reduction based on the literature.
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for tegafur and DPYD:

\n
\n

The Dutch Pharmacogenetics Working Group considers genotyping before starting tegafur with DPD inhibitors to be essential for drug safety. Genotyping must be performed before drug therapy has been initiated to guide drug and dose selection.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n

November 2018 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for tegafur based on DPYD genotype. An alternative drug or starting with a lower dose then adjusting the initial dose based on toxicity and efficacy is recommended for patients with DPYD activity scores of 0, 0.5, 1 and 1.5. Fluorouracil or capecitabine are not an alternatives, as these are also metabolized by DPD.

\n

Wording in table taken from the Dutch guidelines November 2018 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
Activity Score 0tegafurGenetic variation increases the risk of severe, possibly fatal toxicity. A reduced conversion of tegafur to inactive metabolites means that the normal dose is an overdose.Choose an alternative. Do not choose fluorouracil or capecitabine, as these are also metabolised by DPD. If an alternative is not possible: start with a very low dose and adjust the initial dose based on toxicity and efficacy. A substantiated recommendation for dose reduction cannot be made based on the literature. The recommendation for fluorouracil and capecitabine is to determine the residual DPD activity in mononuclear cells from peripheral blood and to adjust the initial dose accordingly. A patient with 0.5% of the normal DPD activity tolerated 0.8% of the standard capecitabine dose (150 mg every 5 days). A patient with undetectable DPD activity tolerated 0.43% of the standard capecitabine dose (150 mg every 5 days with every third dose skipped). The average Caucasian DPD activity is 9.9 nmol/hour per mg protein.
NOTE: If a patient has two different gene variations that lead to a non-functional DPD enzyme (e.g. *2A and *13), this recommendation only applies if the variations are on a different allele. If both variations are on the same allele, this patient has gene activity score 1 and the recommendation for that gene activity score should be followed. These two situations can only be distinguished by determining the enzyme activity (phenotyping).
Activity Score 0.5tegafurGenetic variation increases the risk of severe, possibly fatal toxicity. A reduced conversion of tegafur to inactive metabolites means that the normal dose is an overdose.Choose an alternative or start with a low dose and adjust the initial dose based on toxicity and efficacy. Fluorouracil and capecitabine are not alternatives, as these are also metabolised by DPD. It is not possible to offer substantiated advice for dose reduction based on the literature.
NOTE: This recommendation only applies if the two gene variations are on a different allele. If both variations are on the same allele, this patient has gene activity score 1 and the recommendation for that gene activity score should be followed. These two situations can only be distinguished by determining the enzyme activity (phenotyping).
Activity Score 1tegafurGenetic variation increases the risk of severe, possibly fatal toxicity. A reduced conversion of tegafur into inactive metabolites means that the normal dose is an overdose.Choose an alternative or start with a low dose and adjust the initial dose based on toxicity and efficacy. Fluorouracil and capecitabine are not alternatives, as these are also metabolised by DPD. It is not possible to offer substantiated advice for dose reduction based on the literature.
NOTE: If a patient has two different gene variations that result in a partially functional DPD enzyme (e.g. 2846T and 1236A), this recommendation only applies if the variations are on a different allele. If both variations are on the same allele, the gene activity score is between 1 and 1.5, depending on whether and how the two gene variations influence each other and on other factors that influence the DPD activity. Whether a gene activity score of 1 or 1.5 needs to be assigned in the case of two different genetic variations can only be determined by measuring the enzyme activity (phenotyping).
Activity Score 1.5tegafurGenetic variation increases the risk of severe, possibly fatal toxicity. A reduced conversion of tegafur into inactive metabolites means that the normal dose is an overdose.Choose an alternative or start with a low dose and adjust the initial dose based on toxicity and efficacy. Fluorouracil and capecitabine are not alternatives, as these are also metabolised by DPD. It is not possible to offer substantiated advice for dose reduction based on the literature.
\n

2011 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for tegafur/uracil combination based on DPYD genotype [Article:21412232]. They recommend that an alternate drug be used for poor metabolizer patients, but do not provide a recommendation for intermediate metabolizer patients.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Phenotype (Genotype)Therapeutic Dose RecommendationLevel of EvidenceClinical Relevance
PM (2 inactive alleles, 2 decreased activity alleles, or one inactive and one decreased activity alleles)Select alterantive drug. Fluorouracil or capecitabine are not suitable alternatives because both are also metabolized by DPD.Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Clinical effect (NS). Kinetic effect (NS).
IM (1 active allele and 1 inactive or decreased activity allele)None.Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Clinical effect (NS). Kinetic effect (NS).
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele TypeAlleles
active*1, *4, *5, *6, *9A
decreased activity*9B, *10
inactive*2A, *3, *7, *8, *11, *12, *13, 496A>G, IVS10-15T>C, 1156G>T, 1845G>T
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The guideline does not provide a recommendation for tegafur in patients with a DPYD activity score of 2.

\n", + "id" : 1452061543, + "html" : "

Avoid tegafur or start with a low dose and adjust the initial dose based on toxicity and efficacy.\nFluorouracil and capecitabine are not alternatives, as these are also metabolised by DPD.\nIt is not possible to offer substantiated advice for dose reduction based on the literature.\nFor fluorouracil and capecitabine, it is recommended to determine the residual DPD activity in mononuclear cells from peripheral blood and adjust the initial dose based on phenotype and genotype.

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Avoid tegafur or start with a low dose and adjust the initial dose based on toxicity and efficacy.\nFluorouracil and capecitabine are not alternatives, as these are also metabolised by DPD.\nIt is not possible to offer substantiated advice for dose reduction based on the literature.\nFor fluorouracil and capecitabine, it is recommended to determine the residual DPD activity in mononuclear cells from peripheral blood and adjust the initial dose based on phenotype and genotype.

\n", + "id" : 1452061544, + "html" : "

The guideline does not provide a recommendation for tegafur in patients with a DPYD activity score of 2.

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299183", - "name" : "Recommendation PA166299183", + "id" : "PA166299179", + "name" : "Recommendation PA166299179", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -134362,35 +135765,35 @@ }, "dosingInformation" : true, "implications" : [ - "The gene variation increases the risk of severe, possibly fatal toxicity. A reduced conversion of tegafur into inactive metabolites means that the normal dose is an overdose." + "The gene variation increases the risk of severe, possibly fatal toxicity. A reduced conversion of tegafur to inactive metabolites means that the normal dose is an overdose." ], - "lookupKey" : {"DPYD": "1.5 (Intermediate Metabolizer)"}, + "lookupKey" : {"DPYD": "0.0 (Poor Metabolizer)"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA452620", "name" : "tegafur", - "version" : 26 + "version" : 31 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104944", "name" : "Annotation of DPWG Guideline for tegafur and DPYD", - "version" : 33 + "version" : 69 }, "text" : { - "id" : 1452061546, - "html" : "

Avoid tegafur or start with a low dose and adjust the initial dose based on toxicity and efficacy\nFluorouracil and capecitabine are not alternatives, as these are also metabolised by DPD.\nIt is not possible to offer substantiated advice for dose reduction based on the literature.\nFor fluorouracil and capecitabine, starting with 50 % of the standard dose is recommended and the dose should then be adjusted based on toxicity and effectiveness.\nIn one study, the average dose of fluorouracil/capecitabine after titration was 64% of the standard dose for 17 patients with genotype *1/2846T and 74% of the standard dose for 51 patients with genotype *1/1236A

\n", + "id" : 1452061542, + "html" : "\n", "version" : 0 }, - "version" : 0 + "version" : 4 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299179", - "name" : "Recommendation PA166299179", + "id" : "PA166299183", + "name" : "Recommendation PA166299183", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -134404,30 +135807,30 @@ }, "dosingInformation" : true, "implications" : [ - "The gene variation increases the risk of severe, possibly fatal toxicity. A reduced conversion of tegafur to inactive metabolites means that the normal dose is an overdose." + "The gene variation increases the risk of severe, possibly fatal toxicity. A reduced conversion of tegafur into inactive metabolites means that the normal dose is an overdose." ], - "lookupKey" : {"DPYD": "0.0 (Poor Metabolizer)"}, + "lookupKey" : {"DPYD": "1.5 (Intermediate Metabolizer)"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA452620", "name" : "tegafur", - "version" : 26 + "version" : 31 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104944", "name" : "Annotation of DPWG Guideline for tegafur and DPYD", - "version" : 33 + "version" : 69 }, "text" : { - "id" : 1452061542, - "html" : "\n", + "id" : 1452061546, + "html" : "

Avoid tegafur or start with a low dose and adjust the initial dose based on toxicity and efficacy\nFluorouracil and capecitabine are not alternatives, as these are also metabolised by DPD.\nIt is not possible to offer substantiated advice for dose reduction based on the literature.\nFor fluorouracil and capecitabine, starting with 50 % of the standard dose is recommended and the dose should then be adjusted based on toxicity and effectiveness.\nIn one study, the average dose of fluorouracil/capecitabine after titration was 64% of the standard dose for 17 patients with genotype *1/2846T and 74% of the standard dose for 51 patients with genotype *1/1236A

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", @@ -134455,21 +135858,21 @@ "objCls" : "Chemical", "id" : "PA452620", "name" : "tegafur", - "version" : 26 + "version" : 31 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104944", "name" : "Annotation of DPWG Guideline for tegafur and DPYD", - "version" : 33 + "version" : 69 }, "text" : { "id" : 1452061545, "html" : "

Avoid tegafur or start with a low dose and adjust the initial dose based on toxicity and efficacy\nFluorouracil and capecitabine are not alternatives, as these are also metabolised by DPD.\nIt is not possible to offer substantiated advice for dose reduction based on the literature.\nFor fluorouracil and capecitabine, starting with 50 % of the standard dose is recommended.

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", @@ -134487,21 +135890,21 @@ "objCls" : "Chemical", "id" : "PA452620", "name" : "tegafur", - "version" : 26 + "version" : 31 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104944", "name" : "Annotation of DPWG Guideline for tegafur and DPYD", - "version" : 33 + "version" : 69 }, "text" : { "id" : 1452102463, "html" : "

Avoid tegafur or start with a low dose and adjust the initial dose based on toxicity and efficacy.\nFluorouracil and capecitabine are not alternatives, as these are also metabolised by DPD.\nIt is not possible to offer substantiated advice for dose reduction based on the literature.\nFor fluorouracil and capecitabine, it is recommended to determine the residual DPD activity in mononuclear cells from peripheral blood and adjust the initial dose based on phenotype and genotype.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166104944" @@ -134601,7 +136004,7 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "relatedGenes" : [ @@ -134610,7 +136013,7 @@ "id" : "PA134963132", "symbol" : "NUDT15", "name" : "nudix hydrolase 15", - "version" : 11 + "version" : 39 } ], "source" : "DPWG", @@ -134623,94 +136026,94 @@ "textMarkdown" : { "id" : 1450821367, "html" : "

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

\n

August 2019 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for thioguanine based on NUDT15 genotype. They recommend reducing the initial dose for patients that are intermediate metabolizers and selecting an alternative drug or reducing the initial dose for patients that are poor metabolizers. They updated the wording for the intermediate metabolizer recommendation, reflected in the table below.

\n

Wording in table taken from the Dutch guidelines August 2019 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
NUDT15 IMthioguanineGrade = 2 leukopaenia occurs in an estimated 40% of these patients with standard therapy. The genetic variation increases the concentration of the fully activated metabolite of thioguanine.- IMMUNOSUPPRESSION: start with 75% of the standard dose. Adjustment of the initial dose should be performed based on toxicity (monitoring of the blood counts) and efficacy. Monitoring should be performed at an increased frequency.
NOTE: The percentage of 75% is based on the analogy with TPMT, for which the gene variants have a comparable effect on toxicity to those of NUDT15.
NOTE: Dose adjustment based on the total of 6-TGN metabolites is not possible for these patients, as they develop toxicity within the therapeutic range that applies for patients without gene variants.
- LEUKAEMIA: start with 75% of the standard tioguanine dose or start with the standard dose and reduce to 75% if side effects necessitate a dose reduction. It is not known whether dose reduction in advance results in the same efficacy as dose reduction based on toxicity. Adjustment of the initial dose should be performed based on toxicity (monitoring of the blood counts) and efficacy. Monitoring should be performed at an increased frequency.
NOTE: The percentage of 75% is based on the analogy with TPMT, for which the gene variants have a comparable effect on toxicity to those of NUDT15.
NOTE: Dose adjustment based on the total of 6-TGN metabolites is not possible for these patients, as they develop toxicity within the therapeutic range that applies for patients without gene variants.
Note: more stringent dose reductions are necessary if the patient is also TPMT IM.
NUDT15 PMthioguanineGrade = 2 leukopaenia occurs in an estimated 95% of these patients with standard therapy. The genetic variation increases the concentration of the fully activated metabolite of thioguanine.- avoid thioguanine
- if it is not possible to avoid tioguanine: use 10% of the standard dose and advise patients to seek medical attention when symptoms of myelosuppression (such as severe sore throat in combination with fever, regular nosebleeds and tendency to bruising) occur Any adjustment of the initial dose should be guided by toxicity (monitoring of blood counts) and efficacy. Monitoring should be performed at an increased frequency.
NOTE: The percentage of 10% is based on the analogy with azathioprine and mercaptopurine and the analogy with TPMT, for which the gene variants have a comparable effect on toxicity to those of NUDT15. For NUDT15 PM, a percentage of < 20% was calculated for azathioprine and mercaptopurine, but there were insufficient data available to calculate the exact percentage.
NOTE: Dose adjustment based on the total of 6-TGN metabolites is not possible for these patients, as they develop toxicity within the therapeutic range that applies for patients without gene variants.
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for thioguanine and NUDT15:

\n
\n

The Dutch Pharmacogenetics Working Group considers genotyping before starting thioguanine to be essential for drug safety. Genotyping must be performed before drug therapy has been initiated to guide drug and dose selection.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

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The guideline does not provide a recommendation for thioguanine in normal metabolizers

\n", - "version" : 0 + "id" : 1452061512, + "html" : "\n", + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299149", - "name" : "Recommendation PA166299149", + "id" : "PA166299151", + "name" : "Recommendation PA166299151", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "Grade2 leukopaenia occurs in an estimated 40% of these patients with standard therapy. The genetic variation increases the concentration of the fully activated metabolite of thioguanine." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on thioguanine." ], - "lookupKey" : {"NUDT15": "Intermediate Metabolizer"}, + "lookupKey" : {"NUDT15": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166184612", "name" : "Annotation of DPWG Guideline for thioguanine and NUDT15", - "version" : 9 + "version" : 45 }, "text" : { - "id" : 1452061512, - "html" : "\n", + "id" : 1452061514, + "html" : "

The guideline does not provide a recommendation for thioguanine in normal metabolizers

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -134738,21 +136141,21 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166184612", "name" : "Annotation of DPWG Guideline for thioguanine and NUDT15", - "version" : 9 + "version" : 45 }, "text" : { "id" : 1452061513, "html" : "

Avoid thioguanine.

\n

If it is not possible to avoid tioguanine: use 10% of the standard dose and advise patients to seek medical attention when symptoms of myelosuppression (such as severe sore throat in combination with fever, regular nosebleeds and tendency to bruising) occur. Any adjustment of the initial dose should be guided by toxicity (monitoring of blood counts) and efficacy. Monitoring should be performed at an increased frequency.

\n

NOTE: The percentage of 10% is based on the analogy with azathioprine and mercaptopurine and the analogy with TPMT, for which the gene variants have a comparable effect on toxicity to those of NUDT15. For NUDT15 PM, a percentage of < 20% was calculated for azathioprine and mercaptopurine, but there were insufficient data available to calculate the exact percentage.\nNOTE: Dose adjustment based on the total of 6-TGN metabolites is not possible for these patients, as they develop toxicity within the therapeutic range that applies for patients without gene variants.

\n", - "version" : 0 + "version" : 1 }, - "version" : 0 + "version" : 3 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166184612" @@ -134954,140 +136357,140 @@ "id" : "PA165819268", "symbol" : "TPMT*1", "name" : "*1", - "version" : 16 + "version" : 30 }, { "objCls" : "Haplotype", "id" : "PA165819280", "symbol" : "TPMT*10", "name" : "*10", - "version" : 15 + "version" : 31 }, { "objCls" : "Haplotype", "id" : "PA165819281", "symbol" : "TPMT*11", "name" : "*11", - "version" : 15 + "version" : 31 }, { "objCls" : "Haplotype", "id" : "PA165819282", "symbol" : "TPMT*12", "name" : "*12", - "version" : 15 + "version" : 31 }, { "objCls" : "Haplotype", "id" : "PA165819283", "symbol" : "TPMT*13", "name" : "*13", - "version" : 15 + "version" : 31 }, { "objCls" : "Haplotype", "id" : "PA165819284", "symbol" : "TPMT*14", "name" : "*14", - "version" : 14 + "version" : 30 }, { "objCls" : "Haplotype", "id" : "PA165819285", "symbol" : "TPMT*15", "name" : "*15", - "version" : 14 + "version" : 30 }, { "objCls" : "Haplotype", "id" : "PA165819286", "symbol" : "TPMT*16", "name" : "*16", - "version" : 15 + "version" : 31 }, { "objCls" : "Haplotype", "id" : "PA165819287", "symbol" : "TPMT*17", "name" : "*17", - "version" : 15 + "version" : 31 }, { "objCls" : "Haplotype", "id" : "PA165819288", "symbol" : "TPMT*18", "name" : "*18", - "version" : 15 + "version" : 31 }, { "objCls" : "Haplotype", "id" : "PA165819269", "symbol" : "TPMT*2", "name" : "*2", - "version" : 15 + "version" : 32 }, { "objCls" : "Haplotype", "id" : "PA165819270", "symbol" : "TPMT*3A", "name" : "*3A", - "version" : 16 + "version" : 33 }, { "objCls" : "Haplotype", "id" : "PA165819271", "symbol" : "TPMT*3B", "name" : "*3B", - "version" : 15 + "version" : 32 }, { "objCls" : "Haplotype", "id" : "PA165819272", "symbol" : "TPMT*3C", "name" : "*3C", - "version" : 15 + "version" : 32 }, { "objCls" : "Haplotype", "id" : "PA165819274", "symbol" : "TPMT*4", "name" : "*4", - "version" : 14 + "version" : 31 }, { "objCls" : "Haplotype", "id" : "PA165819275", "symbol" : "TPMT*5", "name" : "*5", - "version" : 15 + "version" : 31 }, { "objCls" : "Haplotype", "id" : "PA165819276", "symbol" : "TPMT*6", "name" : "*6", - "version" : 15 + "version" : 31 }, { "objCls" : "Haplotype", "id" : "PA165819277", "symbol" : "TPMT*7", "name" : "*7", - "version" : 15 + "version" : 31 }, { "objCls" : "Haplotype", "id" : "PA165819278", "symbol" : "TPMT*8", "name" : "*8", - "version" : 15 + "version" : 31 }, { "objCls" : "Haplotype", "id" : "PA165819279", "symbol" : "TPMT*9", "name" : "*9", - "version" : 15 + "version" : 31 } ], "relatedChemicals" : [ @@ -135095,7 +136498,7 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "relatedGenes" : [ @@ -135104,23 +136507,23 @@ "id" : "PA356", "symbol" : "TPMT", "name" : "thiopurine S-methyltransferase", - "version" : 7545 + "version" : 7628 } ], "source" : "DPWG", "summaryMarkdown" : { "id" : 1447981928, "html" : "

Select an alternative drug or reduce the initial dose of thioguanine for patients that are TPMT poor metabolizers and reduce initial dose for patients that are TPMT intermediate metabolizers.

\n", - "version" : 1 + "version" : 2 }, "terms" : [], "textMarkdown" : { "id" : 1447981927, "html" : "

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

\n

August 2019 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for thioguanine based on TPMT genotype. They recommend reducing the initial dose for patients that are intermediate metabolizers and selecting an alternative drug or reducing the initial dose for patients that are poor metabolizers. They updated the wording for the intermediate metabolizer recommendation, reflected in the table below.

\n

Wording in table taken from the Dutch guidelines August 2019 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
TPMT IMthioguanineGenetic variation reduces conversion of thioguanine to inactive metabolites. This increases the risk of serious adverse events such as myelosuppression.- IMMUNOSUPPRESSION: Start with 75% of the standard dose. Adjustment of the initial dose should be guided by toxicity (monitoring of blood counts) and efficacy. The frequency of monitoring should be increased.
- LEUKAEMIA: Start with 75% of the standard thioguanine dose, or start with the standard dose and reduce to 75% if side effects necessitate a dose reduction. It is not known whether dose reduction in advance results in the same efficacy as dose reduction based on toxicity. The initial dose should be adjusted based on toxicity (monitoring of the blood counts) and efficacy. Monitoring should be performed at an increased frequency.
Note: more stringent dose reductions are necessary if the patient is also NUDT15 IM.
TPMT PMthioguanineGenetic variation reduces conversion of thioguanine to inactive metabolites. This increases the risk of serious, life-threatening adverse events such as myelosuppression.1. Choose an alternative or start with 6-7% of the standard dose. Any adjustment of the initial dose should be guided by toxicity (monitoring of blood counts) and effectiveness. The frequency of monitoring should be increased.
2. If the dose is decreased: advise patients to seek medical attention when symptoms of myelosuppression (such as severe sore throat in combination with fever, regular nosebleeds and tendency to bruising) develop.
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for thioguanine and TPMT:

\n
\n

The Dutch Pharmacogenetics Working Group considers genotyping before starting thioguanine to be essential for drug safety. Genotyping must be performed before drug therapy has been initiated to guide drug and dose selection.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n

November 2018 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for thioguanine based on TPMT genotype. They recommend reducing the initial dose for patients that are intermediate metabolizers and selecting an alternative drug or reducing the initial dose for patients that are poor metabolizers.

\n

Wording in table taken from the Dutch guidelines November 2018 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
TPMT IMthioguanineGenetic variation reduces conversion of thioguanine to inactive metabolites. This increases the risk of serious adverse events such as myelosuppression.Start with 75% of the standard dose. Adjustment of the initial dose should be guided by toxicity (monitoring of blood counts) and efficacy. The frequency of monitoring should be increased.
TPMT PMthioguanineGenetic variation reduces conversion of thioguanine to inactive metabolites. This increases the risk of serious adverse events such as myelosuppression.1. Choose an alternative or start with 6-7% of the standard dose. Any adjustment of the initial dose should be guided by toxicity (monitoring of blood counts) and effectiveness. The frequency of monitoring should be increased. 2. If the dose is decreased: advise patients to seek medical attention when symptoms of myelosuppression (such as severe sore throat in combination with fever, regular nosebleeds and tendency to bruising) develop.
\n

2011 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for thioguanine based on TPMT genotype [Article:21412232]. They recommend selecting an alternative drug for patients carrying inactive alleles.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Phenotype (Genotype)Therapeutic Dose RecommendationLevel of EvidenceClinical Relevance
IM (one inactive allele: *2, *3, *4-*18)Select alternative drug. Insufficient data to allow calculation of dose adjustment.Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Clinical effect (S): long-standing discomfort (> 168 hr), permanent symptom or invalidating injury e.g. failure of prophylaxis of atrial fibrillation; venous thromboembolism; decreased effect of clopidogrel on inhibition of platelet aggregation; ADE resulting from increased bioavailability of phenytoin; INR > 6.0; neutropenia 0.5-1.0x109/l; leucopenia 1.0-2.0x109/l; thrombocytopenia 25-50x109/l; severe diarrhea.
PM (two inactive alleles: *2, *3, *4-*18)Select alternative drug. Insufficient data to allow calculation of dose adjustment.Published case reports, well documented, and having relevant pharmacokinetic or clinical endpoints. Well documented case series.Clinical effect (S): death; arrhythmia; unanticipated myelosuppression.
\n\n", - "version" : 17 + "version" : 22 }, "userId" : "katrin", - "version" : 33 + "version" : 86 }, "recommendations" : [ { @@ -135148,21 +136551,21 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104960", "name" : "Annotation of DPWG Guideline for thioguanine and TPMT", - "version" : 33 + "version" : 86 }, "text" : { "id" : 1452061593, "html" : "

The guideline does not provide a recommendation for thioguanine in normal metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", @@ -135190,21 +136593,21 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104960", "name" : "Annotation of DPWG Guideline for thioguanine and TPMT", - "version" : 33 + "version" : 86 }, "text" : { "id" : 1452061592, "html" : "
    \n
  1. Choose an alternative or start with 6-7% of the standard dose. Any adjustment of the initial dose should be guided by toxicity (monitoring of blood counts) and effectiveness. The frequency of monitoring should be increased.
    2. \n
  2. If the dose is decreased: advise patients to seek medical attention when symptoms of myelosuppression (such as severe sore throat in combination with fever, regular nosebleeds and tendency to bruising) develop.
    3. \n
\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", @@ -135232,21 +136635,21 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104960", "name" : "Annotation of DPWG Guideline for thioguanine and TPMT", - "version" : 33 + "version" : 86 }, "text" : { "id" : 1452061591, "html" : "

IMMUNOSUPPRESSION: Start with 75% of the standard dose. Adjustment of the initial dose should be guided by toxicity (monitoring of blood counts) and efficacy. The frequency of monitoring should be increased.\nLEUKAEMIA: Start with 75% of the standard thioguanine dose, or start with the standard dose and reduce to 75% if side effects necessitate a dose reduction. It is not known whether dose reduction in advance results in the same efficacy as dose reduction based on toxicity. The initial dose should be adjusted based on toxicity (monitoring of the blood counts) and efficacy. Monitoring should be performed at an increased frequency.\nNote: more stringent dose reductions are necessary if the patient is also NUDT15 IM.

\n", "version" : 1 }, - "version" : 1 + "version" : 3 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166104960" @@ -135604,7 +137007,7 @@ "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "relatedGenes" : [ @@ -135613,29 +137016,29 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "DPWG", "summaryMarkdown" : { "id" : 1447981886, "html" : "

Be alert to a reduced efficacy of tramadol in CYP2D6 intermediate or poor metabolizers. If tramadol is not effective in these patients, try a dose increase or select an alternative to tramadol (not codeine) and be alert for symptoms of insufficient pain relief. For CYP2D6 ultrarapid metabolizers, use an alternative to tramadol (not codeine) or use 40% of the standard dose and be alert to side effects.

\n", - "version" : 1 + "version" : 2 }, "terms" : [], "textMarkdown" : { "id" : 1447981885, "html" : "

Note that the FDA released a safety announcement on 4/20/2017 stating that codeine and tramadol should not be used in children under 12 years.

\n

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

\n

Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction of CYP2D6 and opioids (codeine, tramadol and oxycodone). European journal of human genetics (2021)

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group published a paper with the guidelines as per the November 2018 update including more details and scoring the clinical implementation [Article:34267337].

\n

November 2018 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for tramadol based on CYP2D6 genotype. They recommend that an alternative analgesic (not codeine) be selected or a dose reduction be considered for CYP2D6 ultrarapid metabolizers (UMs). If tramadol is not effective in CYP2D6 intermediate metabolizers (IMs) and poor metabolizers (PMs), a dose increase or an alternative analgesic (not codeine) can be considered.

\n

Wording in table taken from the Dutch guidelines November 2018 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
CYP2D6 UMtramadolThe genetic variation increases the conversion of tramadol to a metabolite with a stronger opioid effect. This can result in an increase in potentially life-threatening side effects.As the total analgesic effect changes when the ratio between the mother compound and the active metabolite changes, the effect of a dose reduction cannot be predicted with certainty.
1. Select an alternative. Do not choose codeine, as it is contra-indicated for CYP2D6 UM. Morphine is not metabolised by CYP2D6. Oxycodone is metabolised by CYP2D6 to a limited extent, but this does not result in differences in side effects in patients.
2. If an alternative is not possible, use 40% of the standard dose. Advise the patient to report side effects (such as drowsiness, confusion, constipation, nausea and vomiting, respiratory depression or urine retention).
CYP2D6 IMtramadolThe genetic variation reduces the conversion of tramadol to a metabolite with a higher activity. This can result in reduced analgesia.It is not possible to provide a recommendation for dose adjustment, because the total analgesic effect changes when the ratio between the mother compound and the active metabolite changes.
1. be alert to a reduced effectiveness
2. in the case of inadequate effectiveness:
a. try a dose increase
b. if this does not work: choose an alternative. Do not select codeine, as this is also metabolised by CYP2D6. Morphine is not metabolised by CYP2D6. Oxycodone is metabolised by CYP2D6 to a limited extent, but this does not result in differences in analgesia in patients.
3. if no alternative is selected: advise the patient to report inadequate analgesia
CYP2D6 PMtramadolThe genetic variation reduces the conversion of tramadol to a metabolite with a higher activity. This can result in reduced analgesia.It is not possible to provide a recommendation for dose adjustment, because the total analgesic effect changes when the ratio between the mother compound and the active metabolite changes.
1. be alert to a reduced effectiveness
2. in the case of inadequate effectiveness:
a. try a dose increase.
b. if this does not work: choose an alternative Do not select codeine, as this is also metabolised by CYP2D6. Morphine is not metabolised by CYP2D6. Oxycodone is metabolised by CYP2D6 to a limited extent, but this does not result in differences in analgesia in patients.
3. if no alternative is selected: advise the patient to report inadequate analgesia.
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for tramadol and CYP2D6:

\n
\n

The Dutch Pharmacogenetics Working Group considers genotyping before starting tramadol to be potentially beneficial for drug safety and efficacy. Genotyping can be considered on an individual patient basis. If, however, the genotype is available, the Dutch Pharmacogenetics Working Group recommends adhering to the gene-drug guideline.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n

2011 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for tramadol based on CYP2D6 genotypes [Article:21412232]. For PM and IM genotypes, they recommend selecting an alternative drug (not oxycodone or codeine) and/or being extra alert to symptoms of insufficient pain relief. For UM genotypes, they recommend using a 30% decreased dose and being alert for ADEs, or using an alternative drug (not oxycodone or codeine).

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Phenotype (Genotype)Therapeutic Dose RecommendationLevel of EvidenceClinical Relevance
PM (two inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) alleles)Select alternative drug-not oxycodone or codeine- or be alert to symptoms of insufficient pain relief.Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Clinical effect (S): short-lived discomfort (< 48 hr) without permanent injury: e.g. reduced decrease in resting heart rate; reduction in exercise tachycardia; decreased pain relief from oxycodone; ADE resulting from increased bioavailability of atomoxetine (decreased appetite, insomnia, sleep disturbance etc.); neutropenia > 1.5x109/l; leucopenia > 3.0x109/l; thrombocytopenia > 75x109/l; moderate diarrhea not affecting daily activities; reduced glucose increase following oral glucose tolerance test.
IM (two decreased-activity (*9, *10, *17, *29, *36, *41) alleles or carrying one active (*1, *2, *33, *35) and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele, or carrying one decreased-activity (*9, *10, *17, *29, *36, *41) allele and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele)Be alert to decreased efficacy. Consider dose increase. If response is still inadequate, select alternative drug- not oxycodone or codeine-or be alert to symptoms of insufficient pain relief.Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Clinical effect (S): short-lived discomfort (< 48 hr) without permanent injury: e.g. reduced decrease in resting heart rate; reduction in exercise tachycardia; decreased pain relief from oxycodone; ADE resulting from increased bioavailability of atomoxetine (decreased appetite, insomnia, sleep disturbance etc); neutropenia > 1.5x109/l; leucopenia > 3.0x109/l; thrombocytopenia > 75x109/l; moderate diarrhea not affecting daily activities; reduced glucose increase following oral glucose tolerance test.
UM (a gene duplication in absence of inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) or decreased-activity (*9, *10, *17, *29, *36, *41) alleles)Reduce dose by 30% and be alert to ADEs (e.g., nausea, vomiting, constipation, respiratory depression, confusion, urinary retention) or select alternative drug (e.g., acetaminophen, NSAID, morphine-not oxycodone or codeine).Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Clinical effect (S): long-standing discomfort (48-168 hr) without permanent injury e.g. failure of therapy with tricyclic antidepressants, atypical antipsychotic drugs; extrapyramidal side effects; parkinsonism; ADE resulting from increased bioavailability of tricyclic antidepressants, metoprolol, propafenone (central effects e.g. dizziness); INR 4.5-6.0; neutropenia 1.0-1.5x109/l; leucopenia 2.0-3.0x109/l; thrombocytopenia 50-75x109/l.
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The guideline does not provide a recommendation for tramadol in normal metabolizers.

\n", "version" : 0 }, @@ -135675,134 +137078,131 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302877", - "name" : "Recommendation Annotation PA166302877", - "alternateDrugAvailable" : true, + "id" : "PA166302867", + "name" : "Recommendation Annotation PA166302867", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "The genetic variation increases the conversion of tramadol to a metabolite with a stronger opioid effect. This can result in an increase in potentially life-threatening side effects." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on tramadol." ], - "lookupKey" : {"CYP2D6": "≥5.0"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"CYP2D6": "1.5"}, + "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104959", "name" : "Annotation of DPWG Guideline for tramadol and CYP2D6", - "version" : 36 + "version" : 147 }, "text" : { - "id" : 1452104476, - "html" : "

As the total analgesic effect changes when the ratio between the mother compound and the active metabolite changes, the effect of a dose reduction cannot be predicted with certainty.

\n
    \n
  1. Select an alternative. Do not choose codeine, as it is contra-indicated for CYP2D6 UM. Morphine is not metabolised by CYP2D6. Oxycodone is metabolised by CYP2D6 to a limited extent, but this does not result in differences in side effects in patients.
    2. \n
  2. If an alternative is not possible, use 40% of the standard dose. Advise the patient to report side effects (such as drowsiness, confusion, constipation, nausea and vomiting, respiratory depression or urine retention).
    3. \n
\n", + "id" : 1452104466, + "html" : "

The guideline does not provide a recommendation for tramadol in normal metabolizers.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302864", - "name" : "Recommendation Annotation PA166302864", - "alternateDrugAvailable" : true, + "id" : "PA166302868", + "name" : "Recommendation Annotation PA166302868", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "The genetic variation reduces the conversion of tramadol to a metabolite with a higher activity. This can result in reduced analgesia." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on tramadol." ], - "lookupKey" : {"CYP2D6": "0.75"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"CYP2D6": "2.0"}, + "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104959", "name" : "Annotation of DPWG Guideline for tramadol and CYP2D6", - "version" : 36 + "version" : 147 }, "text" : { - "id" : 1452104463, - "html" : "

It is not possible to provide a recommendation for dose adjustment, because the total analgesic effect changes when the ratio between the mother compound and the active metabolite changes.

\n
    \n
  1. Be alert to a reduced effectiveness.
    2. \n
  2. In the case of inadequate effectiveness:
    3. \n
\n\n
    \n
  1. If no alternative is selected: advise the patient to report inadequate analgesia.
    2. \n
\n", + "id" : 1452104467, + "html" : "

The guideline does not provide a recommendation for tramadol in normal metabolizers.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302873", - "name" : "Recommendation Annotation PA166302873", - "alternateDrugAvailable" : true, + "id" : "PA166302869", + "name" : "Recommendation Annotation PA166302869", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "The genetic variation increases the conversion of tramadol to a metabolite with a stronger opioid effect. This can result in an increase in potentially life-threatening side effects." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on tramadol." ], - "lookupKey" : {"CYP2D6": "≥3.0"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"CYP2D6": "2.25"}, + "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104959", "name" : "Annotation of DPWG Guideline for tramadol and CYP2D6", - "version" : 36 + "version" : 147 }, "text" : { - "id" : 1452104472, - "html" : "

As the total analgesic effect changes when the ratio between the mother compound and the active metabolite changes, the effect of a dose reduction cannot be predicted with certainty.

\n
    \n
  1. Select an alternative. Do not choose codeine, as it is contra-indicated for CYP2D6 UM. Morphine is not metabolised by CYP2D6. Oxycodone is metabolised by CYP2D6 to a limited extent, but this does not result in differences in side effects in patients.
    2. \n
  2. If an alternative is not possible, use 40% of the standard dose. Advise the patient to report side effects (such as drowsiness, confusion, constipation, nausea and vomiting, respiratory depression or urine retention).
    3. \n
\n", + "id" : 1452104468, + "html" : "

The guideline does not provide a recommendation for tramadol in normal metabolizers.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302869", - "name" : "Recommendation Annotation PA166302869", + "id" : "PA166302870", + "name" : "Recommendation Annotation PA166302870", "alternateDrugAvailable" : false, "classification" : { "id" : 1448526251, @@ -135817,24 +137217,24 @@ "implications" : [ "The guideline does not provide a description of the impact of a normal metabolizer phenotype on tramadol." ], - "lookupKey" : {"CYP2D6": "2.25"}, + "lookupKey" : {"CYP2D6": "2.5"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104959", "name" : "Annotation of DPWG Guideline for tramadol and CYP2D6", - "version" : 36 + "version" : 147 }, "text" : { - "id" : 1452104468, + "id" : 1452104469, "html" : "

The guideline does not provide a recommendation for tramadol in normal metabolizers.

\n", "version" : 0 }, @@ -135866,26 +137266,26 @@ "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104959", "name" : "Annotation of DPWG Guideline for tramadol and CYP2D6", - "version" : 36 + "version" : 147 }, "text" : { "id" : 1452104477, "html" : "

As the total analgesic effect changes when the ratio between the mother compound and the active metabolite changes, the effect of a dose reduction cannot be predicted with certainty.

\n
    \n
  1. Select an alternative. Do not choose codeine, as it is contra-indicated for CYP2D6 UM. Morphine is not metabolised by CYP2D6. Oxycodone is metabolised by CYP2D6 to a limited extent, but this does not result in differences in side effects in patients.
    2. \n
  2. If an alternative is not possible, use 40% of the standard dose. Advise the patient to report side effects (such as drowsiness, confusion, constipation, nausea and vomiting, respiratory depression or urine retention).
    3. \n
\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302865", - "name" : "Recommendation Annotation PA166302865", + "id" : "PA166302877", + "name" : "Recommendation Annotation PA166302877", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -135899,35 +137299,35 @@ }, "dosingInformation" : true, "implications" : [ - "The genetic variation reduces the conversion of tramadol to a metabolite with a higher activity. This can result in reduced analgesia." + "The genetic variation increases the conversion of tramadol to a metabolite with a stronger opioid effect. This can result in an increase in potentially life-threatening side effects." ], - "lookupKey" : {"CYP2D6": "1.0"}, + "lookupKey" : {"CYP2D6": "≥5.0"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104959", "name" : "Annotation of DPWG Guideline for tramadol and CYP2D6", - "version" : 36 + "version" : 147 }, "text" : { - "id" : 1452104464, - "html" : "

It is not possible to provide a recommendation for dose adjustment, because the total analgesic effect changes when the ratio between the mother compound and the active metabolite changes.

\n
    \n
  1. Be alert to a reduced effectiveness.
    2. \n
  2. In the case of inadequate effectiveness:
    3. \n
\n\n
    \n
  1. If no alternative is selected: advise the patient to report inadequate analgesia.
    2. \n
\n", + "id" : 1452104476, + "html" : "

As the total analgesic effect changes when the ratio between the mother compound and the active metabolite changes, the effect of a dose reduction cannot be predicted with certainty.

\n
    \n
  1. Select an alternative. Do not choose codeine, as it is contra-indicated for CYP2D6 UM. Morphine is not metabolised by CYP2D6. Oxycodone is metabolised by CYP2D6 to a limited extent, but this does not result in differences in side effects in patients.
    2. \n
  2. If an alternative is not possible, use 40% of the standard dose. Advise the patient to report side effects (such as drowsiness, confusion, constipation, nausea and vomiting, respiratory depression or urine retention).
    3. \n
\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302874", - "name" : "Recommendation Annotation PA166302874", + "id" : "PA166302876", + "name" : "Recommendation Annotation PA166302876", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -135943,33 +137343,33 @@ "implications" : [ "The genetic variation increases the conversion of tramadol to a metabolite with a stronger opioid effect. This can result in an increase in potentially life-threatening side effects." ], - "lookupKey" : {"CYP2D6": "≥3.25"}, + "lookupKey" : {"CYP2D6": "≥4.0"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104959", "name" : "Annotation of DPWG Guideline for tramadol and CYP2D6", - "version" : 36 + "version" : 147 }, "text" : { - "id" : 1452104473, + "id" : 1452104475, "html" : "

As the total analgesic effect changes when the ratio between the mother compound and the active metabolite changes, the effect of a dose reduction cannot be predicted with certainty.

\n
    \n
  1. Select an alternative. Do not choose codeine, as it is contra-indicated for CYP2D6 UM. Morphine is not metabolised by CYP2D6. Oxycodone is metabolised by CYP2D6 to a limited extent, but this does not result in differences in side effects in patients.
    2. \n
  2. If an alternative is not possible, use 40% of the standard dose. Advise the patient to report side effects (such as drowsiness, confusion, constipation, nausea and vomiting, respiratory depression or urine retention).
    3. \n
\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302861", - "name" : "Recommendation Annotation PA166302861", + "id" : "PA166302875", + "name" : "Recommendation Annotation PA166302875", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -135983,76 +137383,35 @@ }, "dosingInformation" : true, "implications" : [ - "The genetic variation reduces the conversion of tramadol to a metabolite with a higher activity. This can result in reduced analgesia." + "The genetic variation increases the conversion of tramadol to a metabolite with a stronger opioid effect. This can result in an increase in potentially life-threatening side effects." ], - "lookupKey" : {"CYP2D6": "0.0"}, + "lookupKey" : {"CYP2D6": "≥3.5"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166104959", - "name" : "Annotation of DPWG Guideline for tramadol and CYP2D6", - "version" : 36 - }, - "text" : { - "id" : 1452104460, - "html" : "

It is not possible to provide a recommendation for dose adjustment, because the total analgesic effect changes when the ratio between the mother compound and the active metabolite changes.

\n
    \n
  1. Be alert to a reduced effectiveness.
    2. \n
  2. In the case of inadequate effectiveness:
    3. \n
\n\n
    \n
  1. If no alternative is selected: advise the patient to report inadequate analgesia.
    2. \n
\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166302870", - "name" : "Recommendation Annotation PA166302870", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 1448526251, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on tramadol." - ], - "lookupKey" : {"CYP2D6": "2.5"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA451735", - "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104959", "name" : "Annotation of DPWG Guideline for tramadol and CYP2D6", - "version" : 36 + "version" : 147 }, "text" : { - "id" : 1452104469, - "html" : "

The guideline does not provide a recommendation for tramadol in normal metabolizers.

\n", + "id" : 1452104474, + "html" : "

As the total analgesic effect changes when the ratio between the mother compound and the active metabolite changes, the effect of a dose reduction cannot be predicted with certainty.

\n
    \n
  1. Select an alternative. Do not choose codeine, as it is contra-indicated for CYP2D6 UM. Morphine is not metabolised by CYP2D6. Oxycodone is metabolised by CYP2D6 to a limited extent, but this does not result in differences in side effects in patients.
    2. \n
  2. If an alternative is not possible, use 40% of the standard dose. Advise the patient to report side effects (such as drowsiness, confusion, constipation, nausea and vomiting, respiratory depression or urine retention).
    3. \n
\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302862", - "name" : "Recommendation Annotation PA166302862", + "id" : "PA166302874", + "name" : "Recommendation Annotation PA166302874", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -136066,76 +137425,77 @@ }, "dosingInformation" : true, "implications" : [ - "The genetic variation reduces the conversion of tramadol to a metabolite with a higher activity. This can result in reduced analgesia." + "The genetic variation increases the conversion of tramadol to a metabolite with a stronger opioid effect. This can result in an increase in potentially life-threatening side effects." ], - "lookupKey" : {"CYP2D6": "0.25"}, + "lookupKey" : {"CYP2D6": "≥3.25"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104959", "name" : "Annotation of DPWG Guideline for tramadol and CYP2D6", - "version" : 36 + "version" : 147 }, "text" : { - "id" : 1452104461, - "html" : "

It is not possible to provide a recommendation for dose adjustment, because the total analgesic effect changes when the ratio between the mother compound and the active metabolite changes.

\n
    \n
  1. Be alert to a reduced effectiveness.
    2. \n
  2. In the case of inadequate effectiveness:
    3. \n
\n\n
    \n
  1. If no alternative is selected: advise the patient to report inadequate analgesia.
    2. \n
\n", + "id" : 1452104473, + "html" : "

As the total analgesic effect changes when the ratio between the mother compound and the active metabolite changes, the effect of a dose reduction cannot be predicted with certainty.

\n
    \n
  1. Select an alternative. Do not choose codeine, as it is contra-indicated for CYP2D6 UM. Morphine is not metabolised by CYP2D6. Oxycodone is metabolised by CYP2D6 to a limited extent, but this does not result in differences in side effects in patients.
    2. \n
  2. If an alternative is not possible, use 40% of the standard dose. Advise the patient to report side effects (such as drowsiness, confusion, constipation, nausea and vomiting, respiratory depression or urine retention).
    3. \n
\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302866", - "name" : "Recommendation Annotation PA166302866", - "alternateDrugAvailable" : false, + "id" : "PA166302873", + "name" : "Recommendation Annotation PA166302873", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on tramadol." + "The genetic variation increases the conversion of tramadol to a metabolite with a stronger opioid effect. This can result in an increase in potentially life-threatening side effects." ], - "lookupKey" : {"CYP2D6": "1.25"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"CYP2D6": "≥3.0"}, + "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104959", "name" : "Annotation of DPWG Guideline for tramadol and CYP2D6", - "version" : 36 + "version" : 147 }, "text" : { - "id" : 1452104465, - "html" : "

The guideline does not provide a recommendation for tramadol in normal metabolizers.

\n", + "id" : 1452104472, + "html" : "

As the total analgesic effect changes when the ratio between the mother compound and the active metabolite changes, the effect of a dose reduction cannot be predicted with certainty.

\n
    \n
  1. Select an alternative. Do not choose codeine, as it is contra-indicated for CYP2D6 UM. Morphine is not metabolised by CYP2D6. Oxycodone is metabolised by CYP2D6 to a limited extent, but this does not result in differences in side effects in patients.
    2. \n
  2. If an alternative is not possible, use 40% of the standard dose. Advise the patient to report side effects (such as drowsiness, confusion, constipation, nausea and vomiting, respiratory depression or urine retention).
    3. \n
\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302875", - "name" : "Recommendation Annotation PA166302875", + "id" : "PA166302872", + "name" : "Recommendation Annotation PA166302872", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -136151,28 +137511,28 @@ "implications" : [ "The genetic variation increases the conversion of tramadol to a metabolite with a stronger opioid effect. This can result in an increase in potentially life-threatening side effects." ], - "lookupKey" : {"CYP2D6": "≥3.5"}, + "lookupKey" : {"CYP2D6": "4.0"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104959", "name" : "Annotation of DPWG Guideline for tramadol and CYP2D6", - "version" : 36 + "version" : 147 }, "text" : { - "id" : 1452104474, + "id" : 1452104471, "html" : "

As the total analgesic effect changes when the ratio between the mother compound and the active metabolite changes, the effect of a dose reduction cannot be predicted with certainty.

\n
    \n
  1. Select an alternative. Do not choose codeine, as it is contra-indicated for CYP2D6 UM. Morphine is not metabolised by CYP2D6. Oxycodone is metabolised by CYP2D6 to a limited extent, but this does not result in differences in side effects in patients.
    2. \n
  2. If an alternative is not possible, use 40% of the standard dose. Advise the patient to report side effects (such as drowsiness, confusion, constipation, nausea and vomiting, respiratory depression or urine retention).
    3. \n
\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -136200,67 +137560,68 @@ "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104959", "name" : "Annotation of DPWG Guideline for tramadol and CYP2D6", - "version" : 36 + "version" : 147 }, "text" : { "id" : 1452104470, "html" : "

As the total analgesic effect changes when the ratio between the mother compound and the active metabolite changes, the effect of a dose reduction cannot be predicted with certainty.

\n
    \n
  1. Select an alternative. Do not choose codeine, as it is contra-indicated for CYP2D6 UM. Morphine is not metabolised by CYP2D6. Oxycodone is metabolised by CYP2D6 to a limited extent, but this does not result in differences in side effects in patients.
    2. \n
  2. If an alternative is not possible, use 40% of the standard dose. Advise the patient to report side effects (such as drowsiness, confusion, constipation, nausea and vomiting, respiratory depression or urine retention).
    3. \n
\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302867", - "name" : "Recommendation Annotation PA166302867", - "alternateDrugAvailable" : false, + "id" : "PA166302865", + "name" : "Recommendation Annotation PA166302865", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on tramadol." + "The genetic variation reduces the conversion of tramadol to a metabolite with a higher activity. This can result in reduced analgesia." ], - "lookupKey" : {"CYP2D6": "1.5"}, - "otherPrescribingGuidance" : false, + "lookupKey" : {"CYP2D6": "1.0"}, + "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104959", "name" : "Annotation of DPWG Guideline for tramadol and CYP2D6", - "version" : 36 + "version" : 147 }, "text" : { - "id" : 1452104466, - "html" : "

The guideline does not provide a recommendation for tramadol in normal metabolizers.

\n", + "id" : 1452104464, + "html" : "

It is not possible to provide a recommendation for dose adjustment, because the total analgesic effect changes when the ratio between the mother compound and the active metabolite changes.

\n
    \n
  1. Be alert to a reduced effectiveness.
    2. \n
  2. In the case of inadequate effectiveness:
    3. \n
\n\n
    \n
  1. If no alternative is selected: advise the patient to report inadequate analgesia.
    2. \n
\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302876", - "name" : "Recommendation Annotation PA166302876", + "id" : "PA166302864", + "name" : "Recommendation Annotation PA166302864", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -136274,30 +137635,30 @@ }, "dosingInformation" : true, "implications" : [ - "The genetic variation increases the conversion of tramadol to a metabolite with a stronger opioid effect. This can result in an increase in potentially life-threatening side effects." + "The genetic variation reduces the conversion of tramadol to a metabolite with a higher activity. This can result in reduced analgesia." ], - "lookupKey" : {"CYP2D6": "≥4.0"}, + "lookupKey" : {"CYP2D6": "0.75"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104959", "name" : "Annotation of DPWG Guideline for tramadol and CYP2D6", - "version" : 36 + "version" : 147 }, "text" : { - "id" : 1452104475, - "html" : "

As the total analgesic effect changes when the ratio between the mother compound and the active metabolite changes, the effect of a dose reduction cannot be predicted with certainty.

\n
    \n
  1. Select an alternative. Do not choose codeine, as it is contra-indicated for CYP2D6 UM. Morphine is not metabolised by CYP2D6. Oxycodone is metabolised by CYP2D6 to a limited extent, but this does not result in differences in side effects in patients.
    2. \n
  2. If an alternative is not possible, use 40% of the standard dose. Advise the patient to report side effects (such as drowsiness, confusion, constipation, nausea and vomiting, respiratory depression or urine retention).
    3. \n
\n", + "id" : 1452104463, + "html" : "

It is not possible to provide a recommendation for dose adjustment, because the total analgesic effect changes when the ratio between the mother compound and the active metabolite changes.

\n
    \n
  1. Be alert to a reduced effectiveness.
    2. \n
  2. In the case of inadequate effectiveness:
    3. \n
\n\n
    \n
  1. If no alternative is selected: advise the patient to report inadequate analgesia.
    2. \n
\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -136325,26 +137686,26 @@ "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104959", "name" : "Annotation of DPWG Guideline for tramadol and CYP2D6", - "version" : 36 + "version" : 147 }, "text" : { "id" : 1452104462, "html" : "

It is not possible to provide a recommendation for dose adjustment, because the total analgesic effect changes when the ratio between the mother compound and the active metabolite changes.

\n
    \n
  1. Be alert to a reduced effectiveness.
    2. \n
  2. In the case of inadequate effectiveness:
    3. \n
\n\n
    \n
  1. If no alternative is selected: advise the patient to report inadequate analgesia.
    2. \n
\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302872", - "name" : "Recommendation Annotation PA166302872", + "id" : "PA166302862", + "name" : "Recommendation Annotation PA166302862", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -136358,30 +137719,72 @@ }, "dosingInformation" : true, "implications" : [ - "The genetic variation increases the conversion of tramadol to a metabolite with a stronger opioid effect. This can result in an increase in potentially life-threatening side effects." + "The genetic variation reduces the conversion of tramadol to a metabolite with a higher activity. This can result in reduced analgesia." ], - "lookupKey" : {"CYP2D6": "4.0"}, + "lookupKey" : {"CYP2D6": "0.25"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104959", "name" : "Annotation of DPWG Guideline for tramadol and CYP2D6", - "version" : 36 + "version" : 147 }, "text" : { - "id" : 1452104471, - "html" : "

As the total analgesic effect changes when the ratio between the mother compound and the active metabolite changes, the effect of a dose reduction cannot be predicted with certainty.

\n
    \n
  1. Select an alternative. Do not choose codeine, as it is contra-indicated for CYP2D6 UM. Morphine is not metabolised by CYP2D6. Oxycodone is metabolised by CYP2D6 to a limited extent, but this does not result in differences in side effects in patients.
    2. \n
  2. If an alternative is not possible, use 40% of the standard dose. Advise the patient to report side effects (such as drowsiness, confusion, constipation, nausea and vomiting, respiratory depression or urine retention).
    3. \n
\n", + "id" : 1452104461, + "html" : "

It is not possible to provide a recommendation for dose adjustment, because the total analgesic effect changes when the ratio between the mother compound and the active metabolite changes.

\n
    \n
  1. Be alert to a reduced effectiveness.
    2. \n
  2. In the case of inadequate effectiveness:
    3. \n
\n\n
    \n
  1. If no alternative is selected: advise the patient to report inadequate analgesia.
    2. \n
\n", "version" : 0 }, - "version" : 0 + "version" : 1 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166302861", + "name" : "Recommendation Annotation PA166302861", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981501929, + "description" : "Not Applicable", + "parents" : [], + "resource" : "Guideline Strength", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", + "valid" : true, + "version" : 1 + }, + "dosingInformation" : true, + "implications" : [ + "The genetic variation reduces the conversion of tramadol to a metabolite with a higher activity. This can result in reduced analgesia." + ], + "lookupKey" : {"CYP2D6": "0.0"}, + "otherPrescribingGuidance" : true, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA451735", + "name" : "tramadol", + "version" : 40 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104959", + "name" : "Annotation of DPWG Guideline for tramadol and CYP2D6", + "version" : 147 + }, + "text" : { + "id" : 1452104460, + "html" : "

It is not possible to provide a recommendation for dose adjustment, because the total analgesic effect changes when the ratio between the mother compound and the active metabolite changes.

\n
    \n
  1. Be alert to a reduced effectiveness.
    2. \n
  2. In the case of inadequate effectiveness:
    3. \n
\n\n
    \n
  1. If no alternative is selected: advise the patient to report inadequate analgesia.
    2. \n
\n", + "version" : 0 + }, + "version" : 1 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166104959" @@ -136646,7 +138049,7 @@ "objCls" : "Chemical", "id" : "PA451866", "name" : "venlafaxine", - "version" : 8 + "version" : 40 } ], "relatedGenes" : [ @@ -136655,29 +138058,29 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "DPWG", "summaryMarkdown" : { "id" : 1447981908, "html" : "

For CYP2D6 poor (PM) and intermediate metabolizers (IM), select an alternative to venlafaxine or reduce the dose and monitor patient's plasma metabolite level. For CYP2D6 ultrarapid metabolizers (UM), increase dose to 150% of the normal dose or select an alternative to venlafaxine.

\n", - "version" : 1 + "version" : 2 }, "terms" : [], "textMarkdown" : { "id" : 1447981907, "html" : "

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

\n

August 2019 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for venlafaxine based on CYP2D6 genotype. They recommend that an alternative drug that is not metabolized by CYP2D6 or a dose reduction be considered for CYP2D6 intermediate metabolizers (IMs) and poor metabolizers (PMs). Clinicians should be alert to possible decreases in venlafaxine plasma concentrations in CYP2D6 ultrarapid metabolizers (UMs) and, if necessary, increase the dose to 150% of the standard dose. If a dose increase is not possible, an alternative drug that is not metabolized by CYP2D6 should be selected.

\n

Wording in table taken from Dutch guidelines August 2019 update

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
CYP2D6 UMvenlafaxineIt may be difficult to adjust the dose for patients due to altered metabolism between venlafaxine and the active metabolite O- desmethylvenlafaxine. The gene variation increases the conversion of venlafaxine to O-desmethylvenlafaxine and reduces the sum of venlafaxine plus O-desmethylvenlafaxine.1. be alert to a possible decrease in the sum of the plasma concentrations of venlafaxine and the active metabolite O- desmethylvenlafaxine
2. if necessary, increase the dose to 150% of the standard dose
3. if dose adjustment does not result in efficacy without unacceptable side effects or if dose adjustment based on therapeutic drug monitoring is not possible, then venlafaxine should be avoided
Antidepressants that are not metabolised by CYP2D6 - or to a lesser extent - include, for example, duloxetine, mirtazapine, citalopram and sertraline.
CYP2D6 IMvenlafaxineThere are indications of an increased risk of side effects and a reduced chance of efficacy. The gene variation reduces the conversion of venlafaxine to the active metabolite O-desmethylvenlafaxine, whilst an association between high O-desmethylvenlafaxine/venlafaxine ratios and response without side effects was found.It is not possible to offer adequately substantiated advice for dose reduction based on the literature.
- avoid venlafaxine. Antidepressants that are not metabolised by CYP2D6 - or to a lesser extent - include, for example, duloxetine, mirtazapine, citalopram and sertraline.
- if it is not possible to avoid venlafaxine and side effects occur:
1. reduce the dose
2. monitor the effect and side effects or check the plasma concentrations of venlafaxine and O-desmethylvenlafaxine.
It is not known whether it is possible to reduce the dose to such an extent that the side effects disappear, while the effectiveness is maintained. In general, it is assumed that the effectiveness is determined by the sum of the plasma concentrations of venlafaxine and O-desmethylvenlafaxine. However, the side effects do not appear to be related to this sum.
CYP2D6 PMvenlafaxineThere are indications of an increased risk of side effects and a reduced chance of efficacy. The gene variation reduces the conversion of venlafaxine to the active metabolite O-desmethylvenlafaxine, whilst an association between high O-desmethylvenlafaxine/venlafaxine ratios and response without side effects was found.It is not possible to offer adequately substantiated advice for dose reduction based on the literature.
- avoid venlafaxine. Antidepressants that are not metabolised by CYP2D6 - or to a lesser extent - include, for example, duloxetine, mirtazapine, citalopram and sertraline.
- If it is not possible to avoid venlafaxine and side effects occur:
1. reduce the dose
2. monitor the effect and side effects or check the plasma concentrations of venlafaxine and O-desmethylvenlafaxine
It is not known whether it is possible to reduce the dose to such an extent that the side effects disappear, while the effectiveness is maintained. In general, it is assumed that the effectiveness is determined by the sum of the plasma concentrations of venlafaxine and O-desmethylvenlafaxine. However, the side effects do not appear to be related to this sum. Furthermore, a reduced effectiveness of venlafaxine has been observed in depression patients with this gene variation.
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for venlafaxine and CYP2D6:

\n
\n

The Dutch Pharmacogenetics Working Group considers genotyping before starting venlafaxine to be potentially beneficial for drug efficacy and prevention of adverse events. Genotyping can be considered on an individual patient basis. If, however, the genotype is available, the Dutch Pharmacogenetics Working Group recommends adhering to the gene-drug guideline.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n

November 2018 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for venlafaxine based on CYP2D6 genotype. They recommend that an alternative drug that is not metabolized by CYP2D6 or a dose reduction be considered for CYP2D6 intermediate metabolizers (IMs) and poor metabolizers (PMs). Clinicians should be alert to possible decreases in venlafaxine plasma concentrations in CYP2D6 ultrarapid metabolizers (UMs) and, if necessary, increase the dose to 150% of the standard dose. If a dose increase is not possible, an alternative drug that is not metabolized by CYP2D6 should be selected.

\n

Wording in table taken from the Dutch guidelines November 2018 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
CYP2D6 UMvenlafaxineThe genetic polymorphism leads to increased metabolic capacity of CYP2D6. This can cause a decrease in the plasma concentration of venlafaxine and an increase in the plasma concentration of the active metabolite O-desmethylvenlafaxine.Recommendation:
1. be alert to a possible decrease in the sum of the plasma concentrations of venlafaxine and the active metabolite O-desmethylvenlafaxine
2. if necessary, increase the dose to 150% of the standard dose
3. if dose adjustment based on therapeutic drug monitoring is not possible, an alternative should be selected. Antidepressants that are not metabolised by CYP2D6 - or to a lesser extent - include, for example, citalopram and sertraline.
CYP2D6 IMvenlafaxineThe genetic polymorphism leads to decreased metabolic capacity of CYP2D6. This can cause an increase in the plasma concentration of venlafaxine and a decrease in the plasma concentration of the active metabolite O-desmethylvenlafaxine.It is not possible to offer adequately substantiated advice for dose reduction based on the literature.
1. Choose an alternative. Antidepressants that are not metabolised by CYP2D6 - or to a lesser extent - include, for example, citalopram and sertraline.
2. If an alternative is not an option and side effects occur:
a. reduce the dose
b. check the plasma concentrations of venlafaxine and O-desmethylvenlafaxine. It is not known whether it is possible to reduce the dose to such an extent that the side effects disappear, while the effectiveness is maintained. In general, it is assumed that the effectiveness is determined by the sum of the plasma concentrations of venlafaxine and O-desmethylvenlafaxine. However, the side effects do not appear to be related to this sum.
CYP2D6 PMvenlafaxineThe genetic polymorphism leads to decreased metabolic capacity of CYP2D6. This can cause an increase in the plasma concentration of venlafaxine and a decrease in the plasma concentration of the active metabolite O-desmethylvenlafaxine. There are indications that the effectiveness of venlafaxine is reduced in depression patients with this genetic polymorphism.It is not possible to offer adequately substantiated advice for dose reduction based on the literature.
1. Choose an alternative. Antidepressants that are not metabolised by CYP2D6 - or to a lesser extent - include, for example, citalopram and sertraline.
2. If an alternative is not an option and side effects occur:
a. reduce the dose
b. check the plasma concentrations of venlafaxine and O-desmethylvenlafaxine. It is not known whether it is possible to reduce the dose to such an extent that the side effects disappear, while the effectiveness is maintained. In general, it is assumed that the effectiveness is determined by the sum of the plasma concentrations of venlafaxine and O-desmethylvenlafaxine. However, the side effects do not appear to be related to this sum. Furthermore, a reduced effectiveness of venlafaxine has been observed in depression patients with this genetic polymorphism.
\n

2011 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for venlafaxine based on CYP2D6 genotypes [Article:21412232]. For PM and IM genotypes, they state that there are not sufficient data to allow calculation of dose adjustment, and they recommend selecting an alternative drug or adjusting dose to clinical response and monitoring (O-desmethyl)venlafaxine plasma concentration. For UM genotypes, they recommend titrating dose to a maximum of 150% of the normal dose(based on venlafaxine and (O-desmethyl)venlafaxine plasma concentration) or selecting an alternative drug.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Phenotype (Genotype)Therapeutic Dose RecommendationLevel of EvidenceClinical Relevance
PM (two inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) alleles)Insufficient data to allow calculation of dose adjustment. Select alternative drug (e.g., citalopram, sertraline) or adjust dose to clinical response and monitor (O-desmethyl)venlafaxine plasma concentration.Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Clinical effect (S): long-standing discomfort (48-168 hr) without permanent injury e.g. failure of therapy with tricyclic antidepressants, atypical antipsychotic drugs; extrapyramidal side effects; parkinsonism; ADE resulting from increased bioavailability of tricyclic antidepressants, metoprolol, propafenone (central effects e.g. dizziness); INR 4.5-6.0; neutropenia 1.0-1.5x109/l; leucopenia 2.0-3.0x109/l; thrombocytopenia 50-75x109/l.
IM (two decreased-activity (*9, *10, *17, *29, *36, *41) alleles or carrying one active (*1, *2, *33, *35) and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele, or carrying one decreased-activity (*9, *10, *17, *29, *36, *41) allele and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele)Insufficient data to allow calculation of dose adjustment. Select alternative drug (e.g., citalopram, sertraline) or adjust dose to clinical response and monitor (O-desmethyl)venlafaxine plasma concentration.Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Clinical effect (S): long-standing discomfort (48-168 hr) without permanent injury e.g. failure of therapy with tricyclic antidepressants, atypical antipsychotic drugs; extrapyramidal side effects; parkinsonism; ADE resulting from increased bioavailability of tricyclic antidepressants, metoprolol, propafenone (central effects e.g. dizziness); INR 4.5-6.0; neutropenia 1.0-1.5x109/l; leucopenia 2.0-3.0x109/l; thrombocytopenia 50-75x109/l.
UM (a gene duplication in absence of inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) or decreased-activity (*9, *10, *17, *29, *36, *41) alleles)Be alert to decreased venlafaxine and increased (O-desmethyl)venlafaxine plasma concentration. Titrate dose to a maximum of 150% of the normal dose or select alternative drug (e.g., citalopram, sertraline).Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Minor clinical effect (S): QTc prolongation (<450 ms female, <470 ms male); INR increase < 4.5. Kinetic effect (S).
\n\n", - "version" : 16 + "version" : 21 }, "userId" : "cfthorn", - "version" : 33 + "version" : 97 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166302881", - "name" : "Recommendation Annotation PA166302881", + "id" : "PA166302880", + "name" : "Recommendation Annotation PA166302880", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -136693,24 +138096,24 @@ "implications" : [ "There are indications of an increased risk of side effects and a reduced chance of efficacy. The gene variation reduces the conversion of venlafaxine to the active metabolite O-desmethylvenlafaxine, whilst an association between high O-desmethylvenlafaxine/venlafaxine ratios and response without side effects was found." ], - "lookupKey" : {"CYP2D6": "0.5"}, + "lookupKey" : {"CYP2D6": "0.25"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451866", "name" : "venlafaxine", - "version" : 8 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104968", "name" : "Annotation of DPWG Guideline for venlafaxine and CYP2D6", - "version" : 33 + "version" : 97 }, "text" : { - "id" : 1452104480, + "id" : 1452104479, "html" : "

It is not possible to offer adequately substantiated advice for dose reduction based on the literature.

\n\n
    \n
  1. Reduce the dose
    2. \n
  2. Monitor the effect and side effects or check the plasma concentrations of venlafaxine and O-desmethylvenlafaxine.\nIt is not known whether it is possible to reduce the dose to such an extent that the side effects disappear, while the effectiveness is maintained. In general, it is assumed that the effectiveness is determined by the sum of the plasma concentrations of venlafaxine and O-desmethylvenlafaxine. However, the side effects do not appear to be related to this sum.
    3. \n
\n", "version" : 0 }, @@ -136718,8 +138121,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302890", - "name" : "Recommendation Annotation PA166302890", + "id" : "PA166302881", + "name" : "Recommendation Annotation PA166302881", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -136733,76 +138136,35 @@ }, "dosingInformation" : true, "implications" : [ - "It may be difficult to adjust the dose for patients due to altered metabolism between venlafaxine and the active metabolite O- desmethylvenlafaxine. The gene variation increases the conversion of venlafaxine to O-desmethylvenlafaxine and reduces the sum of venlafaxine plus O-desmethylvenlafaxine." - ], - "lookupKey" : {"CYP2D6": "4.0"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA451866", - "name" : "venlafaxine", - "version" : 8 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166104968", - "name" : "Annotation of DPWG Guideline for venlafaxine and CYP2D6", - "version" : 33 - }, - "text" : { - "id" : 1452104489, - "html" : "
    \n
  1. Be alert to a possible decrease in the sum of the plasma concentrations of venlafaxine and the active metabolite O- desmethylvenlafaxine.
    2. \n
  2. If necessary, increase the dose to 150% of the standard dose.
    3. \n
  3. If dose adjustment does not result in efficacy without unacceptable side effects or if dose adjustment based on therapeutic drug monitoring is not possible, then venlafaxine should be avoided.\nAntidepressants that are not metabolised by CYP2D6 - or to a lesser extent - include, for example, duloxetine, mirtazapine, citalopram and sertraline.
    4. \n
\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166302886", - "name" : "Recommendation Annotation PA166302886", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 1448526251, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on venlafaxine." + "There are indications of an increased risk of side effects and a reduced chance of efficacy. The gene variation reduces the conversion of venlafaxine to the active metabolite O-desmethylvenlafaxine, whilst an association between high O-desmethylvenlafaxine/venlafaxine ratios and response without side effects was found." ], - "lookupKey" : {"CYP2D6": "2.0"}, + "lookupKey" : {"CYP2D6": "0.5"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451866", "name" : "venlafaxine", - "version" : 8 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104968", "name" : "Annotation of DPWG Guideline for venlafaxine and CYP2D6", - "version" : 33 + "version" : 97 }, "text" : { - "id" : 1452104485, - "html" : "

The guideline does not provide a recommendation for venlafaxine in normal metabolizers.

\n", + "id" : 1452104480, + "html" : "

It is not possible to offer adequately substantiated advice for dose reduction based on the literature.

\n\n
    \n
  1. Reduce the dose
    2. \n
  2. Monitor the effect and side effects or check the plasma concentrations of venlafaxine and O-desmethylvenlafaxine.\nIt is not known whether it is possible to reduce the dose to such an extent that the side effects disappear, while the effectiveness is maintained. In general, it is assumed that the effectiveness is determined by the sum of the plasma concentrations of venlafaxine and O-desmethylvenlafaxine. However, the side effects do not appear to be related to this sum.
    3. \n
\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302895", - "name" : "Recommendation Annotation PA166302895", + "id" : "PA166302882", + "name" : "Recommendation Annotation PA166302882", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -136816,35 +138178,35 @@ }, "dosingInformation" : true, "implications" : [ - "It may be difficult to adjust the dose for patients due to altered metabolism between venlafaxine and the active metabolite O- desmethylvenlafaxine. The gene variation increases the conversion of venlafaxine to O-desmethylvenlafaxine and reduces the sum of venlafaxine plus O-desmethylvenlafaxine." + "There are indications of an increased risk of side effects and a reduced chance of efficacy. The gene variation reduces the conversion of venlafaxine to the active metabolite O-desmethylvenlafaxine, whilst an association between high O-desmethylvenlafaxine/venlafaxine ratios and response without side effects was found." ], - "lookupKey" : {"CYP2D6": "≥5.0"}, + "lookupKey" : {"CYP2D6": "0.75"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451866", "name" : "venlafaxine", - "version" : 8 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104968", "name" : "Annotation of DPWG Guideline for venlafaxine and CYP2D6", - "version" : 33 + "version" : 97 }, "text" : { - "id" : 1452104494, - "html" : "
    \n
  1. Be alert to a possible decrease in the sum of the plasma concentrations of venlafaxine and the active metabolite O- desmethylvenlafaxine.
    2. \n
  2. If necessary, increase the dose to 150% of the standard dose.
    3. \n
  3. If dose adjustment does not result in efficacy without unacceptable side effects or if dose adjustment based on therapeutic drug monitoring is not possible, then venlafaxine should be avoided.\nAntidepressants that are not metabolised by CYP2D6 - or to a lesser extent - include, for example, duloxetine, mirtazapine, citalopram and sertraline.
    4. \n
\n", + "id" : 1452104481, + "html" : "

It is not possible to offer adequately substantiated advice for dose reduction based on the literature.

\n\n
    \n
  1. Reduce the dose
    2. \n
  2. Monitor the effect and side effects or check the plasma concentrations of venlafaxine and O-desmethylvenlafaxine.\nIt is not known whether it is possible to reduce the dose to such an extent that the side effects disappear, while the effectiveness is maintained. In general, it is assumed that the effectiveness is determined by the sum of the plasma concentrations of venlafaxine and O-desmethylvenlafaxine. However, the side effects do not appear to be related to this sum.
    3. \n
\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302882", - "name" : "Recommendation Annotation PA166302882", + "id" : "PA166302883", + "name" : "Recommendation Annotation PA166302883", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -136860,24 +138222,24 @@ "implications" : [ "There are indications of an increased risk of side effects and a reduced chance of efficacy. The gene variation reduces the conversion of venlafaxine to the active metabolite O-desmethylvenlafaxine, whilst an association between high O-desmethylvenlafaxine/venlafaxine ratios and response without side effects was found." ], - "lookupKey" : {"CYP2D6": "0.75"}, + "lookupKey" : {"CYP2D6": "1.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451866", "name" : "venlafaxine", - "version" : 8 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104968", "name" : "Annotation of DPWG Guideline for venlafaxine and CYP2D6", - "version" : 33 + "version" : 97 }, "text" : { - "id" : 1452104481, + "id" : 1452104482, "html" : "

It is not possible to offer adequately substantiated advice for dose reduction based on the literature.

\n\n
    \n
  1. Reduce the dose
    2. \n
  2. Monitor the effect and side effects or check the plasma concentrations of venlafaxine and O-desmethylvenlafaxine.\nIt is not known whether it is possible to reduce the dose to such an extent that the side effects disappear, while the effectiveness is maintained. In general, it is assumed that the effectiveness is determined by the sum of the plasma concentrations of venlafaxine and O-desmethylvenlafaxine. However, the side effects do not appear to be related to this sum.
    3. \n
\n", "version" : 0 }, @@ -136885,8 +138247,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302891", - "name" : "Recommendation Annotation PA166302891", + "id" : "PA166302879", + "name" : "Recommendation Annotation PA166302879", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -136900,35 +138262,35 @@ }, "dosingInformation" : true, "implications" : [ - "It may be difficult to adjust the dose for patients due to altered metabolism between venlafaxine and the active metabolite O- desmethylvenlafaxine. The gene variation increases the conversion of venlafaxine to O-desmethylvenlafaxine and reduces the sum of venlafaxine plus O-desmethylvenlafaxine." + "There are indications of an increased risk of side effects and a reduced chance of efficacy. The gene variation reduces the conversion of venlafaxine to the active metabolite O-desmethylvenlafaxine, whilst an association between high O-desmethylvenlafaxine/venlafaxine ratios and response without side effects was found." ], - "lookupKey" : {"CYP2D6": "≥3.0"}, + "lookupKey" : {"CYP2D6": "0.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451866", "name" : "venlafaxine", - "version" : 8 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104968", "name" : "Annotation of DPWG Guideline for venlafaxine and CYP2D6", - "version" : 33 + "version" : 97 }, "text" : { - "id" : 1452104490, - "html" : "
    \n
  1. Be alert to a possible decrease in the sum of the plasma concentrations of venlafaxine and the active metabolite O- desmethylvenlafaxine.
    2. \n
  2. If necessary, increase the dose to 150% of the standard dose.
    3. \n
  3. If dose adjustment does not result in efficacy without unacceptable side effects or if dose adjustment based on therapeutic drug monitoring is not possible, then venlafaxine should be avoided.\nAntidepressants that are not metabolised by CYP2D6 - or to a lesser extent - include, for example, duloxetine, mirtazapine, citalopram and sertraline.
    4. \n
\n", - "version" : 0 + "id" : 1452104478, + "html" : "

It is not possible to offer adequately substantiated advice for dose reduction based on the literature.

\n\n
    \n
  1. Reduce the dose
    2. \n
  2. Monitor the effect and side effects or check the plasma concentrations of venlafaxine and O-desmethylvenlafaxine.\nIt is not known whether it is possible to reduce the dose to such an extent that the side effects disappear, while the effectiveness is maintained. In general, it is assumed that the effectiveness is determined by the sum of the plasma concentrations of venlafaxine and O-desmethylvenlafaxine. However, the side effects do not appear to be related to this sum. Furthermore, a reduced effectiveness of venlafaxine has been observed in depression patients with this gene variation.
    3. \n
\n", + "version" : 1 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302887", - "name" : "Recommendation Annotation PA166302887", + "id" : "PA166302884", + "name" : "Recommendation Annotation PA166302884", "alternateDrugAvailable" : false, "classification" : { "id" : 1448526251, @@ -136943,24 +138305,24 @@ "implications" : [ "The guideline does not provide a description of the impact of a normal metabolizer phenotype on venlafaxine." ], - "lookupKey" : {"CYP2D6": "2.25"}, + "lookupKey" : {"CYP2D6": "1.25"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451866", "name" : "venlafaxine", - "version" : 8 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104968", "name" : "Annotation of DPWG Guideline for venlafaxine and CYP2D6", - "version" : 33 + "version" : 97 }, "text" : { - "id" : 1452104486, + "id" : 1452104483, "html" : "

The guideline does not provide a recommendation for venlafaxine in normal metabolizers.

\n", "version" : 0 }, @@ -136968,168 +138330,123 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302896", - "name" : "Recommendation Annotation PA166302896", - "alternateDrugAvailable" : true, + "id" : "PA166302885", + "name" : "Recommendation Annotation PA166302885", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 - }, - "dosingInformation" : true, - "implications" : [ - "It may be difficult to adjust the dose for patients due to altered metabolism between venlafaxine and the active metabolite O- desmethylvenlafaxine. The gene variation increases the conversion of venlafaxine to O-desmethylvenlafaxine and reduces the sum of venlafaxine plus O-desmethylvenlafaxine." - ], - "lookupKey" : {"CYP2D6": "≥6.0"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA451866", - "name" : "venlafaxine", - "version" : 8 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166104968", - "name" : "Annotation of DPWG Guideline for venlafaxine and CYP2D6", - "version" : 33 - }, - "text" : { - "id" : 1452104495, - "html" : "
    \n
  1. Be alert to a possible decrease in the sum of the plasma concentrations of venlafaxine and the active metabolite O- desmethylvenlafaxine.
    2. \n
  2. If necessary, increase the dose to 150% of the standard dose.
    3. \n
  3. If dose adjustment does not result in efficacy without unacceptable side effects or if dose adjustment based on therapeutic drug monitoring is not possible, then venlafaxine should be avoided.\nAntidepressants that are not metabolised by CYP2D6 - or to a lesser extent - include, for example, duloxetine, mirtazapine, citalopram and sertraline.
    4. \n
\n", "version" : 0 }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166302883", - "name" : "Recommendation Annotation PA166302883", - "alternateDrugAvailable" : true, - "classification" : { - "id" : 981501929, - "description" : "Not Applicable", - "parents" : [], - "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", - "valid" : true, - "version" : 1 - }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "There are indications of an increased risk of side effects and a reduced chance of efficacy. The gene variation reduces the conversion of venlafaxine to the active metabolite O-desmethylvenlafaxine, whilst an association between high O-desmethylvenlafaxine/venlafaxine ratios and response without side effects was found." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on venlafaxine." ], - "lookupKey" : {"CYP2D6": "1.0"}, + "lookupKey" : {"CYP2D6": "1.5"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451866", "name" : "venlafaxine", - "version" : 8 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104968", "name" : "Annotation of DPWG Guideline for venlafaxine and CYP2D6", - "version" : 33 + "version" : 97 }, "text" : { - "id" : 1452104482, - "html" : "

It is not possible to offer adequately substantiated advice for dose reduction based on the literature.

\n\n
    \n
  1. Reduce the dose
    2. \n
  2. Monitor the effect and side effects or check the plasma concentrations of venlafaxine and O-desmethylvenlafaxine.\nIt is not known whether it is possible to reduce the dose to such an extent that the side effects disappear, while the effectiveness is maintained. In general, it is assumed that the effectiveness is determined by the sum of the plasma concentrations of venlafaxine and O-desmethylvenlafaxine. However, the side effects do not appear to be related to this sum.
    3. \n
\n", + "id" : 1452104484, + "html" : "

The guideline does not provide a recommendation for venlafaxine in normal metabolizers.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302892", - "name" : "Recommendation Annotation PA166302892", - "alternateDrugAvailable" : true, + "id" : "PA166302886", + "name" : "Recommendation Annotation PA166302886", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "It may be difficult to adjust the dose for patients due to altered metabolism between venlafaxine and the active metabolite O- desmethylvenlafaxine. The gene variation increases the conversion of venlafaxine to O-desmethylvenlafaxine and reduces the sum of venlafaxine plus O-desmethylvenlafaxine." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on venlafaxine." ], - "lookupKey" : {"CYP2D6": "≥3.25"}, + "lookupKey" : {"CYP2D6": "2.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451866", "name" : "venlafaxine", - "version" : 8 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104968", "name" : "Annotation of DPWG Guideline for venlafaxine and CYP2D6", - "version" : 33 + "version" : 97 }, "text" : { - "id" : 1452104491, - "html" : "
    \n
  1. Be alert to a possible decrease in the sum of the plasma concentrations of venlafaxine and the active metabolite O- desmethylvenlafaxine.
    2. \n
  2. If necessary, increase the dose to 150% of the standard dose.
    3. \n
  3. If dose adjustment does not result in efficacy without unacceptable side effects or if dose adjustment based on therapeutic drug monitoring is not possible, then venlafaxine should be avoided.\nAntidepressants that are not metabolised by CYP2D6 - or to a lesser extent - include, for example, duloxetine, mirtazapine, citalopram and sertraline.
    4. \n
\n", + "id" : 1452104485, + "html" : "

The guideline does not provide a recommendation for venlafaxine in normal metabolizers.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302879", - "name" : "Recommendation Annotation PA166302879", - "alternateDrugAvailable" : true, + "id" : "PA166302887", + "name" : "Recommendation Annotation PA166302887", + "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "There are indications of an increased risk of side effects and a reduced chance of efficacy. The gene variation reduces the conversion of venlafaxine to the active metabolite O-desmethylvenlafaxine, whilst an association between high O-desmethylvenlafaxine/venlafaxine ratios and response without side effects was found." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on venlafaxine." ], - "lookupKey" : {"CYP2D6": "0.0"}, + "lookupKey" : {"CYP2D6": "2.25"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451866", "name" : "venlafaxine", - "version" : 8 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104968", "name" : "Annotation of DPWG Guideline for venlafaxine and CYP2D6", - "version" : 33 + "version" : 97 }, "text" : { - "id" : 1452104478, - "html" : "

It is not possible to offer adequately substantiated advice for dose reduction based on the literature.

\n\n
    \n
  1. Reduce the dose
    2. \n
  2. Monitor the effect and side effects or check the plasma concentrations of venlafaxine and O-desmethylvenlafaxine.\nIt is not known whether it is possible to reduce the dose to such an extent that the side effects disappear, while the effectiveness is maintained. In general, it is assumed that the effectiveness is determined by the sum of the plasma concentrations of venlafaxine and O-desmethylvenlafaxine. However, the side effects do not appear to be related to this sum. Furthermore, a reduced effectiveness of venlafaxine has been observed in depression patients with this gene variation.
    3. \n
\n", + "id" : 1452104486, + "html" : "

The guideline does not provide a recommendation for venlafaxine in normal metabolizers.

\n", "version" : 0 }, "version" : 0 @@ -137159,14 +138476,14 @@ "objCls" : "Chemical", "id" : "PA451866", "name" : "venlafaxine", - "version" : 8 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104968", "name" : "Annotation of DPWG Guideline for venlafaxine and CYP2D6", - "version" : 33 + "version" : 97 }, "text" : { "id" : 1452104487, @@ -137177,49 +138494,50 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302884", - "name" : "Recommendation Annotation PA166302884", - "alternateDrugAvailable" : false, + "id" : "PA166302889", + "name" : "Recommendation Annotation PA166302889", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on venlafaxine." + "It may be difficult to adjust the dose for patients due to altered metabolism between venlafaxine and the active metabolite O- desmethylvenlafaxine. The gene variation increases the conversion of venlafaxine to O-desmethylvenlafaxine and reduces the sum of venlafaxine plus O-desmethylvenlafaxine." ], - "lookupKey" : {"CYP2D6": "1.25"}, + "lookupKey" : {"CYP2D6": "3.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451866", "name" : "venlafaxine", - "version" : 8 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104968", "name" : "Annotation of DPWG Guideline for venlafaxine and CYP2D6", - "version" : 33 + "version" : 97 }, "text" : { - "id" : 1452104483, - "html" : "

The guideline does not provide a recommendation for venlafaxine in normal metabolizers.

\n", + "id" : 1452104488, + "html" : "
    \n
  1. Be alert to a possible decrease in the sum of the plasma concentrations of venlafaxine and the active metabolite O- desmethylvenlafaxine.
    2. \n
  2. If necessary, increase the dose to 150% of the standard dose.
    3. \n
  3. If dose adjustment does not result in efficacy without unacceptable side effects or if dose adjustment based on therapeutic drug monitoring is not possible, then venlafaxine should be avoided.\nAntidepressants that are not metabolised by CYP2D6 - or to a lesser extent - include, for example, duloxetine, mirtazapine, citalopram and sertraline.
    4. \n
\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302893", - "name" : "Recommendation Annotation PA166302893", + "id" : "PA166302890", + "name" : "Recommendation Annotation PA166302890", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -137235,24 +138553,24 @@ "implications" : [ "It may be difficult to adjust the dose for patients due to altered metabolism between venlafaxine and the active metabolite O- desmethylvenlafaxine. The gene variation increases the conversion of venlafaxine to O-desmethylvenlafaxine and reduces the sum of venlafaxine plus O-desmethylvenlafaxine." ], - "lookupKey" : {"CYP2D6": "≥3.5"}, + "lookupKey" : {"CYP2D6": "4.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451866", "name" : "venlafaxine", - "version" : 8 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104968", "name" : "Annotation of DPWG Guideline for venlafaxine and CYP2D6", - "version" : 33 + "version" : 97 }, "text" : { - "id" : 1452104492, + "id" : 1452104489, "html" : "
    \n
  1. Be alert to a possible decrease in the sum of the plasma concentrations of venlafaxine and the active metabolite O- desmethylvenlafaxine.
    2. \n
  2. If necessary, increase the dose to 150% of the standard dose.
    3. \n
  3. If dose adjustment does not result in efficacy without unacceptable side effects or if dose adjustment based on therapeutic drug monitoring is not possible, then venlafaxine should be avoided.\nAntidepressants that are not metabolised by CYP2D6 - or to a lesser extent - include, for example, duloxetine, mirtazapine, citalopram and sertraline.
    4. \n
\n", "version" : 0 }, @@ -137260,8 +138578,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302880", - "name" : "Recommendation Annotation PA166302880", + "id" : "PA166302891", + "name" : "Recommendation Annotation PA166302891", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -137275,35 +138593,35 @@ }, "dosingInformation" : true, "implications" : [ - "There are indications of an increased risk of side effects and a reduced chance of efficacy. The gene variation reduces the conversion of venlafaxine to the active metabolite O-desmethylvenlafaxine, whilst an association between high O-desmethylvenlafaxine/venlafaxine ratios and response without side effects was found." + "It may be difficult to adjust the dose for patients due to altered metabolism between venlafaxine and the active metabolite O- desmethylvenlafaxine. The gene variation increases the conversion of venlafaxine to O-desmethylvenlafaxine and reduces the sum of venlafaxine plus O-desmethylvenlafaxine." ], - "lookupKey" : {"CYP2D6": "0.25"}, + "lookupKey" : {"CYP2D6": "≥3.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451866", "name" : "venlafaxine", - "version" : 8 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104968", "name" : "Annotation of DPWG Guideline for venlafaxine and CYP2D6", - "version" : 33 + "version" : 97 }, "text" : { - "id" : 1452104479, - "html" : "

It is not possible to offer adequately substantiated advice for dose reduction based on the literature.

\n\n
    \n
  1. Reduce the dose
    2. \n
  2. Monitor the effect and side effects or check the plasma concentrations of venlafaxine and O-desmethylvenlafaxine.\nIt is not known whether it is possible to reduce the dose to such an extent that the side effects disappear, while the effectiveness is maintained. In general, it is assumed that the effectiveness is determined by the sum of the plasma concentrations of venlafaxine and O-desmethylvenlafaxine. However, the side effects do not appear to be related to this sum.
    3. \n
\n", + "id" : 1452104490, + "html" : "
    \n
  1. Be alert to a possible decrease in the sum of the plasma concentrations of venlafaxine and the active metabolite O- desmethylvenlafaxine.
    2. \n
  2. If necessary, increase the dose to 150% of the standard dose.
    3. \n
  3. If dose adjustment does not result in efficacy without unacceptable side effects or if dose adjustment based on therapeutic drug monitoring is not possible, then venlafaxine should be avoided.\nAntidepressants that are not metabolised by CYP2D6 - or to a lesser extent - include, for example, duloxetine, mirtazapine, citalopram and sertraline.
    4. \n
\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302889", - "name" : "Recommendation Annotation PA166302889", + "id" : "PA166302892", + "name" : "Recommendation Annotation PA166302892", "alternateDrugAvailable" : true, "classification" : { "id" : 981501929, @@ -137319,24 +138637,24 @@ "implications" : [ "It may be difficult to adjust the dose for patients due to altered metabolism between venlafaxine and the active metabolite O- desmethylvenlafaxine. The gene variation increases the conversion of venlafaxine to O-desmethylvenlafaxine and reduces the sum of venlafaxine plus O-desmethylvenlafaxine." ], - "lookupKey" : {"CYP2D6": "3.0"}, + "lookupKey" : {"CYP2D6": "≥3.25"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451866", "name" : "venlafaxine", - "version" : 8 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104968", "name" : "Annotation of DPWG Guideline for venlafaxine and CYP2D6", - "version" : 33 + "version" : 97 }, "text" : { - "id" : 1452104488, + "id" : 1452104491, "html" : "
    \n
  1. Be alert to a possible decrease in the sum of the plasma concentrations of venlafaxine and the active metabolite O- desmethylvenlafaxine.
    2. \n
  2. If necessary, increase the dose to 150% of the standard dose.
    3. \n
  3. If dose adjustment does not result in efficacy without unacceptable side effects or if dose adjustment based on therapeutic drug monitoring is not possible, then venlafaxine should be avoided.\nAntidepressants that are not metabolised by CYP2D6 - or to a lesser extent - include, for example, duloxetine, mirtazapine, citalopram and sertraline.
    4. \n
\n", "version" : 0 }, @@ -137344,41 +138662,42 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302885", - "name" : "Recommendation Annotation PA166302885", - "alternateDrugAvailable" : false, + "id" : "PA166302893", + "name" : "Recommendation Annotation PA166302893", + "alternateDrugAvailable" : true, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on venlafaxine." + "It may be difficult to adjust the dose for patients due to altered metabolism between venlafaxine and the active metabolite O- desmethylvenlafaxine. The gene variation increases the conversion of venlafaxine to O-desmethylvenlafaxine and reduces the sum of venlafaxine plus O-desmethylvenlafaxine." ], - "lookupKey" : {"CYP2D6": "1.5"}, + "lookupKey" : {"CYP2D6": "≥3.5"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451866", "name" : "venlafaxine", - "version" : 8 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104968", "name" : "Annotation of DPWG Guideline for venlafaxine and CYP2D6", - "version" : 33 + "version" : 97 }, "text" : { - "id" : 1452104484, - "html" : "

The guideline does not provide a recommendation for venlafaxine in normal metabolizers.

\n", + "id" : 1452104492, + "html" : "
    \n
  1. Be alert to a possible decrease in the sum of the plasma concentrations of venlafaxine and the active metabolite O- desmethylvenlafaxine.
    2. \n
  2. If necessary, increase the dose to 150% of the standard dose.
    3. \n
  3. If dose adjustment does not result in efficacy without unacceptable side effects or if dose adjustment based on therapeutic drug monitoring is not possible, then venlafaxine should be avoided.\nAntidepressants that are not metabolised by CYP2D6 - or to a lesser extent - include, for example, duloxetine, mirtazapine, citalopram and sertraline.
    4. \n
\n", "version" : 0 }, "version" : 0 @@ -137409,14 +138728,14 @@ "objCls" : "Chemical", "id" : "PA451866", "name" : "venlafaxine", - "version" : 8 + "version" : 40 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104968", "name" : "Annotation of DPWG Guideline for venlafaxine and CYP2D6", - "version" : 33 + "version" : 97 }, "text" : { "id" : 1452104493, @@ -137424,6 +138743,90 @@ "version" : 0 }, "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166302895", + "name" : "Recommendation Annotation PA166302895", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981501929, + "description" : "Not Applicable", + "parents" : [], + "resource" : "Guideline Strength", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", + "valid" : true, + "version" : 1 + }, + "dosingInformation" : true, + "implications" : [ + "It may be difficult to adjust the dose for patients due to altered metabolism between venlafaxine and the active metabolite O- desmethylvenlafaxine. The gene variation increases the conversion of venlafaxine to O-desmethylvenlafaxine and reduces the sum of venlafaxine plus O-desmethylvenlafaxine." + ], + "lookupKey" : {"CYP2D6": "≥5.0"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA451866", + "name" : "venlafaxine", + "version" : 40 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104968", + "name" : "Annotation of DPWG Guideline for venlafaxine and CYP2D6", + "version" : 97 + }, + "text" : { + "id" : 1452104494, + "html" : "
    \n
  1. Be alert to a possible decrease in the sum of the plasma concentrations of venlafaxine and the active metabolite O- desmethylvenlafaxine.
    2. \n
  2. If necessary, increase the dose to 150% of the standard dose.
    3. \n
  3. If dose adjustment does not result in efficacy without unacceptable side effects or if dose adjustment based on therapeutic drug monitoring is not possible, then venlafaxine should be avoided.\nAntidepressants that are not metabolised by CYP2D6 - or to a lesser extent - include, for example, duloxetine, mirtazapine, citalopram and sertraline.
    4. \n
\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166302896", + "name" : "Recommendation Annotation PA166302896", + "alternateDrugAvailable" : true, + "classification" : { + "id" : 981501929, + "description" : "Not Applicable", + "parents" : [], + "resource" : "Guideline Strength", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", + "valid" : true, + "version" : 1 + }, + "dosingInformation" : true, + "implications" : [ + "It may be difficult to adjust the dose for patients due to altered metabolism between venlafaxine and the active metabolite O- desmethylvenlafaxine. The gene variation increases the conversion of venlafaxine to O-desmethylvenlafaxine and reduces the sum of venlafaxine plus O-desmethylvenlafaxine." + ], + "lookupKey" : {"CYP2D6": "≥6.0"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA451866", + "name" : "venlafaxine", + "version" : 40 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104968", + "name" : "Annotation of DPWG Guideline for venlafaxine and CYP2D6", + "version" : 97 + }, + "text" : { + "id" : 1452104495, + "html" : "
    \n
  1. Be alert to a possible decrease in the sum of the plasma concentrations of venlafaxine and the active metabolite O- desmethylvenlafaxine.
    2. \n
  2. If necessary, increase the dose to 150% of the standard dose.
    3. \n
  3. If dose adjustment does not result in efficacy without unacceptable side effects or if dose adjustment based on therapeutic drug monitoring is not possible, then venlafaxine should be avoided.\nAntidepressants that are not metabolised by CYP2D6 - or to a lesser extent - include, for example, duloxetine, mirtazapine, citalopram and sertraline.
    4. \n
\n", + "version" : 0 + }, + "version" : 0 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166104968" @@ -137597,7 +139000,7 @@ "objCls" : "Chemical", "id" : "PA10233", "name" : "voriconazole", - "version" : 7 + "version" : 37 } ], "relatedGenes" : [ @@ -137606,112 +139009,112 @@ "id" : "PA124", "symbol" : "CYP2C19", "name" : "cytochrome P450 family 2 subfamily C member 19", - "version" : 7210 + "version" : 7266 } ], "source" : "DPWG", "summaryMarkdown" : { "id" : 1447982004, "html" : "

Patients who are CYP2C19 poor metabolizers should receive 50% of the standard dose, and CYP2C19 ultrarapid metabolizers should receive a 1.5 times higher initial dose. Monitor voriconazole plasma concentrations for CYP2C19 poor, intermediate and ultrarapid metabolizers.

\n", - "version" : 1 + "version" : 3 }, "terms" : [], "textMarkdown" : { "id" : 1447982003, "html" : "

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

\n

November 2018 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for voriconazole based on CYP2C19 genotype. Patients who are CYP2C19 poor metabolizers should receive 50% of the standard dose, and CYP2C19 ultrarapid metabolizers should receive a 1.5 times higher initial dose. Monitor voriconazole plasma concentrations for CYP2C19 poor, intermediate and ultrarapid metabolizers.

\n

Wording in table taken from the Dutch guidelines November 2018 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
CYP2C19 PMvoriconazoleThe gene variation can reduce the conversion of voriconazole and consequently increase the plasma concentration. This could result in improved efficacy or an increase in the risk of side effects. Initially, the risk of side effects is of particular interest.Use 50% of the standard dose and monitor the plasma concentration.
CYP2C19 IMvoriconazoleThe gene variation can reduce the conversion of voriconazole and consequently increase the plasma concentration. This could result in improved efficacy or an increase in the risk of side effects.Monitor the plasma concentration.
CYP2C19 UMvoriconazoleThe gene variation increases the conversion of voriconazole, which increases the risk of ineffectiveness.Use an initial dose that is 1.5x higher and monitor the plasma concentration.
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for voriconazole and CYP2C19:

\n
\n

The KNMP Pharmacogenetics Working Group considers genotyping before starting voriconazole to be potentially\nbeneficial. Genotyping can be considered on an individual patient basis. If, however, the genotype is available, the\nKNMP Pharmacogenetics Working Group recommends adhering to the gene-drug guideline.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n

2011 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for voriconazole based on CYP2C19 genotype [Article:21412232]. They conclude to monitor serum concentration for patients carrying the CYP2C19 PM or IM phenotype.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Phenotype (Genotype)Therapeutic Dose RecommendationLevel of EvidenceClinical Relevance
CYP2C19 PM (*2/*2, *2/*3, *3/*3)Monitor serum concentrationPublished controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpointsMinor clinical effect (statistically significant difference): QTc prolongation (<450 ms female, <470 ms male); international normalized ratio increase < 4.5 ; Kinetic effect (statistically significant difference)
CYP2C19 IM (*1/*2, *1/*3, *17/*2, *17/*3)Monitor serum concentrationPublished controlled studies of moderate quality# relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpointsMinor clinical effect (statistically significant difference): QTc prolongation (<450 ms female, <470 ms male); international normalized ratio increase < 4.5 ; Kinetic effect (statistically significant difference)
CYP2C19 UM (*17/*17)NonePublished controlled studies of moderate quality# relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpointsMinor clinical effect (statistically significant difference): QTc prolongation (<450 ms female, <470 ms male); international normalized ratio increase < 4.5 ; Kinetic effect (statistically significant difference)
\n\n", - "version" : 16 + "version" : 24 }, "userId" : "alie", - "version" : 29 + "version" : 67 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166299274", - "name" : "Recommendation PA166299274", + "id" : "PA166299273", + "name" : "Recommendation PA166299273", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "The gene variation increases the conversion of voriconazole, which increases the risk of ineffectiveness." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on voriconazole." ], - "lookupKey" : {"CYP2C19": "Ultrarapid Metabolizer"}, + "lookupKey" : {"CYP2C19": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA10233", "name" : "voriconazole", - "version" : 7 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104990", "name" : "Annotation of DPWG Guideline for voriconazole and CYP2C19", - "version" : 29 + "version" : 67 }, "text" : { - "id" : 1452061637, - "html" : "

Use an initial dose that is 1.5x higher and monitor the plasma concentration.

\n", + "id" : 1452061636, + "html" : "

The guideline does not provide a recommendation for voriconazole in normal metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299273", - "name" : "Recommendation PA166299273", + "id" : "PA166299276", + "name" : "Recommendation PA166299276", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on voriconazole." + "The gene variation can reduce the conversion of voriconazole and consequently increase the plasma concentration. This could result in improved efficacy or an increase in the risk of side effects. Initially, the risk of side effects is of particular interest." ], - "lookupKey" : {"CYP2C19": "Normal Metabolizer"}, + "lookupKey" : {"CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA10233", "name" : "voriconazole", - "version" : 7 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104990", "name" : "Annotation of DPWG Guideline for voriconazole and CYP2C19", - "version" : 29 + "version" : 67 }, "text" : { - "id" : 1452061636, - "html" : "

The guideline does not provide a recommendation for voriconazole in normal metabolizers.

\n", + "id" : 1452061639, + "html" : "

Use 50% of the standard dose and monitor the plasma concentration.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299276", - "name" : "Recommendation PA166299276", + "id" : "PA166299274", + "name" : "Recommendation PA166299274", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -137725,30 +139128,30 @@ }, "dosingInformation" : true, "implications" : [ - "The gene variation can reduce the conversion of voriconazole and consequently increase the plasma concentration. This could result in improved efficacy or an increase in the risk of side effects. Initially, the risk of side effects is of particular interest." + "The gene variation increases the conversion of voriconazole, which increases the risk of ineffectiveness." ], - "lookupKey" : {"CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2C19": "Ultrarapid Metabolizer"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA10233", "name" : "voriconazole", - "version" : 7 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104990", "name" : "Annotation of DPWG Guideline for voriconazole and CYP2C19", - "version" : 29 + "version" : 67 }, "text" : { - "id" : 1452061639, - "html" : "

Use 50% of the standard dose and monitor the plasma concentration.

\n", + "id" : 1452061637, + "html" : "

Use an initial dose that is 1.5x higher and monitor the plasma concentration.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", @@ -137776,21 +139179,21 @@ "objCls" : "Chemical", "id" : "PA10233", "name" : "voriconazole", - "version" : 7 + "version" : 37 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104990", "name" : "Annotation of DPWG Guideline for voriconazole and CYP2C19", - "version" : 29 + "version" : 67 }, "text" : { "id" : 1452061638, "html" : "

Monitor the plasma concentration.

\n", "version" : 0 }, - "version" : 0 + "version" : 2 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166104990" @@ -137812,7 +139215,7 @@ "date" : "2019-05-27T00:00:00-07:00", "description" : "Annotation current with November 2018 DPWG Guideline release", "type" : "Create", - "version" : 0 + "version" : 1 }, { "id" : 1450820676, @@ -137882,7 +139285,7 @@ "date" : "2024-03-18T00:00:00-07:00", "description" : "Updated links for risk analysis pdf.", "type" : "Update", - "version" : 0 + "version" : 1 }, { "id" : 1452414803, @@ -137912,14 +139315,14 @@ "id" : "PA165816543", "symbol" : "CYP2C9*2", "name" : "*2", - "version" : 23 + "version" : 52 }, { "objCls" : "Haplotype", "id" : "PA165816544", "symbol" : "CYP2C9*3", "name" : "*3", - "version" : 25 + "version" : 55 } ], "relatedChemicals" : [ @@ -137927,7 +139330,7 @@ "objCls" : "Chemical", "id" : "PA451906", "name" : "warfarin", - "version" : 17 + "version" : 70 } ], "relatedGenes" : [ @@ -137936,7 +139339,7 @@ "id" : "PA126", "symbol" : "CYP2C9", "name" : "cytochrome P450 family 2 subfamily C member 9", - "version" : 7877 + "version" : 7952 } ], "source" : "DPWG", @@ -137949,12 +139352,54 @@ "textMarkdown" : { "id" : 1450415239, "html" : "

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

\n

May 2021 update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has made some minor changes to the names of some phenotype groups in this guideline. The table below has been updated to reflect this but the recommendations themselves have not changed.

\n

November 2018 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for warfarin based on CYP2C9 genotype/phenotype. They recommend reducing warfarin dose for CYP2C9 poor and intermediate metabolizers (PM and IM) and patients with CYP2C9*1/*3, *2/*3, *2/*2 or *3/*3 genotype. The genotype-specific initial dose and maintenance dose can be calculated using an algorithm, as used in EU-PACT.

\n

Download the warfarin loading doses algorithm used in EU-PACT provided by DPWG this is an excel file retrieved from DPWG on 3/19/2024.\nDownload the warfarin day 4-5 algorithm used in EU-PACT provided by DPWG this is an excel file retrieved from DPWG on 3/20/2024.

\n

Wording in table taken from the Dutch guidelines November 2018 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
CYP2C9 IM otherawarfarinThis gene variation reduces the conversion of warfarin to inactive metabolites. This can increase the risk of bleeding.1. use 65% of the standard initial dose. The genotype-specific initial dose and maintenance dose can be calculated using an algorithm. Algorithms for Caucasian patients usually contain only the *2 and *3 allele. If the activity of the reduced-activity alleles is comparable to the activity of *2 or *3, then the algorithm can be completed as if *1/*2 or *1/*3 is present. See Excel files containing calculation modules for oral and equivalent intravenous doses. From day 6 on the standard algorithm without genotype information can be used to calculate the dose. Modified dose algorithms have been developed for patients of African or (East) Asian heritage.
CYP2C9 PM otherawarfarinThis gene variation reduces the conversion of warfarin to inactive metabolites. This can increase the risk of bleeding.1. use 20% of the standard initial dose. The genotype-specific initial dose and maintenance dose can be calculated using an algorithm. Algorithms for Caucasian patients usually contain only the *2 and *3 allele. If the activity of the reduced-activity alleles is comparable to the activity of *2 or *3, then the algorithm can be completed as if *2 or *3 is present. See Excel files containing calculation modules for oral and equivalent intravenous doses. From day 6 on the standard algorithm without genotype information can be used to calculate the dose. Modified dose algorithms have been developed for patients of African or (East) Asian heritage.
CYP2C9*1/*2warfarinGenetic variation may lead to a decrease in the required maintenance dose. However, there is insufficient evidence that this causes problems when therapy is initiated as usual.NO action is required for this gene-drug interaction.
CYP2C9*1/*3warfarinThis gene variation reduces the conversion of warfarin to inactive metabolites. This can increase the risk of bleeding.1. use 65% of the standard initial dose. The genotype-specific initial dose and maintenance dose can be calculated using an algorithm, as used in EU-PACT. From day 6 on the standard algorithm without genotype information can be used to calculate the dose.
CYP2C9*2/*2warfarinThis gene variation reduces the conversion of warfarin to inactive metabolites. This can increase the risk of bleeding.1. use 65% of the standard initial dose. The genotype-specific initial dose and maintenance dose can be calculated using an algorithm, as used in EU-PACT. From day 6 on the standard algorithm without genotype information can be used to calculate the dose.
CYP2C9*2/*3warfarinThis gene variation reduces the conversion of warfarin to inactive metabolites. This can increase the risk of bleeding.1. use 45% of the standard initial dose. The genotype-specific initial dose and maintenance dose can be calculated using an algorithm, as used in EU-PACT. From day 6 on the standard algorithm without genotype information can be used to calculate the dose.
CYP2C9*3/*3warfarinThis gene variation reduces the conversion of warfarin to inactive metabolites. This can increase the risk of bleeding.1. use 20% of the standard initial dose. The genotype-specific initial dose and maintenance dose can be calculated using an algorithm, as used in EU-PACT. From day 6 on the standard algorithm without genotype information can be used to calculate the dose.
\n

a These groups are referred to in the DPWG recommendation PDF as 'IM ANDERS' and 'PM ANDERS', which use the Dutch word 'anders'. PharmGKB has translated these as 'IM other' and PM other', respectively.

\n

Read for more information about this recommendation, Read about gene information from DPWG

\n", - "version" : 6 + "version" : 11 }, "userId" : "lgong", - "version" : 11 + "version" : 57 }, "recommendations" : [ + { + "objCls" : "Recommendation Annotation", + "id" : "PA166299068", + "name" : "Recommendation PA166299068", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501929, + "description" : "Not Applicable", + "parents" : [], + "resource" : "Guideline Strength", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", + "valid" : true, + "version" : 1 + }, + "dosingInformation" : false, + "implications" : [ + "Genetic variation may lead to a decrease in the required maintenance dose. However, there is insufficient evidence that this causes problems when therapy is initiated as usual." + ], + "lookupKey" : {"CYP2C9": {"*1": 1, "*2": 1}}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA451906", + "name" : "warfarin", + "version" : 70 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166182842", + "name" : "Annotation of DPWG Guideline for warfarin and CYP2C9", + "version" : 57 + }, + "text" : { + "id" : 1452061431, + "html" : "

NO action is required for this gene-drug interaction.

\n", + "version" : 0 + }, + "version" : 1 + }, { "objCls" : "Recommendation Annotation", "id" : "PA166299075", @@ -137980,21 +139425,21 @@ "objCls" : "Chemical", "id" : "PA451906", "name" : "warfarin", - "version" : 17 + "version" : 70 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182842", "name" : "Annotation of DPWG Guideline for warfarin and CYP2C9", - "version" : 11 + "version" : 57 }, "text" : { "id" : 1452061438, "html" : "

The guideline does not provide a recommendation for warfarin in normal metabolizers.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -138022,26 +139467,26 @@ "objCls" : "Chemical", "id" : "PA451906", "name" : "warfarin", - "version" : 17 + "version" : 70 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182842", "name" : "Annotation of DPWG Guideline for warfarin and CYP2C9", - "version" : 11 + "version" : 57 }, "text" : { "id" : 1452061434, - "html" : "
    \n
  1. use 65% of the standard initial dose. The genotype-specific initial dose and maintenance dose can be calculated using an algorithm, as used in EU-PACT: see Algorithms coumarins. From day 6 on the standard algorithm without genotype information can be used to calculate the dose.
    2. \n
\n", - "version" : 0 + "html" : "
    \n
  1. use 65% of the standard initial dose. The genotype-specific initial dose and maintenance dose can be calculated using an algorithm, as used in EU-PACT. From day 6 on the standard algorithm without genotype information can be used to calculate the dose.
    2. \n
\n", + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299074", - "name" : "Recommendation PA166299074", + "id" : "PA166299072", + "name" : "Recommendation PA166299072", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -138057,28 +139502,28 @@ "implications" : [ "This gene variation reduces the conversion of warfarin to inactive metabolites. This can increase the risk of bleeding." ], - "lookupKey" : {"CYP2C9": "Poor Metabolizer"}, + "lookupKey" : {"CYP2C9": {"*2": 1, "*3": 1}}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451906", "name" : "warfarin", - "version" : 17 + "version" : 70 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182842", "name" : "Annotation of DPWG Guideline for warfarin and CYP2C9", - "version" : 11 + "version" : 57 }, "text" : { - "id" : 1452061437, - "html" : "
    \n
  1. use 20% of the standard initial dose. The genotype-specific initial dose and maintenance dose can be calculated using an algorithm. Algorithms for Caucasian patients usually contain only the *2 and *3 allele. If the activity of the reduced-activity alleles is comparable to the activity of *2 or *3, then the algorithm can be completed as if *2 or *3 is present. See Algorithms coumarins for Excel files containing calculation modules for oral and equivalent intravenous doses. From day 6 on the standard algorithm without genotype information can be used to calculate the dose. Modified dose algorithms have been developed for patients of African or (East) Asian heritage.
    2. \n
\n", - "version" : 0 + "id" : 1452061435, + "html" : "
    \n
  1. use 45% of the standard initial dose. The genotype-specific initial dose and maintenance dose can be calculated using an algorithm, as used in EU-PACT. From day 6 on the standard algorithm without genotype information can be used to calculate the dose.
    2. \n
\n", + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", @@ -138106,26 +139551,26 @@ "objCls" : "Chemical", "id" : "PA451906", "name" : "warfarin", - "version" : 17 + "version" : 70 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182842", "name" : "Annotation of DPWG Guideline for warfarin and CYP2C9", - "version" : 11 + "version" : 57 }, "text" : { "id" : 1452061433, - "html" : "
    \n
  1. use 65% of the standard initial dose. The genotype-specific initial dose and maintenance dose can be calculated using an algorithm, as used in EU-PACT: see Algorithms coumarins. From day 6 on the standard algorithm without genotype information can be used to calculate the dose.
    2. \n
\n", - "version" : 0 + "html" : "
    \n
  1. use 65% of the standard initial dose. The genotype-specific initial dose and maintenance dose can be calculated using an algorithm, as used in EU-PACT. From day 6 on the standard algorithm without genotype information can be used to calculate the dose.
    2. \n
\n", + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299073", - "name" : "Recommendation PA166299073", + "id" : "PA166299074", + "name" : "Recommendation PA166299074", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -138141,28 +139586,28 @@ "implications" : [ "This gene variation reduces the conversion of warfarin to inactive metabolites. This can increase the risk of bleeding." ], - "lookupKey" : {"CYP2C9": {"*3": 2}}, + "lookupKey" : {"CYP2C9": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451906", "name" : "warfarin", - "version" : 17 + "version" : 70 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182842", "name" : "Annotation of DPWG Guideline for warfarin and CYP2C9", - "version" : 11 + "version" : 57 }, "text" : { - "id" : 1452061436, - "html" : "
    \n
  1. use 20% of the standard initial dose. The genotype-specific initial dose and maintenance dose can be calculated using an algorithm, as used in EU-PACT: see Algorithms coumarins. From day 6 on the standard algorithm without genotype information can be used to calculate the dose.
    2. \n
\n", - "version" : 0 + "id" : 1452061437, + "html" : "
    \n
  1. use 20% of the standard initial dose. The genotype-specific initial dose and maintenance dose can be calculated using an algorithm. Algorithms for Caucasian patients usually contain only the *2 and *3 allele. If the activity of the reduced-activity alleles is comparable to the activity of *2 or *3, then the algorithm can be completed as if *2 or *3 is present. See annotation for Excel files containing calculation modules for oral and equivalent intravenous doses. From day 6 on the standard algorithm without genotype information can be used to calculate the dose. Modified dose algorithms have been developed for patients of African or (East) Asian heritage.
    2. \n
\n", + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", @@ -138190,26 +139635,26 @@ "objCls" : "Chemical", "id" : "PA451906", "name" : "warfarin", - "version" : 17 + "version" : 70 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182842", "name" : "Annotation of DPWG Guideline for warfarin and CYP2C9", - "version" : 11 + "version" : 57 }, "text" : { "id" : 1452061432, - "html" : "
    \n
  1. use 65% of the standard initial dose. The genotype-specific initial dose and maintenance dose can be calculated using an algorithm. Algorithms for Caucasian patients usually contain only the *2 and *3 allele. If the activity of the reduced-activity alleles is comparable to the activity of *2 or *3, then the algorithm can be completed as if *1/*2 or *1/*3 is present. See Algorithms coumarins for Excel files containing calculation modules for oral and equivalent intravenous doses. From day 6 on the standard algorithm without genotype information can be used to calculate the dose. Modified dose algorithms have been developed for patients of African or (East) Asian heritage.
    2. \n
\n", - "version" : 0 + "html" : "
    \n
  1. use 65% of the standard initial dose. The genotype-specific initial dose and maintenance dose can be calculated using an algorithm. Algorithms for Caucasian patients usually contain only the *2 and *3 allele. If the activity of the reduced-activity alleles is comparable to the activity of *2 or *3, then the algorithm can be completed as if *1/*2 or *1/*3 is present. See annotation for Excel files containing calculation modules for oral and equivalent intravenous doses. From day 6 on the standard algorithm without genotype information can be used to calculate the dose. Modified dose algorithms have been developed for patients of African or (East) Asian heritage.
    2. \n
\n", + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299072", - "name" : "Recommendation PA166299072", + "id" : "PA166299073", + "name" : "Recommendation PA166299073", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -138225,70 +139670,28 @@ "implications" : [ "This gene variation reduces the conversion of warfarin to inactive metabolites. This can increase the risk of bleeding." ], - "lookupKey" : {"CYP2C9": {"*2": 1, "*3": 1}}, + "lookupKey" : {"CYP2C9": {"*3": 2}}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451906", "name" : "warfarin", - "version" : 17 + "version" : 70 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182842", "name" : "Annotation of DPWG Guideline for warfarin and CYP2C9", - "version" : 11 + "version" : 57 }, "text" : { - "id" : 1452061435, - "html" : "
    \n
  1. use 45% of the standard initial dose. The genotype-specific initial dose and maintenance dose can be calculated using an algorithm, as used in EU-PACT: see Algorithms coumarins. From day 6 on the standard algorithm without genotype information can be used to calculate the dose.
    2. \n
\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166299068", - "name" : "Recommendation PA166299068", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 981501929, - "description" : "Not Applicable", - "parents" : [], - "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", - "valid" : true, + "id" : 1452061436, + "html" : "
    \n
  1. use 20% of the standard initial dose. The genotype-specific initial dose and maintenance dose can be calculated using an algorithm, as used in EU-PACT. From day 6 on the standard algorithm without genotype information can be used to calculate the dose.
    2. \n
\n", "version" : 1 }, - "dosingInformation" : false, - "implications" : [ - "Genetic variation may lead to a decrease in the required maintenance dose. However, there is insufficient evidence that this causes problems when therapy is initiated as usual." - ], - "lookupKey" : {"CYP2C9": {"*1": 1, "*2": 1}}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA451906", - "name" : "warfarin", - "version" : 17 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166182842", - "name" : "Annotation of DPWG Guideline for warfarin and CYP2C9", - "version" : 11 - }, - "text" : { - "id" : 1452061431, - "html" : "

NO action is required for this gene-drug interaction.

\n", - "version" : 0 - }, - "version" : 1 + "version" : 2 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166182842" @@ -138310,7 +139713,7 @@ "date" : "2019-05-27T00:00:00-07:00", "description" : "Annotation current with November 2018 DPWG Guideline release", "type" : "Update", - "version" : 0 + "version" : 1 }, { "id" : 1450820675, @@ -138389,7 +139792,7 @@ "id" : "PA166155091", "symbol" : "rs9923231", "name" : "rs9923231", - "version" : 5 + "version" : 10 } ], "relatedChemicals" : [ @@ -138397,7 +139800,7 @@ "objCls" : "Chemical", "id" : "PA451906", "name" : "warfarin", - "version" : 17 + "version" : 70 } ], "relatedGenes" : [ @@ -138406,7 +139809,7 @@ "id" : "PA133787052", "symbol" : "VKORC1", "name" : "vitamin K epoxide reductase complex subunit 1", - "version" : 16 + "version" : 52 } ], "source" : "DPWG", @@ -138419,10 +139822,10 @@ "textMarkdown" : { "id" : 1450415235, "html" : "

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

\n

November 2018 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group (DPWG) has evaluated therapeutic dose recommendations for warfarin based on VKORC1 genotype. They recommend that patients with the VKORC1 rs9923231 TT genotype (-1639 AA genotype) receive 60% of the standard initial dose.The genotype-specific initial dose and maintenance dose can be calculated using an algorithm. No action is needed for patients with the VKORC1 rs9923231 CT genotype (-1639 AG genotype).

\n

Download the warfarin loading doses algorithm used in EU-PACT provided by DPWG this is an excel file retrieved from DPWG on 3/19/2024.\nDownload the warfarin day 4-5 algorithm used in EU-PACT provided by DPWG this is an excel file retrieved from DPWG on 3/20/2024.

\n

Wording in table taken from the Dutch guidelines November 2018 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
VKORC1 -1639 AAwarfarinThe genetic variation results in increased sensitivity to warfarin. This results in an increase in the risk of excessively severe inhibition of blood clotting (INR > 4) during the first month of the treatment.1. use 60% of the standard initial dose. The genotype-specific initial dose and maintenance dose can be calculated using an algorithm, as used in EU-PACT. From day 6 on the standard algorithm without genotype information can be used to calculate the dose.
VKORC1 -1639 AGwarfarinThe genetic variation results in a reduction in the required dose and an increase in the risk of excessively severe inhibition of blood clotting during the first month of the treatment. However, the effect is small and GA is also the most common genotype, meaning that the standard treatment will primarily be based on patients with this genotype.NO action is needed for this gene-drug interaction
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n", - "version" : 6 + "version" : 9 }, "userId" : "lgong", - "version" : 13 + "version" : 42 }, "recommendations" : [ { @@ -138451,14 +139854,14 @@ "objCls" : "Chemical", "id" : "PA451906", "name" : "warfarin", - "version" : 17 + "version" : 70 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182841", "name" : "Annotation of DPWG Guideline for warfarin and VKORC1", - "version" : 13 + "version" : 42 }, "text" : { "id" : 1452061439, @@ -138469,86 +139872,86 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299078", - "name" : "Recommendation PA166299078", + "id" : "PA166299077", + "name" : "Recommendation PA166299077", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "The genetic variation results in increased sensitivity to warfarin. This results in an increase in the risk of excessively severe inhibition of blood clotting (INR > 4) during the\nfirst month of the treatment." + "The guideline does not provide a description of the impact of the VKORC1 rs9923231 CC genotype (-1639 GG genotype) on warfarin." ], - "lookupKey" : {"VKORC1": "-1639 AA"}, + "lookupKey" : {"VKORC1": "-1639 GG"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451906", "name" : "warfarin", - "version" : 17 + "version" : 70 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182841", "name" : "Annotation of DPWG Guideline for warfarin and VKORC1", - "version" : 13 + "version" : 42 }, "text" : { - "id" : 1452061441, - "html" : "

Use 60% of the standard initial dose.

\n

The genotype-specific initial dose and maintenance dose can be calculated using an algorithm, as used in EU-PACT: see\nhttps://www.knmp.nl/patientenzorg/medicatiebewaking/farmacogenetica.

\n

From day 6 on the standard algorithm without genotype information can be used to calculate the dose.

\n", + "id" : 1452061440, + "html" : "

The guideline does not provide a recommendation for warfarin in patients with the VKORC1 rs9923231 CC genotype (-1639 GG genotype).

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166299077", - "name" : "Recommendation PA166299077", + "id" : "PA166299078", + "name" : "Recommendation PA166299078", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, - "version" : 0 + "version" : 1 }, - "dosingInformation" : false, + "dosingInformation" : true, "implications" : [ - "The guideline does not provide a description of the impact of the VKORC1 rs9923231 CC genotype (-1639 GG genotype) on warfarin." + "The genetic variation results in increased sensitivity to warfarin. This results in an increase in the risk of excessively severe inhibition of blood clotting (INR > 4) during the\nfirst month of the treatment." ], - "lookupKey" : {"VKORC1": "-1639 GG"}, + "lookupKey" : {"VKORC1": "-1639 AA"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451906", "name" : "warfarin", - "version" : 17 + "version" : 70 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166182841", "name" : "Annotation of DPWG Guideline for warfarin and VKORC1", - "version" : 13 + "version" : 42 }, "text" : { - "id" : 1452061440, - "html" : "

The guideline does not provide a recommendation for warfarin in patients with the VKORC1 rs9923231 CC genotype (-1639 GG genotype).

\n", - "version" : 0 + "id" : 1452061441, + "html" : "

Use 60% of the standard initial dose.

\n

The genotype-specific initial dose and maintenance dose can be calculated using an algorithm, as used in EU-PACT.

\n

From day 6 on the standard algorithm without genotype information can be used to calculate the dose.

\n", + "version" : 1 }, - "version" : 0 + "version" : 2 } ], "url" : "https://www.pharmgkb.org/guidelineAnnotation/PA166182841" @@ -138843,7 +140246,7 @@ "objCls" : "Chemical", "id" : "PA452629", "name" : "zuclopenthixol", - "version" : 6 + "version" : 20 } ], "relatedGenes" : [ @@ -138852,70 +140255,29 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "DPWG", "summaryMarkdown" : { "id" : 1447982014, "html" : "

For CYP2D6 poor and intermediate metabolizers, reduce zuclopenthixol dose. For ultrarapid metabolizers, if the effectiveness is insufficient a dose increase not exceeding 1.5x normal dose is suggested.

\n", - "version" : 2 + "version" : 3 }, "terms" : [], "textMarkdown" : { "id" : 1447982013, "html" : "

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

\n

Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction between CYP2D6, CYP3A4 and CYP1A2 and antipsychotics. European journal of human genetics (2023)

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group published a paper with the guidelines for zuclopenthixol and CYP2D6 as per the February 2022 guidelines and further details on the assessed literature [Article:37002327]. Wording in the poor, intermediate, and ultrarapid metabolizer recommendation changed from "standard" to "normal" and is reflected in the table below.

\n

February 2022 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has updated their therapeutic dose recommendations for zuclopenthixol based on CYP2D6 genotype. An alternate drug is no longer recommended for ultrarapid metabolizer (UM) patients and the guideline notes the relative lack of evidence available to guide dose changes for UM patients.

\n

Wording in table taken from the Dutch guidelines February 2022 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
CYP2D6 UMzuclopenthixolThe risk of ineffectiveness may be elevated. The genetic variation leads to an increased conversion of zuclopentixol, which can result in a reduction of the plasma concentrationThere is insufficient information available to make a dosage recommendation. - if the effectiveness is insufficient: try a dose increase. Do not exceed 1.5 times the normal dose.
CYP2D6 IMzuclopenthixolThe risk of side effects may be elevated. The genetic variation leads to decreased conversion of zuclopentixol, which causes the plasma concentration to be approximately 1.35-fold higher.Use 75% of the normal dose.
CYP2D6 PMzuclopenthixolThe risk of side effects may be elevated. The genetic variation results in a decreased conversion of zuclopentixol, which causes the plasma concentration to be approximately 1.6-fold higher.Use with 50% of the normal dose.
\n

Read for more information about this recommendation, Read about gene information from DPWG

\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for zuclopenthixol and CYP2D6:

\n
\n

The KNMP Pharmacogenetics Working Group considers genotyping before starting zuclopenthixol to be potentially beneficial for the prevention of side effects and for effectiveness. Genotyping can be considered on an individual patient basis. If, however, the genotype is available, the KNMP Pharmacogenetics Working Group recommends adhering to the gene-drug guideline.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n

May 2021 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has updated their therapeutic dose recommendations for zuclopenthixol based on CYP2D6 genotype. They now recommend a dose reduction for patients who are CYP2D6 intermediate metabolizers (IMs) or poor metabolizers (PMs). They also recommend a dose increase or an alternative drug that is not metabolized by CYP2D6 for patients who are CYP2D6 ultrarapid metabolizers (UMs).

\n

Wording in table taken from the Dutch guidelines May 2021 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
CYP2D6 UMzuclopenthixolThe risk of ineffectiveness may be elevated. The genetic variation leads to an increased conversion of zuclopentixol, which causes the plasma concentration to be approximately 33% lower.Use 1.5 times the standard dose or choose an alternative.
Antipsychotics that are not metabolised by CYP2D6 - or to a lesser extent - include, for example, flupentixol, quetiapine, olanzapine and clozapine.
CYP2D6 IMzuclopenthixolThe risk of side effects may be elevated. The genetic variation leads to decreased conversion of zuclopentixol, which causes the plasma concentration to be approximately 1.35-fold higher.Use 75% of the standard dose.
CYP2D6 PMzuclopenthixolThe risk of side effects may be elevated. The genetic variation results in a decreased conversion of zuclopentixol, which causes the plasma concentration to be approximately 1.7-fold higher.Use with 50% of the standard dose.
\n

Preemptive genotyping

\n

Excerpts from the DPWG risk analysis document for zuclopenthixol and CYP2D6:

\n
\n

The KNMP Pharmacogenetics Working Group considers genotyping before starting zuclopenthixol to be potentially beneficial for the prevention of side effects and for effectiveness. Genotyping can be considered on an individual patient basis. If, however, the genotype is available, the KNMP Pharmacogenetics Working Group recommends adhering to the gene-drug guideline.

\n
\n

Read more about how DPWG assigns their recommendations for preemptive genotyping.

\n

November 2018 Update

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for zuclopenthixol based on CYP2D6 genotype. They recommend a dose reduction or an alternative drug that is not metabolized by CYP2D6 for patients who are CYP2D6 intermediate metabolizers (IMs) or poor metabolizers (PMs). They also recommend a dose increase or an alternative drug that is not metabolized by CYP2D6 for patients who are CYP2D6 ultrarapid metabolizers (UMs) who have low zuclopenthixol plasma concentrations.

\n

Wording in table taken from the Dutch guidelines November 2018 update.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
CYP2D6 UMzuclopenthixolThe genetic polymorphism leads to increased metabolic capacity of CYP2D6, which may cause decreased zuclopentixol plasma concentrations.No data have been published from studies into the pharmacokinetics and effects of zuclopentixol for this phenotype.
As a precaution, the prescriber should advised to be alert to a decreased zuclopentixol plasma concentration and - if necessary - the dose should be increased on the basis of the clinical effect, or an alternative should be prescribed according to the current guidelines. Antipsychotics that are not metabolised via CYP2D6 - or to a lesser extent - include, for example, flupentixol, quetiapine, olanzapine and clozapine.
CYP2D6 IMzuclopenthixolThe genetic polymorphism leads to decreased metabolic capacity of CYP2D6, which may cause increased zuclopentixol plasma concentrations.Advise the prescriber to start with 75% of the standard dose or to choose an alternative according to the current guidelines. Antipsychotics that are not metabolised via CYP2D6 - or to a lesser extent - include, for example, flupentixol, quetiapine, olanzapine and clozapine.
CYP2D6 PMzuclopenthixolThe genetic polymorphism leads to decreased metabolic capacity of CYP2D6, which may cause increased zuclopentixol plasma concentrations.Advise the prescriber to start with 50% of the standard dose or to choose an alternative according to the current guidelines. Antipsychotics that are not metabolised via CYP2D6 - or to a lesser extent - include, for example, flupentixol, quetiapine, olanzapine and clozapine.
\n

2011 Guideline

\n

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for zuclopenthixol based on CYP2D6 genotypes [Article:21412232]. For PM genotypes, they recommend reducing dose by 50% or selecting an alternative drug. For IM genotypes, they recommend reducing dose by 25% or selecting an alternative drug. For UM genotypes, they state that there are insufficient data to allow calculation of dose adjustment, and to be alert to low zuclopenthixol plasma concentrations or to select an alternative drug.

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Phenotype (Genotype)Therapeutic Dose RecommendationLevel of EvidenceClinical Relevance
PM (two inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) alleles)Reduce dose by 50% or select alternative drug (e.g., flupenthixol, quetiapine, olanzapine, clozapine).Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Minor clinical effect (S): QTc prolongation (<450 ms , <470 ms ); INR increase < 4.5. Kinetic effect (S).
IM (two decreased-activity (*9, *10, *17, *29, *36, *41) alleles or carrying one active (*1, *2, *33, *35) and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele, or carrying one decreased-activity (*9, *10, *17, *29, *36, *41) allele and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele)Reduce dose by 25% or select alternative drug (flupenthixol, quetiapine, olanzapine, clozapine).Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Minor clinical effect (S): QTc prolongation (<450 ms female, <470 ms male); INR increase < 4.5. Kinetic effect (S).
UM (a gene duplication in absence of inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) or decreased-activity (*9, *10, *17, *29, *36, *41) alleles)Insufficient data to allow calculation of dose adjustment. Be alert to low zuclopenthixol plasma concentrations or select alternative drug (flupenthixol, quetiapine, olanzapine, clozapine).not given.not given.
\n\n", - "version" : 18 + "version" : 26 }, "userId" : "lester", - "version" : 36 + "version" : 130 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166302908", - "name" : "Recommendation Annotation PA166302908", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 1448526251, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on zuclopenthixol." - ], - "lookupKey" : {"CYP2D6": "2.0"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA452629", - "name" : "zuclopenthixol", - "version" : 6 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166104992", - "name" : "Annotation of DPWG Guideline for zuclopenthixol and CYP2D6", - "version" : 36 - }, - "text" : { - "id" : 1452104507, - "html" : "

The guideline does not provide a recommendation for zuclopenthixol in normal metabolizers.

\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166302917", - "name" : "Recommendation Annotation PA166302917", + "id" : "PA166302901", + "name" : "Recommendation Annotation PA166302901", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -138929,35 +140291,35 @@ }, "dosingInformation" : true, "implications" : [ - "The risk of ineffectiveness may be elevated. genetic variation leads to an increased conversion of zuclopentixol, which can result in a reduction of the plasma concentration." + "The risk of side effects may be elevated. The genetic variation results in a decreased conversion of zuclopentixol, which causes the plasma concentration to be approximately 1.6-fold higher." ], - "lookupKey" : {"CYP2D6": "≥5.0"}, + "lookupKey" : {"CYP2D6": "0.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA452629", "name" : "zuclopenthixol", - "version" : 6 + "version" : 20 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104992", "name" : "Annotation of DPWG Guideline for zuclopenthixol and CYP2D6", - "version" : 36 + "version" : 130 }, "text" : { - "id" : 1452104516, - "html" : "

There is insufficient information available to make a dosage recommendation.

\n\n", + "id" : 1452104500, + "html" : "

Use 50% of the normal dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302904", - "name" : "Recommendation Annotation PA166302904", + "id" : "PA166302902", + "name" : "Recommendation Annotation PA166302902", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -138973,24 +140335,24 @@ "implications" : [ "The risk of side effects may be elevated. The genetic variation leads to decreased conversion of zuclopentixol, which causes the plasma concentration to be approximately 1.35-fold higher." ], - "lookupKey" : {"CYP2D6": "0.75"}, + "lookupKey" : {"CYP2D6": "0.25"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA452629", "name" : "zuclopenthixol", - "version" : 6 + "version" : 20 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104992", "name" : "Annotation of DPWG Guideline for zuclopenthixol and CYP2D6", - "version" : 36 + "version" : 130 }, "text" : { - "id" : 1452104503, + "id" : 1452104501, "html" : "

Use 75% of the normal dose.

\n", "version" : 0 }, @@ -138998,8 +140360,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302913", - "name" : "Recommendation Annotation PA166302913", + "id" : "PA166302903", + "name" : "Recommendation Annotation PA166302903", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -139013,76 +140375,35 @@ }, "dosingInformation" : true, "implications" : [ - "The risk of ineffectiveness may be elevated. genetic variation leads to an increased conversion of zuclopentixol, which can result in a reduction of the plasma concentration." - ], - "lookupKey" : {"CYP2D6": "≥3.0"}, - "otherPrescribingGuidance" : false, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA452629", - "name" : "zuclopenthixol", - "version" : 6 - } - ], - "source" : { - "objCls" : "Guideline Annotation", - "id" : "PA166104992", - "name" : "Annotation of DPWG Guideline for zuclopenthixol and CYP2D6", - "version" : 36 - }, - "text" : { - "id" : 1452104512, - "html" : "

There is insufficient information available to make a dosage recommendation.

\n\n", - "version" : 0 - }, - "version" : 0 - }, - { - "objCls" : "Recommendation Annotation", - "id" : "PA166302909", - "name" : "Recommendation Annotation PA166302909", - "alternateDrugAvailable" : false, - "classification" : { - "id" : 1448526251, - "parents" : [], - "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", - "valid" : true, - "version" : 0 - }, - "dosingInformation" : false, - "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on zuclopenthixol." + "The risk of side effects may be elevated. The genetic variation leads to decreased conversion of zuclopentixol, which causes the plasma concentration to be approximately 1.35-fold higher." ], - "lookupKey" : {"CYP2D6": "2.25"}, + "lookupKey" : {"CYP2D6": "0.5"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA452629", "name" : "zuclopenthixol", - "version" : 6 + "version" : 20 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104992", "name" : "Annotation of DPWG Guideline for zuclopenthixol and CYP2D6", - "version" : 36 + "version" : 130 }, "text" : { - "id" : 1452104508, - "html" : "

The guideline does not provide a recommendation for zuclopenthixol in normal metabolizers.

\n", + "id" : 1452104502, + "html" : "

Use 75% of the normal dose.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302918", - "name" : "Recommendation Annotation PA166302918", + "id" : "PA166302904", + "name" : "Recommendation Annotation PA166302904", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -139096,27 +140417,27 @@ }, "dosingInformation" : true, "implications" : [ - "The risk of ineffectiveness may be elevated. genetic variation leads to an increased conversion of zuclopentixol, which can result in a reduction of the plasma concentration." + "The risk of side effects may be elevated. The genetic variation leads to decreased conversion of zuclopentixol, which causes the plasma concentration to be approximately 1.35-fold higher." ], - "lookupKey" : {"CYP2D6": "≥6.0"}, + "lookupKey" : {"CYP2D6": "0.75"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA452629", "name" : "zuclopenthixol", - "version" : 6 + "version" : 20 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104992", "name" : "Annotation of DPWG Guideline for zuclopenthixol and CYP2D6", - "version" : 36 + "version" : 130 }, "text" : { - "id" : 1452104517, - "html" : "

There is insufficient information available to make a dosage recommendation.

\n\n", + "id" : 1452104503, + "html" : "

Use 75% of the normal dose.

\n", "version" : 0 }, "version" : 0 @@ -139147,14 +140468,14 @@ "objCls" : "Chemical", "id" : "PA452629", "name" : "zuclopenthixol", - "version" : 6 + "version" : 20 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104992", "name" : "Annotation of DPWG Guideline for zuclopenthixol and CYP2D6", - "version" : 36 + "version" : 130 }, "text" : { "id" : 1452104504, @@ -139165,92 +140486,90 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302914", - "name" : "Recommendation Annotation PA166302914", + "id" : "PA166302906", + "name" : "Recommendation Annotation PA166302906", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "The risk of ineffectiveness may be elevated. genetic variation leads to an increased conversion of zuclopentixol, which can result in a reduction of the plasma concentration." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on zuclopenthixol." ], - "lookupKey" : {"CYP2D6": "≥3.25"}, + "lookupKey" : {"CYP2D6": "1.25"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA452629", "name" : "zuclopenthixol", - "version" : 6 + "version" : 20 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104992", "name" : "Annotation of DPWG Guideline for zuclopenthixol and CYP2D6", - "version" : 36 + "version" : 130 }, "text" : { - "id" : 1452104513, - "html" : "

There is insufficient information available to make a dosage recommendation.

\n\n", + "id" : 1452104505, + "html" : "

The guideline does not provide a recommendation for zuclopenthixol in normal metabolizers.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302901", - "name" : "Recommendation Annotation PA166302901", + "id" : "PA166302907", + "name" : "Recommendation Annotation PA166302907", "alternateDrugAvailable" : false, "classification" : { - "id" : 981501929, - "description" : "Not Applicable", + "id" : 1448526251, "parents" : [], "resource" : "Guideline Strength", - "term" : "N/A", - "termId" : "guidelineStrength:981501929", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", "valid" : true, - "version" : 1 + "version" : 0 }, - "dosingInformation" : true, + "dosingInformation" : false, "implications" : [ - "The risk of side effects may be elevated. The genetic variation results in a decreased conversion of zuclopentixol, which causes the plasma concentration to be approximately 1.6-fold higher." + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on zuclopenthixol." ], - "lookupKey" : {"CYP2D6": "0.0"}, + "lookupKey" : {"CYP2D6": "1.5"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA452629", "name" : "zuclopenthixol", - "version" : 6 + "version" : 20 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104992", "name" : "Annotation of DPWG Guideline for zuclopenthixol and CYP2D6", - "version" : 36 + "version" : 130 }, "text" : { - "id" : 1452104500, - "html" : "

Use 50% of the normal dose.

\n", + "id" : 1452104506, + "html" : "

The guideline does not provide a recommendation for zuclopenthixol in normal metabolizers.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302910", - "name" : "Recommendation Annotation PA166302910", + "id" : "PA166302908", + "name" : "Recommendation Annotation PA166302908", "alternateDrugAvailable" : false, "classification" : { "id" : 1448526251, @@ -139265,24 +140584,24 @@ "implications" : [ "The guideline does not provide a description of the impact of a normal metabolizer phenotype on zuclopenthixol." ], - "lookupKey" : {"CYP2D6": "2.5"}, + "lookupKey" : {"CYP2D6": "2.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA452629", "name" : "zuclopenthixol", - "version" : 6 + "version" : 20 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104992", "name" : "Annotation of DPWG Guideline for zuclopenthixol and CYP2D6", - "version" : 36 + "version" : 130 }, "text" : { - "id" : 1452104509, + "id" : 1452104507, "html" : "

The guideline does not provide a recommendation for zuclopenthixol in normal metabolizers.

\n", "version" : 0 }, @@ -139290,8 +140609,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302906", - "name" : "Recommendation Annotation PA166302906", + "id" : "PA166302909", + "name" : "Recommendation Annotation PA166302909", "alternateDrugAvailable" : false, "classification" : { "id" : 1448526251, @@ -139306,24 +140625,24 @@ "implications" : [ "The guideline does not provide a description of the impact of a normal metabolizer phenotype on zuclopenthixol." ], - "lookupKey" : {"CYP2D6": "1.25"}, + "lookupKey" : {"CYP2D6": "2.25"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA452629", "name" : "zuclopenthixol", - "version" : 6 + "version" : 20 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104992", "name" : "Annotation of DPWG Guideline for zuclopenthixol and CYP2D6", - "version" : 36 + "version" : 130 }, "text" : { - "id" : 1452104505, + "id" : 1452104508, "html" : "

The guideline does not provide a recommendation for zuclopenthixol in normal metabolizers.

\n", "version" : 0 }, @@ -139331,8 +140650,49 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302915", - "name" : "Recommendation Annotation PA166302915", + "id" : "PA166302910", + "name" : "Recommendation Annotation PA166302910", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 1448526251, + "parents" : [], + "resource" : "Guideline Strength", + "term" : "No recommendation", + "termId" : "guidelineStrength:1448526251", + "valid" : true, + "version" : 0 + }, + "dosingInformation" : false, + "implications" : [ + "The guideline does not provide a description of the impact of a normal metabolizer phenotype on zuclopenthixol." + ], + "lookupKey" : {"CYP2D6": "2.5"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA452629", + "name" : "zuclopenthixol", + "version" : 20 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104992", + "name" : "Annotation of DPWG Guideline for zuclopenthixol and CYP2D6", + "version" : 130 + }, + "text" : { + "id" : 1452104509, + "html" : "

The guideline does not provide a recommendation for zuclopenthixol in normal metabolizers.

\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166302911", + "name" : "Recommendation Annotation PA166302911", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -139348,24 +140708,24 @@ "implications" : [ "The risk of ineffectiveness may be elevated. genetic variation leads to an increased conversion of zuclopentixol, which can result in a reduction of the plasma concentration." ], - "lookupKey" : {"CYP2D6": "≥3.5"}, + "lookupKey" : {"CYP2D6": "3.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA452629", "name" : "zuclopenthixol", - "version" : 6 + "version" : 20 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104992", "name" : "Annotation of DPWG Guideline for zuclopenthixol and CYP2D6", - "version" : 36 + "version" : 130 }, "text" : { - "id" : 1452104514, + "id" : 1452104510, "html" : "

There is insufficient information available to make a dosage recommendation.

\n\n", "version" : 0 }, @@ -139373,8 +140733,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302902", - "name" : "Recommendation Annotation PA166302902", + "id" : "PA166302912", + "name" : "Recommendation Annotation PA166302912", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -139388,35 +140748,35 @@ }, "dosingInformation" : true, "implications" : [ - "The risk of side effects may be elevated. The genetic variation leads to decreased conversion of zuclopentixol, which causes the plasma concentration to be approximately 1.35-fold higher." + "The risk of ineffectiveness may be elevated. genetic variation leads to an increased conversion of zuclopentixol, which can result in a reduction of the plasma concentration." ], - "lookupKey" : {"CYP2D6": "0.25"}, + "lookupKey" : {"CYP2D6": "4.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA452629", "name" : "zuclopenthixol", - "version" : 6 + "version" : 20 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104992", "name" : "Annotation of DPWG Guideline for zuclopenthixol and CYP2D6", - "version" : 36 + "version" : 130 }, "text" : { - "id" : 1452104501, - "html" : "

Use 75% of the normal dose.

\n", + "id" : 1452104511, + "html" : "

There is insufficient information available to make a dosage recommendation.

\n\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302911", - "name" : "Recommendation Annotation PA166302911", + "id" : "PA166302913", + "name" : "Recommendation Annotation PA166302913", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -139432,24 +140792,24 @@ "implications" : [ "The risk of ineffectiveness may be elevated. genetic variation leads to an increased conversion of zuclopentixol, which can result in a reduction of the plasma concentration." ], - "lookupKey" : {"CYP2D6": "3.0"}, + "lookupKey" : {"CYP2D6": "≥3.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA452629", "name" : "zuclopenthixol", - "version" : 6 + "version" : 20 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104992", "name" : "Annotation of DPWG Guideline for zuclopenthixol and CYP2D6", - "version" : 36 + "version" : 130 }, "text" : { - "id" : 1452104510, + "id" : 1452104512, "html" : "

There is insufficient information available to make a dosage recommendation.

\n\n", "version" : 0 }, @@ -139457,41 +140817,84 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302907", - "name" : "Recommendation Annotation PA166302907", + "id" : "PA166302914", + "name" : "Recommendation Annotation PA166302914", "alternateDrugAvailable" : false, "classification" : { - "id" : 1448526251, + "id" : 981501929, + "description" : "Not Applicable", "parents" : [], "resource" : "Guideline Strength", - "term" : "No recommendation", - "termId" : "guidelineStrength:1448526251", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", "valid" : true, + "version" : 1 + }, + "dosingInformation" : true, + "implications" : [ + "The risk of ineffectiveness may be elevated. genetic variation leads to an increased conversion of zuclopentixol, which can result in a reduction of the plasma concentration." + ], + "lookupKey" : {"CYP2D6": "≥3.25"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA452629", + "name" : "zuclopenthixol", + "version" : 20 + } + ], + "source" : { + "objCls" : "Guideline Annotation", + "id" : "PA166104992", + "name" : "Annotation of DPWG Guideline for zuclopenthixol and CYP2D6", + "version" : 130 + }, + "text" : { + "id" : 1452104513, + "html" : "

There is insufficient information available to make a dosage recommendation.

\n\n", "version" : 0 }, - "dosingInformation" : false, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166302915", + "name" : "Recommendation Annotation PA166302915", + "alternateDrugAvailable" : false, + "classification" : { + "id" : 981501929, + "description" : "Not Applicable", + "parents" : [], + "resource" : "Guideline Strength", + "term" : "N/A", + "termId" : "guidelineStrength:981501929", + "valid" : true, + "version" : 1 + }, + "dosingInformation" : true, "implications" : [ - "The guideline does not provide a description of the impact of a normal metabolizer phenotype on zuclopenthixol." + "The risk of ineffectiveness may be elevated. genetic variation leads to an increased conversion of zuclopentixol, which can result in a reduction of the plasma concentration." ], - "lookupKey" : {"CYP2D6": "1.5"}, + "lookupKey" : {"CYP2D6": "≥3.5"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA452629", "name" : "zuclopenthixol", - "version" : 6 + "version" : 20 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104992", "name" : "Annotation of DPWG Guideline for zuclopenthixol and CYP2D6", - "version" : 36 + "version" : 130 }, "text" : { - "id" : 1452104506, - "html" : "

The guideline does not provide a recommendation for zuclopenthixol in normal metabolizers.

\n", + "id" : 1452104514, + "html" : "

There is insufficient information available to make a dosage recommendation.

\n\n", "version" : 0 }, "version" : 0 @@ -139522,14 +140925,14 @@ "objCls" : "Chemical", "id" : "PA452629", "name" : "zuclopenthixol", - "version" : 6 + "version" : 20 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104992", "name" : "Annotation of DPWG Guideline for zuclopenthixol and CYP2D6", - "version" : 36 + "version" : 130 }, "text" : { "id" : 1452104515, @@ -139540,8 +140943,8 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302903", - "name" : "Recommendation Annotation PA166302903", + "id" : "PA166302917", + "name" : "Recommendation Annotation PA166302917", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -139555,35 +140958,35 @@ }, "dosingInformation" : true, "implications" : [ - "The risk of side effects may be elevated. The genetic variation leads to decreased conversion of zuclopentixol, which causes the plasma concentration to be approximately 1.35-fold higher." + "The risk of ineffectiveness may be elevated. genetic variation leads to an increased conversion of zuclopentixol, which can result in a reduction of the plasma concentration." ], - "lookupKey" : {"CYP2D6": "0.5"}, + "lookupKey" : {"CYP2D6": "≥5.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA452629", "name" : "zuclopenthixol", - "version" : 6 + "version" : 20 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104992", "name" : "Annotation of DPWG Guideline for zuclopenthixol and CYP2D6", - "version" : 36 + "version" : 130 }, "text" : { - "id" : 1452104502, - "html" : "

Use 75% of the normal dose.

\n", + "id" : 1452104516, + "html" : "

There is insufficient information available to make a dosage recommendation.

\n\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166302912", - "name" : "Recommendation Annotation PA166302912", + "id" : "PA166302918", + "name" : "Recommendation Annotation PA166302918", "alternateDrugAvailable" : false, "classification" : { "id" : 981501929, @@ -139599,24 +141002,24 @@ "implications" : [ "The risk of ineffectiveness may be elevated. genetic variation leads to an increased conversion of zuclopentixol, which can result in a reduction of the plasma concentration." ], - "lookupKey" : {"CYP2D6": "4.0"}, + "lookupKey" : {"CYP2D6": "≥6.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA452629", "name" : "zuclopenthixol", - "version" : 6 + "version" : 20 } ], "source" : { "objCls" : "Guideline Annotation", "id" : "PA166104992", "name" : "Annotation of DPWG Guideline for zuclopenthixol and CYP2D6", - "version" : 36 + "version" : 130 }, "text" : { - "id" : 1452104511, + "id" : 1452104517, "html" : "

There is insufficient information available to make a dosage recommendation.

\n\n", "version" : 0 }, @@ -139654,7 +141057,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 3, + "version" : 4, "year" : -1 } ], @@ -139691,7 +141094,7 @@ "id" : "PA28469", "symbol" : "G6PD", "name" : "glucose-6-phosphate dehydrogenase", - "version" : 135 + "version" : 1326 } ], "prescribingMarkdown" : { @@ -139705,19 +141108,19 @@ "objCls" : "Chemical", "id" : "PA164712515", "name" : "Ascorbic acid (vitamin C), combinations", - "version" : 3 + "version" : 2 }, { "objCls" : "Chemical", "id" : "PA164712516", "name" : "Ascorbic acid (vitamin C), plain", - "version" : 3 + "version" : 2 }, { "objCls" : "Chemical", "id" : "PA166163262", "name" : "sodium ascorbate", - "version" : 4 + "version" : 3 } ], "relatedGenes" : [ @@ -139726,7 +141129,7 @@ "id" : "PA28469", "symbol" : "G6PD", "name" : "glucose-6-phosphate dehydrogenase", - "version" : 135 + "version" : 1326 } ], "source" : "FDA", @@ -139752,38 +141155,38 @@ "version" : 1 }, "userId" : "cfthorn", - "version" : 9 + "version" : 16 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166312385", - "name" : "Recommendation Annotation PA166312385", + "id" : "PA166315181", + "name" : "Recommendation Annotation PA166315181", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"G6PD": "Deficient"}, + "lookupKey" : {"G6PD": "Variable"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA164712516", "name" : "Ascorbic acid (vitamin C), plain", - "version" : 3 + "version" : 2 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166293282", "name" : "Annotation of FDA Label for Ascorbic acid (vitamin C), combinations, Ascorbic acid (vitamin C), plain, sodium ascorbate and G6PD", - "version" : 9 + "version" : 16 }, "text" : { - "id" : 1452216665, + "id" : 1452245820, "html" : "

"Patients with glucose-6-phosphate dehydrogenase deficiency may be at increased risk for severe hemolysis during treatment with ascorbic acid. Monitor hemoglobin and blood count and use a reduced dose of ASCOR in patients with glucose-6-phosphate dehydrogenase deficiency." See label for more information.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -139799,14 +141202,14 @@ "objCls" : "Chemical", "id" : "PA164712516", "name" : "Ascorbic acid (vitamin C), plain", - "version" : 3 + "version" : 2 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166293282", "name" : "Annotation of FDA Label for Ascorbic acid (vitamin C), combinations, Ascorbic acid (vitamin C), plain, sodium ascorbate and G6PD", - "version" : 9 + "version" : 16 }, "text" : { "id" : 1452216664, @@ -139817,29 +141220,29 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166315181", - "name" : "Recommendation Annotation PA166315181", + "id" : "PA166312385", + "name" : "Recommendation Annotation PA166312385", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"G6PD": "Variable"}, + "lookupKey" : {"G6PD": "Deficient"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA164712516", "name" : "Ascorbic acid (vitamin C), plain", - "version" : 3 + "version" : 2 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166293282", "name" : "Annotation of FDA Label for Ascorbic acid (vitamin C), combinations, Ascorbic acid (vitamin C), plain, sodium ascorbate and G6PD", - "version" : 9 + "version" : 16 }, "text" : { - "id" : 1452245820, + "id" : 1452216665, "html" : "

"Patients with glucose-6-phosphate dehydrogenase deficiency may be at increased risk for severe hemolysis during treatment with ascorbic acid. Monitor hemoglobin and blood count and use a reduced dose of ASCOR in patients with glucose-6-phosphate dehydrogenase deficiency." See label for more information.

\n", "version" : 0 }, @@ -139877,7 +141280,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 4, + "version" : 5, "year" : -1 } ], @@ -139927,7 +141330,7 @@ "id" : "PA35056", "symbol" : "HLA-B", "name" : "major histocompatibility complex, class I, B", - "version" : 40 + "version" : 2920 } ], "prescribingMarkdown" : { @@ -139941,7 +141344,7 @@ "id" : "PA165987830", "symbol" : "HLA-B*57:01", "name" : "*57:01", - "version" : 6 + "version" : 21 } ], "relatedChemicals" : [ @@ -139949,7 +141352,7 @@ "objCls" : "Chemical", "id" : "PA448004", "name" : "abacavir", - "version" : 11 + "version" : 41 } ], "relatedGenes" : [ @@ -139958,7 +141361,7 @@ "id" : "PA35056", "symbol" : "HLA-B", "name" : "major histocompatibility complex, class I, B", - "version" : 40 + "version" : 2920 } ], "source" : "FDA", @@ -139981,10 +141384,10 @@ "textMarkdown" : { "id" : 1450042734, "html" : "

Excerpts from the abacavir (ZIAGEN) drug label:

\n
\n

All patients should be screened for the HLA-B*5701 allele prior to initiating therapy with ZIAGEN or reinitiation of therapy with ZIAGEN, unless patients have a previously documented HLA-B*5701 allele assessment.

\n
\n
\n

ZIAGEN is contraindicated in patients: who have the HLA-B*5701 allele.

\n
\n

In the CNA106030 (PREDICT-1) study of 1650 HIV-infected adults, it was found that pre-screening for the HLA-B*5701 allele reduced the incidence of suspected hypersensitivity reactions from 7.8% to 3.4%. Based on this study, it is estimated that 61% of patients carrying the HLA-B*5701 allele will develop a hypersensitivity reaction to abacavir vs. 4% of patients who do not have this allele.

\n

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the abacavir drug label.

\n

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

\n", - "version" : 2 + "version" : 7 }, "userId" : "jmbarbarino", - "version" : 47 + "version" : 104 }, "recommendations" : [ { @@ -140001,14 +141404,14 @@ "objCls" : "Chemical", "id" : "PA448004", "name" : "abacavir", - "version" : 11 + "version" : 41 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104833", "name" : "Annotation of FDA Label for abacavir and HLA-B", - "version" : 47 + "version" : 104 }, "text" : { "id" : 1452213200, @@ -140049,7 +141452,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 3, + "version" : 4, "year" : -1 } ], @@ -140093,7 +141496,7 @@ "id" : "PA124", "symbol" : "CYP2C19", "name" : "cytochrome P450 family 2 subfamily C member 19", - "version" : 7210 + "version" : 7266 } ], "prescribingMarkdown" : { @@ -140107,7 +141510,7 @@ "objCls" : "Chemical", "id" : "PA166272921", "name" : "abrocitinib", - "version" : 3 + "version" : 10 } ], "relatedGenes" : [ @@ -140116,7 +141519,7 @@ "id" : "PA124", "symbol" : "CYP2C19", "name" : "cytochrome P450 family 2 subfamily C member 19", - "version" : 7210 + "version" : 7266 } ], "source" : "FDA", @@ -140142,7 +141545,7 @@ "version" : 0 }, "userId" : "cfthorn", - "version" : 5 + "version" : 13 }, "recommendations" : [ { @@ -140159,21 +141562,21 @@ "objCls" : "Chemical", "id" : "PA166272921", "name" : "abrocitinib", - "version" : 3 + "version" : 10 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166272961", "name" : "Annotation of FDA Label for abrocitinib and CYP2C19", - "version" : 5 + "version" : 13 }, "text" : { "id" : 1452193820, "html" : "

"In patients who are known or suspected to be CYP2C19 poor metabolizers, the recommended dosage of CIBINQO [abrocitinib] is 50 mg once daily. If an adequate response is not achieved with CIBINQO 50 mg orally daily after 12 weeks, consider increasing dosage to 100 mg orally once daily. Discontinue therapy if inadequate response is seen after dosage increase to 100 mg once daily." See label for more information

\n", - "version" : 0 + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", @@ -140189,21 +141592,21 @@ "objCls" : "Chemical", "id" : "PA166272921", "name" : "abrocitinib", - "version" : 3 + "version" : 10 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166272961", "name" : "Annotation of FDA Label for abrocitinib and CYP2C19", - "version" : 5 + "version" : 13 }, "text" : { "id" : 1452193840, "html" : "

"In patients who are known or suspected to be CYP2C19 poor metabolizers, the recommended dosage of CIBINQO [abrocitinib] is 50 mg once daily. If an adequate response is not achieved with CIBINQO 50 mg orally daily after 12 weeks, consider increasing dosage to 100 mg orally once daily. Discontinue therapy if inadequate response is seen after dosage increase to 100 mg once daily." See label for more information.

\n", - "version" : 0 + "version" : 1 }, - "version" : 0 + "version" : 2 } ], "url" : "https://www.pharmgkb.org/labelAnnotation/PA166272961" @@ -140237,7 +141640,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 3, + "version" : 4, "year" : -1 } ], @@ -140270,7 +141673,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "prescribingMarkdown" : { @@ -140284,7 +141687,7 @@ "objCls" : "Chemical", "id" : "PA166246281", "name" : "acetaminophen / caffeine / dihydrocodeine", - "version" : 5 + "version" : 4 } ], "relatedGenes" : [ @@ -140293,14 +141696,14 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "FDA", "summaryMarkdown" : { "id" : 1451470000, "html" : "

The FDA-approved drug label for acetaminophen/caffeine/dihydrocodeine (TREZIX) states that respiratory depression and death have occurred in children who received codeine following a tonsillectomy and/or adenoidectomy and who had evidence of being CYP2D6 ultra-rapid metabolizers. The label also states that CYP2D6 ultrarapid metabolizers should not use codeine.

\n", - "version" : 0 + "version" : 1 }, "terms" : [], "testing" : { @@ -140316,51 +141719,51 @@ "textMarkdown" : { "id" : 1451470001, "html" : "

Excerpts from the acetaminophen/caffeine/dihydrocodeine label:

\n
\n

Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-threatening Respiratory Depression in Children.
\nLife-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to CYP2D6 polymorphism [see WARNINGS and PRECAUTIONS].

\n
\n
\n

Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-threatening Respiratory Depression in Children.
\nLife-threatening respiratory depression and death have occurred in children who received codeine. Codeine is subject to\nvariability in metabolism based upon CYP2D6 genotype (described below), which can lead to an increased exposure to the\nactive metabolite morphine. Based upon post-marketing reports, children less than 12 years old appear to be more susceptible\nto the respiratory depressant effects of codeine, particularly if there are risk factors for respiratory depression. For example,\nmany reported cases of death occurred in the post-operative period following tonsillectomy and/or adenoidectomy, and many\nof the children had evidence of being ultra-rapid metabolizers of codeine. Furthermore, children with obstructive sleep apnea\nwho are treated with codeine for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to its respiratory\ndepressant effect.

\n
\n
\n

Nursing Mothers.
\nAt least one death was reported in a nursing infant who was exposed to high levels of morphine in breast milk because the\nmother was an ultra-rapid metabolizer of codeine. Breastfeeding is not recommended during treatment with TREZIX™ [see\nPRECAUTIONS; Nursing Mothers].

\n
\n
\n

Dihydrocodeine bitartrate and its active metabolite, morphine, are present in human milk. There are published studies and\ncases that have reported excessive sedation, respiratory depression, and death in infants exposed to codeine via breast milk.\nWomen who are ultra-rapid metabolizers of dihydrocodeine achieve higher than expected serum levels of morphine,\npotentially leading to higher levels of morphine in breast milk that can be dangerous in their breastfed infants. In women with\nnormal dihydrocodeine metabolism (normal CYP2D6 activity), the amount of dihydrocodeine secreted into human milk is low\nand dose-dependent.

\n
\n
\n

CYP2D6 Genetic Variability: Ultra-rapid metabolizer.
\nSome individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype (e.g., gene duplications denoted as\n*1/*1xN or *1/*2xN). The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 1 to 10% for Whites\n(European, North American), 3 to 4% for Blacks (African Americans), 1 to 2% for East Asians (Chinese, Japanese, Korean),\nand may be greater than 10% in certain ethnic groups (i.e., Oceanian, Northern African, Middle Eastern, Ashkenazi Jews,\nPuerto Rican). These individuals convert codeine into its active metabolite, morphine, more rapidly and completely than other\npeople. This rapid conversion results in higher than expected serum morphine levels. Even at labeled dosage regimens,\nindividuals who are ultra-rapid metabolizers may have life-threatening or fatal respiratory depression or experience signs of\noverdose (such as extreme sleepiness, confusion, or shallow breathing) [see OVERDOSAGE]. Therefore, individuals who are\nultra-rapid metabolizers should not use codeine.

\n
\n

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the acetaminophen/caffeine/dihydrocodeine drug label.

\n

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

\n", - "version" : 0 + "version" : 2 }, "userId" : "rachel", - "version" : 5 + "version" : 14 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166312462", - "name" : "Recommendation Annotation PA166312462", + "id" : "PA166312547", + "name" : "Recommendation Annotation PA166312547", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "2.75"}, + "lookupKey" : {"CYP2D6": "≥4.0"}, "otherPrescribingGuidance" : false, - "population" : "adults", + "population" : "pediatrics", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166246281", "name" : "acetaminophen / caffeine / dihydrocodeine", - "version" : 5 + "version" : 4 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166246301", "name" : "Annotation of FDA Label for acetaminophen / caffeine / dihydrocodeine and CYP2D6", - "version" : 5 + "version" : 14 }, "text" : { - "id" : 1452216761, - "html" : "

"Individuals who are ultra-rapid metabolizers should not use codeine." See label for more information

\n", + "id" : 1452216846, + "html" : "

"Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-threatening Respiratory Depression in Children.\nLife-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to CYP2D6 polymorphism." See label for more information

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312504", - "name" : "Recommendation Annotation PA166312504", + "id" : "PA166312548", + "name" : "Recommendation Annotation PA166312548", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "2.5"}, + "lookupKey" : {"CYP2D6": "≥5.0"}, "otherPrescribingGuidance" : false, "population" : "pediatrics", "relatedChemicals" : [ @@ -140368,17 +141771,17 @@ "objCls" : "Chemical", "id" : "PA166246281", "name" : "acetaminophen / caffeine / dihydrocodeine", - "version" : 5 + "version" : 4 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166246301", "name" : "Annotation of FDA Label for acetaminophen / caffeine / dihydrocodeine and CYP2D6", - "version" : 5 + "version" : 14 }, "text" : { - "id" : 1452216803, + "id" : 1452216847, "html" : "

"Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-threatening Respiratory Depression in Children.\nLife-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to CYP2D6 polymorphism." See label for more information

\n", "version" : 0 }, @@ -140386,74 +141789,74 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312464", - "name" : "Recommendation Annotation PA166312464", + "id" : "PA166312549", + "name" : "Recommendation Annotation PA166312549", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "4.0"}, + "lookupKey" : {"CYP2D6": "≥6.0"}, "otherPrescribingGuidance" : false, - "population" : "adults", + "population" : "pediatrics", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166246281", "name" : "acetaminophen / caffeine / dihydrocodeine", - "version" : 5 + "version" : 4 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166246301", "name" : "Annotation of FDA Label for acetaminophen / caffeine / dihydrocodeine and CYP2D6", - "version" : 5 + "version" : 14 }, "text" : { - "id" : 1452216763, - "html" : "

"Individuals who are ultra-rapid metabolizers should not use codeine." See label for more information

\n", + "id" : 1452216848, + "html" : "

"Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-threatening Respiratory Depression in Children.\nLife-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to CYP2D6 polymorphism." See label for more information

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312482", - "name" : "Recommendation Annotation PA166312482", + "id" : "PA166312504", + "name" : "Recommendation Annotation PA166312504", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "≥3.5"}, + "lookupKey" : {"CYP2D6": "2.5"}, "otherPrescribingGuidance" : false, - "population" : "adults", + "population" : "pediatrics", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166246281", "name" : "acetaminophen / caffeine / dihydrocodeine", - "version" : 5 + "version" : 4 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166246301", "name" : "Annotation of FDA Label for acetaminophen / caffeine / dihydrocodeine and CYP2D6", - "version" : 5 + "version" : 14 }, "text" : { - "id" : 1452216781, - "html" : "

"Individuals who are ultra-rapid metabolizers should not use codeine." See label for more information

\n", + "id" : 1452216803, + "html" : "

"Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-threatening Respiratory Depression in Children.\nLife-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to CYP2D6 polymorphism." See label for more information

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312548", - "name" : "Recommendation Annotation PA166312548", + "id" : "PA166312521", + "name" : "Recommendation Annotation PA166312521", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "≥5.0"}, + "lookupKey" : {"CYP2D6": "2.75"}, "otherPrescribingGuidance" : false, "population" : "pediatrics", "relatedChemicals" : [ @@ -140461,17 +141864,17 @@ "objCls" : "Chemical", "id" : "PA166246281", "name" : "acetaminophen / caffeine / dihydrocodeine", - "version" : 5 + "version" : 4 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166246301", "name" : "Annotation of FDA Label for acetaminophen / caffeine / dihydrocodeine and CYP2D6", - "version" : 5 + "version" : 14 }, "text" : { - "id" : 1452216847, + "id" : 1452216820, "html" : "

"Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-threatening Respiratory Depression in Children.\nLife-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to CYP2D6 polymorphism." See label for more information

\n", "version" : 0 }, @@ -140479,31 +141882,31 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312502", - "name" : "Recommendation Annotation PA166312502", + "id" : "PA166312541", + "name" : "Recommendation Annotation PA166312541", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "≥5.0"}, + "lookupKey" : {"CYP2D6": "3.0"}, "otherPrescribingGuidance" : false, - "population" : "adults", + "population" : "pediatrics", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166246281", "name" : "acetaminophen / caffeine / dihydrocodeine", - "version" : 5 + "version" : 4 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166246301", "name" : "Annotation of FDA Label for acetaminophen / caffeine / dihydrocodeine and CYP2D6", - "version" : 5 + "version" : 14 }, "text" : { - "id" : 1452216801, - "html" : "

"Individuals who are ultra-rapid metabolizers should not use codeine." See label for more information

\n", + "id" : 1452216840, + "html" : "

"Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-threatening Respiratory Depression in Children.\nLife-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to CYP2D6 polymorphism." See label for more information

\n", "version" : 0 }, "version" : 0 @@ -140523,14 +141926,14 @@ "objCls" : "Chemical", "id" : "PA166246281", "name" : "acetaminophen / caffeine / dihydrocodeine", - "version" : 5 + "version" : 4 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166246301", "name" : "Annotation of FDA Label for acetaminophen / caffeine / dihydrocodeine and CYP2D6", - "version" : 5 + "version" : 14 }, "text" : { "id" : 1452216841, @@ -140541,12 +141944,12 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312544", - "name" : "Recommendation Annotation PA166312544", + "id" : "PA166312543", + "name" : "Recommendation Annotation PA166312543", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "≥3.25"}, + "lookupKey" : {"CYP2D6": "≥3.0"}, "otherPrescribingGuidance" : false, "population" : "pediatrics", "relatedChemicals" : [ @@ -140554,17 +141957,17 @@ "objCls" : "Chemical", "id" : "PA166246281", "name" : "acetaminophen / caffeine / dihydrocodeine", - "version" : 5 + "version" : 4 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166246301", "name" : "Annotation of FDA Label for acetaminophen / caffeine / dihydrocodeine and CYP2D6", - "version" : 5 + "version" : 14 }, "text" : { - "id" : 1452216843, + "id" : 1452216842, "html" : "

"Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-threatening Respiratory Depression in Children.\nLife-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to CYP2D6 polymorphism." See label for more information

\n", "version" : 0 }, @@ -140572,12 +141975,12 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312546", - "name" : "Recommendation Annotation PA166312546", + "id" : "PA166312544", + "name" : "Recommendation Annotation PA166312544", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "≥3.75"}, + "lookupKey" : {"CYP2D6": "≥3.25"}, "otherPrescribingGuidance" : false, "population" : "pediatrics", "relatedChemicals" : [ @@ -140585,17 +141988,17 @@ "objCls" : "Chemical", "id" : "PA166246281", "name" : "acetaminophen / caffeine / dihydrocodeine", - "version" : 5 + "version" : 4 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166246301", "name" : "Annotation of FDA Label for acetaminophen / caffeine / dihydrocodeine and CYP2D6", - "version" : 5 + "version" : 14 }, "text" : { - "id" : 1452216845, + "id" : 1452216843, "html" : "

"Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-threatening Respiratory Depression in Children.\nLife-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to CYP2D6 polymorphism." See label for more information

\n", "version" : 0 }, @@ -140603,74 +142006,74 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312465", - "name" : "Recommendation Annotation PA166312465", + "id" : "PA166312545", + "name" : "Recommendation Annotation PA166312545", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "≥3.0"}, + "lookupKey" : {"CYP2D6": "≥3.5"}, "otherPrescribingGuidance" : false, - "population" : "adults", + "population" : "pediatrics", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166246281", "name" : "acetaminophen / caffeine / dihydrocodeine", - "version" : 5 + "version" : 4 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166246301", "name" : "Annotation of FDA Label for acetaminophen / caffeine / dihydrocodeine and CYP2D6", - "version" : 5 + "version" : 14 }, "text" : { - "id" : 1452216764, - "html" : "

"Individuals who are ultra-rapid metabolizers should not use codeine." See label for more information

\n", + "id" : 1452216844, + "html" : "

"Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-threatening Respiratory Depression in Children.\nLife-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to CYP2D6 polymorphism." See label for more information

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312461", - "name" : "Recommendation Annotation PA166312461", + "id" : "PA166312546", + "name" : "Recommendation Annotation PA166312546", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "2.5"}, + "lookupKey" : {"CYP2D6": "≥3.75"}, "otherPrescribingGuidance" : false, - "population" : "adults", + "population" : "pediatrics", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166246281", "name" : "acetaminophen / caffeine / dihydrocodeine", - "version" : 5 + "version" : 4 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166246301", "name" : "Annotation of FDA Label for acetaminophen / caffeine / dihydrocodeine and CYP2D6", - "version" : 5 + "version" : 14 }, "text" : { - "id" : 1452216760, - "html" : "

"Individuals who are ultra-rapid metabolizers should not use codeine." See label for more information

\n", + "id" : 1452216845, + "html" : "

"Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-threatening Respiratory Depression in Children.\nLife-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to CYP2D6 polymorphism." See label for more information

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312503", - "name" : "Recommendation Annotation PA166312503", + "id" : "PA166312461", + "name" : "Recommendation Annotation PA166312461", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "≥6.0"}, + "lookupKey" : {"CYP2D6": "2.5"}, "otherPrescribingGuidance" : false, "population" : "adults", "relatedChemicals" : [ @@ -140678,17 +142081,17 @@ "objCls" : "Chemical", "id" : "PA166246281", "name" : "acetaminophen / caffeine / dihydrocodeine", - "version" : 5 + "version" : 4 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166246301", "name" : "Annotation of FDA Label for acetaminophen / caffeine / dihydrocodeine and CYP2D6", - "version" : 5 + "version" : 14 }, "text" : { - "id" : 1452216802, + "id" : 1452216760, "html" : "

"Individuals who are ultra-rapid metabolizers should not use codeine." See label for more information

\n", "version" : 0 }, @@ -140696,12 +142099,12 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312463", - "name" : "Recommendation Annotation PA166312463", + "id" : "PA166312462", + "name" : "Recommendation Annotation PA166312462", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "3.0"}, + "lookupKey" : {"CYP2D6": "2.75"}, "otherPrescribingGuidance" : false, "population" : "adults", "relatedChemicals" : [ @@ -140709,17 +142112,17 @@ "objCls" : "Chemical", "id" : "PA166246281", "name" : "acetaminophen / caffeine / dihydrocodeine", - "version" : 5 + "version" : 4 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166246301", "name" : "Annotation of FDA Label for acetaminophen / caffeine / dihydrocodeine and CYP2D6", - "version" : 5 + "version" : 14 }, "text" : { - "id" : 1452216762, + "id" : 1452216761, "html" : "

"Individuals who are ultra-rapid metabolizers should not use codeine." See label for more information

\n", "version" : 0 }, @@ -140727,12 +142130,12 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312481", - "name" : "Recommendation Annotation PA166312481", + "id" : "PA166312463", + "name" : "Recommendation Annotation PA166312463", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "≥3.25"}, + "lookupKey" : {"CYP2D6": "3.0"}, "otherPrescribingGuidance" : false, "population" : "adults", "relatedChemicals" : [ @@ -140740,17 +142143,17 @@ "objCls" : "Chemical", "id" : "PA166246281", "name" : "acetaminophen / caffeine / dihydrocodeine", - "version" : 5 + "version" : 4 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166246301", "name" : "Annotation of FDA Label for acetaminophen / caffeine / dihydrocodeine and CYP2D6", - "version" : 5 + "version" : 14 }, "text" : { - "id" : 1452216780, + "id" : 1452216762, "html" : "

"Individuals who are ultra-rapid metabolizers should not use codeine." See label for more information

\n", "version" : 0 }, @@ -140758,43 +142161,43 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312547", - "name" : "Recommendation Annotation PA166312547", + "id" : "PA166312464", + "name" : "Recommendation Annotation PA166312464", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "≥4.0"}, + "lookupKey" : {"CYP2D6": "4.0"}, "otherPrescribingGuidance" : false, - "population" : "pediatrics", + "population" : "adults", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166246281", "name" : "acetaminophen / caffeine / dihydrocodeine", - "version" : 5 + "version" : 4 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166246301", "name" : "Annotation of FDA Label for acetaminophen / caffeine / dihydrocodeine and CYP2D6", - "version" : 5 + "version" : 14 }, "text" : { - "id" : 1452216846, - "html" : "

"Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-threatening Respiratory Depression in Children.\nLife-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to CYP2D6 polymorphism." See label for more information

\n", + "id" : 1452216763, + "html" : "

"Individuals who are ultra-rapid metabolizers should not use codeine." See label for more information

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312483", - "name" : "Recommendation Annotation PA166312483", + "id" : "PA166312465", + "name" : "Recommendation Annotation PA166312465", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "≥3.75"}, + "lookupKey" : {"CYP2D6": "≥3.0"}, "otherPrescribingGuidance" : false, "population" : "adults", "relatedChemicals" : [ @@ -140802,17 +142205,17 @@ "objCls" : "Chemical", "id" : "PA166246281", "name" : "acetaminophen / caffeine / dihydrocodeine", - "version" : 5 + "version" : 4 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166246301", "name" : "Annotation of FDA Label for acetaminophen / caffeine / dihydrocodeine and CYP2D6", - "version" : 5 + "version" : 14 }, "text" : { - "id" : 1452216782, + "id" : 1452216764, "html" : "

"Individuals who are ultra-rapid metabolizers should not use codeine." See label for more information

\n", "version" : 0 }, @@ -140820,43 +142223,43 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312549", - "name" : "Recommendation Annotation PA166312549", + "id" : "PA166312481", + "name" : "Recommendation Annotation PA166312481", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "≥6.0"}, + "lookupKey" : {"CYP2D6": "≥3.25"}, "otherPrescribingGuidance" : false, - "population" : "pediatrics", + "population" : "adults", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166246281", "name" : "acetaminophen / caffeine / dihydrocodeine", - "version" : 5 + "version" : 4 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166246301", "name" : "Annotation of FDA Label for acetaminophen / caffeine / dihydrocodeine and CYP2D6", - "version" : 5 + "version" : 14 }, "text" : { - "id" : 1452216848, - "html" : "

"Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-threatening Respiratory Depression in Children.\nLife-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to CYP2D6 polymorphism." See label for more information

\n", + "id" : 1452216780, + "html" : "

"Individuals who are ultra-rapid metabolizers should not use codeine." See label for more information

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312501", - "name" : "Recommendation Annotation PA166312501", + "id" : "PA166312482", + "name" : "Recommendation Annotation PA166312482", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "≥4.0"}, + "lookupKey" : {"CYP2D6": "≥3.5"}, "otherPrescribingGuidance" : false, "population" : "adults", "relatedChemicals" : [ @@ -140864,17 +142267,17 @@ "objCls" : "Chemical", "id" : "PA166246281", "name" : "acetaminophen / caffeine / dihydrocodeine", - "version" : 5 + "version" : 4 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166246301", "name" : "Annotation of FDA Label for acetaminophen / caffeine / dihydrocodeine and CYP2D6", - "version" : 5 + "version" : 14 }, "text" : { - "id" : 1452216800, + "id" : 1452216781, "html" : "

"Individuals who are ultra-rapid metabolizers should not use codeine." See label for more information

\n", "version" : 0 }, @@ -140882,127 +142285,127 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312543", - "name" : "Recommendation Annotation PA166312543", + "id" : "PA166312483", + "name" : "Recommendation Annotation PA166312483", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "≥3.0"}, + "lookupKey" : {"CYP2D6": "≥3.75"}, "otherPrescribingGuidance" : false, - "population" : "pediatrics", + "population" : "adults", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166246281", "name" : "acetaminophen / caffeine / dihydrocodeine", - "version" : 5 + "version" : 4 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166246301", "name" : "Annotation of FDA Label for acetaminophen / caffeine / dihydrocodeine and CYP2D6", - "version" : 5 + "version" : 14 }, "text" : { - "id" : 1452216842, - "html" : "

"Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-threatening Respiratory Depression in Children.\nLife-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to CYP2D6 polymorphism." See label for more information

\n", + "id" : 1452216782, + "html" : "

"Individuals who are ultra-rapid metabolizers should not use codeine." See label for more information

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312545", - "name" : "Recommendation Annotation PA166312545", + "id" : "PA166312501", + "name" : "Recommendation Annotation PA166312501", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "≥3.5"}, + "lookupKey" : {"CYP2D6": "≥4.0"}, "otherPrescribingGuidance" : false, - "population" : "pediatrics", + "population" : "adults", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166246281", "name" : "acetaminophen / caffeine / dihydrocodeine", - "version" : 5 + "version" : 4 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166246301", "name" : "Annotation of FDA Label for acetaminophen / caffeine / dihydrocodeine and CYP2D6", - "version" : 5 + "version" : 14 }, "text" : { - "id" : 1452216844, - "html" : "

"Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-threatening Respiratory Depression in Children.\nLife-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to CYP2D6 polymorphism." See label for more information

\n", + "id" : 1452216800, + "html" : "

"Individuals who are ultra-rapid metabolizers should not use codeine." See label for more information

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312521", - "name" : "Recommendation Annotation PA166312521", + "id" : "PA166312503", + "name" : "Recommendation Annotation PA166312503", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "2.75"}, + "lookupKey" : {"CYP2D6": "≥6.0"}, "otherPrescribingGuidance" : false, - "population" : "pediatrics", + "population" : "adults", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166246281", "name" : "acetaminophen / caffeine / dihydrocodeine", - "version" : 5 + "version" : 4 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166246301", "name" : "Annotation of FDA Label for acetaminophen / caffeine / dihydrocodeine and CYP2D6", - "version" : 5 + "version" : 14 }, "text" : { - "id" : 1452216820, - "html" : "

"Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-threatening Respiratory Depression in Children.\nLife-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to CYP2D6 polymorphism." See label for more information

\n", + "id" : 1452216802, + "html" : "

"Individuals who are ultra-rapid metabolizers should not use codeine." See label for more information

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312541", - "name" : "Recommendation Annotation PA166312541", + "id" : "PA166312502", + "name" : "Recommendation Annotation PA166312502", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "3.0"}, + "lookupKey" : {"CYP2D6": "≥5.0"}, "otherPrescribingGuidance" : false, - "population" : "pediatrics", + "population" : "adults", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166246281", "name" : "acetaminophen / caffeine / dihydrocodeine", - "version" : 5 + "version" : 4 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166246301", "name" : "Annotation of FDA Label for acetaminophen / caffeine / dihydrocodeine and CYP2D6", - "version" : 5 + "version" : 14 }, "text" : { - "id" : 1452216840, - "html" : "

"Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-threatening Respiratory Depression in Children.\nLife-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to CYP2D6 polymorphism." See label for more information

\n", + "id" : 1452216801, + "html" : "

"Individuals who are ultra-rapid metabolizers should not use codeine." See label for more information

\n", "version" : 0 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/labelAnnotation/PA166246301" @@ -141036,7 +142439,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 7, + "version" : 8, "year" : -1 } ], @@ -141063,6 +142466,13 @@ "description" : "update text", "type" : "Update", "version" : 0 + }, + { + "id" : 1452482100, + "date" : "2024-05-23T11:47:52.502-07:00", + "description" : "fixed typo", + "type" : "Update", + "version" : 0 } ], "indication" : false, @@ -141080,13 +142490,13 @@ "id" : "PA35056", "symbol" : "HLA-B", "name" : "major histocompatibility complex, class I, B", - "version" : 40 + "version" : 2920 } ], "prescribingMarkdown" : { "id" : 1451391603, "html" : "

Excerpt from the allopurinol (ALOPRIM) drug label:

\n
\n

Prior to starting ALOPRIM, consider testing for the HLA-B*58:01 allele in genetically at-risk populations. Screening is generally not recommended in patients from populations in which the prevalence of HLA-B*58:01 is low, or in current allopurinol users, as the risk of SJS/TEN/DRESS is largely confined to the first few months of therapy, regardless of HLA­ B*58:01 status.

\n
\n", - "version" : 1 + "version" : 2 }, "relatedAlleles" : [ { @@ -141094,7 +142504,7 @@ "id" : "PA165987831", "symbol" : "HLA-B*58:01", "name" : "*58:01", - "version" : 4 + "version" : 21 } ], "relatedChemicals" : [ @@ -141102,7 +142512,7 @@ "objCls" : "Chemical", "id" : "PA448320", "name" : "allopurinol", - "version" : 9 + "version" : 35 } ], "relatedGenes" : [ @@ -141111,14 +142521,14 @@ "id" : "PA35056", "symbol" : "HLA-B", "name" : "major histocompatibility complex, class I, B", - "version" : 40 + "version" : 2920 } ], "source" : "FDA", "summaryMarkdown" : { "id" : 1451391601, - "html" : "

The FDA-approved label for allopurinol (ALOPRIM) states that patients who carry the HLA-B*58:01 allele, found at a higher frequency in individuals of African, Asian (e.g., Han Chinese, Korean, Thai), and Native Hawaiian/Pacific Islander ancestry, are at a higher risk of allopurinol hypersensitivity syndrome (AHS). The label recommends testing for HLA-B*58:01 in genetically at-risk populations and states that ALOPRIM is not recommended in HLA-B*58-01 positive patients unless the benefits outweigh the risks.

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The FDA-approved label for allopurinol (ALOPRIM) states that patients who carry the HLA-B*58:01 allele, found at a higher frequency in individuals of African, Asian (e.g., Han Chinese, Korean, Thai), and Native Hawaiian/Pacific Islander ancestry, are at a higher risk of allopurinol hypersensitivity syndrome (AHS). The label recommends testing for HLA-B*58:01 in genetically at-risk populations and states that ALOPRIM is not recommended in HLA-B*58:01 positive patients unless the benefits outweigh the risks.

\n", + "version" : 1 }, "terms" : [], "testing" : { @@ -141137,7 +142547,7 @@ "version" : 1 }, "userId" : "racheldalton", - "version" : 14 + "version" : 42 }, "recommendations" : [ { @@ -141154,14 +142564,14 @@ "objCls" : "Chemical", "id" : "PA448320", "name" : "allopurinol", - "version" : 9 + "version" : 35 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166234701", "name" : "Annotation of FDA Label for allopurinol and HLA-B", - "version" : 14 + "version" : 42 }, "text" : { "id" : 1452213282, @@ -141173,6 +142583,158 @@ ], "url" : "https://www.pharmgkb.org/labelAnnotation/PA166234701" }, + { + "citations" : [ + { + "id" : 15148922, + "title" : "Drugs@FDA: Drug Product ARIKAYCE (Amikacin), NDA207356, Insmed Incorporated", + "_sameAs" : "https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=207356", + "authors" : [], + "crossReferences" : [ + { + "id" : 1452495640, + "resource" : "FDA Application", + "resourceId" : "NDA207356/SUPPL-12", + "_url" : "https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=207356", + "version" : 0 + } + ], + "day" : 10, + "hasKeyword" : false, + "meshDiseases" : [], + "meshTerms" : [], + "month" : 2, + "nonHuman" : false, + "objCls" : "Literature", + "pediatric" : false, + "pgkbPublication" : false, + "pubDate" : "2023-02-10T00:00:00-08:00", + "terms" : [ + {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} + ], + "type" : "Drug Label", + "version" : 6, + "year" : 2023 + } + ], + "guideline" : { + "objCls" : "Label Annotation", + "id" : "PA166316321", + "name" : "Annotation of FDA Label for amikacin and MT-RNR1", + "alternateDrugAvailable" : true, + "biomarkerStatus" : "On FDA Biomarker List", + "cancerGenome" : false, + "crossReferences" : [], + "dosingInformation" : false, + "history" : [], + "indication" : false, + "labelApplications" : [], + "labelDocumentAvailable" : true, + "literature" : [ + {"id":15148922,"title":"Drugs@FDA: Drug Product ARIKAYCE (Amikacin), NDA207356, Insmed Incorporated","_sameAs":"https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=207356","crossReferences":[{"id":1452495640,"resource":"FDA Application","resourceId":"NDA207356/SUPPL-12","_url":"https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=207356"}],"objCls":"Literature","pubDate":"2023-02-10T00:00:00-08:00","terms":[{"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"}],"type":"Drug Label"} + ], + "otherPrescribingGuidance" : false, + "pediatric" : false, + "pgxRelated" : true, + "prescribingGenes" : [ + { + "objCls" : "Gene", + "id" : "PA31274", + "symbol" : "MT-RNR1", + "name" : "mitochondrially encoded 12S RNA", + "version" : 12 + } + ], + "prescribingMarkdown" : { + "id" : 1452252462, + "html" : "
\n

In case of known maternal history of ototoxicity due to aminoglycoside use or a known mitochondrial DNA variant in the patient, consider alternative treatments other than aminoglycosides unless the increased risk of permanent hearing loss is outweighed by the severity of infection and lack of safe and effective alternative therapies.

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Amikacin (ARIKAYCE) is an aminoglycoside antibacterial indicated in adults who have limited or no alternative treatment options, for the treatment of Mycobacterium avium complex (MAC) lung disease as part of a combination antibacterial drug regimen in patients who do not achieve negative sputum cultures after a minimum of 6 consecutive months of a multidrug background regimen therapy.

\n

Cases of ototoxicity with aminoglycosides have been observed in patients with certain variants in the mitochondrially encoded 12S rRNA gene (MT-RNR1), particularly the m.1555A>G variant. In case of known maternal history of ototoxicity due to aminoglycoside use or a known mitochondrial DNA variant in the patient, consider alternative treatments other than aminoglycosides unless the increased risk of permanent hearing loss is outweighed by the severity of infection and lack of safe and effective alternative therapies.

\n", + "version" : 1 + }, + "terms" : [], + "testing" : { + "id" : 1183672111, + "description" : "The label does not discuss genetic or other testing for gene/protein/chromosomal variants, but does contain information about changes in efficacy, dosage or toxicity due to such variants. The label may mention contraindication of the drug in a particular subset of patients but does not require or recommend gene, protein or chromosomal testing.", + "parents" : [], + "resource" : "Genetic Testing Level", + "term" : "Actionable PGx", + "termId" : "geneTestLevel:1183672111", + "valid" : true, + "version" : 2 + }, + "textMarkdown" : { + "id" : 1452252461, + "html" : "

Excerpt from the amikacin (ARIKAYCE) label:

\n
\n

Cases of ototoxicity with aminoglycosides have been observed in patients with certain variants in the mitochondrially encoded 12S rRNA gene (MT-RNR1), particularly the m.1555A>G variant. Ototoxicity occurred in some patients even when their aminoglycoside serum levels were within the recommended range. Mitochondrial DNA variants are present in less than 1% of the general US population, and the proportion of the variant carriers who may develop ototoxicity as well as the severity of ototoxicity is unknown. In case of known maternal history of ototoxicity due to aminoglycoside use or a known mitochondrial DNA variant in the patient, consider alternative treatments other than aminoglycosides unless the increased risk of permanent hearing loss is outweighed by the severity of infection and lack of safe and effective alternative therapies.

\n
\n

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the amikacin drug label.

\n

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

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The amikacin label states: "Cases of ototoxicity with aminoglycosides have been observed in patients with certain variants in the mitochondrially encoded 12S rRNA gene (MT-RNR1), particularly the m.1555A>G variant. ... In case of known maternal history of ototoxicity due to aminoglycoside use or a known mitochondrial DNA variant in the patient, consider alternative treatments other than aminoglycosides unless the increased risk of permanent hearing loss is outweighed by the severity of infection and lack of safe and effective alternative therapies." See label for more information.

\n", + "version" : 0 + }, + "version" : 0 + } + ], + "url" : "https://www.pharmgkb.org/labelAnnotation/PA166316321" + }, { "citations" : [ { @@ -141203,7 +142765,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 3, + "version" : 4, "year" : -1 }, { @@ -141234,7 +142796,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 3, + "version" : 4, "year" : -1 } ], @@ -141278,7 +142840,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "prescribingMarkdown" : { @@ -141292,7 +142854,7 @@ "objCls" : "Chemical", "id" : "PA10026", "name" : "aripiprazole", - "version" : 10 + "version" : 41 } ], "relatedGenes" : [ @@ -141301,7 +142863,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "FDA", @@ -141327,7 +142889,7 @@ "version" : 1 }, "userId" : "matt", - "version" : 32 + "version" : 80 }, "recommendations" : [ { @@ -141344,21 +142906,21 @@ "objCls" : "Chemical", "id" : "PA10026", "name" : "aripiprazole", - "version" : 10 + "version" : 41 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104839", "name" : "Annotation of FDA Label for aripiprazole and CYP2D6", - "version" : 32 + "version" : 80 }, "text" : { "id" : 1452216422, "html" : "

The ABILIFY label states, "Dosage adjustments are recommended in patients who are known CYP2D6 poor metabolizers." For known CYP2D6 poor metabolizers, administer half of usual dose. For known CYP2D6 poor metabolizers taking concomitant strong CYP3A4 inhibitors (e.g., itraconazole, clarithromycin), administer a quarter of usual dose. The ABILIFY MAINTENA label states, "Known CYP2D6 poor metabolizers: Recommended starting and maintenance dose is 300 mg administered monthly as a single injection." For known CYP2D6 poor metabolizers taking concomitant CYP3A4 inhibitors, recommended dose is 200 mg. See labels for more information.

\n", - "version" : 0 + "version" : 2 }, - "version" : 0 + "version" : 2 } ], "url" : "https://www.pharmgkb.org/labelAnnotation/PA166104839" @@ -141393,7 +142955,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 3, + "version" : 4, "year" : -1 }, { @@ -141424,7 +142986,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 3, + "version" : 4, "year" : -1 } ], @@ -141454,13 +143016,13 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "prescribingMarkdown" : { "id" : 1450399530, "html" : "

Excerpt from the ARISTADA label:

\n
\n

Concomitant Medicine...Strong CYP3A4 Inhibitor...Dose Change for ARISTADA...For patients known to be poor metabolizers of CYP2D6: Reduce dose to 441 mg from 662 mg, 882 mg, or 1064 mg. No dosage adjustment is necessary in patients taking 441 mg ARISTADA, if tolerated.

\n
\n

Excerpt from the ARISTADA INITIO label:

\n
\n

ARISTADA INITIO is only available at a single strength as a single-dose pre-filled syringe, so dosage adjustments are not possible. Therefore, avoid use in patients who are known CYP2D6 poor metabolizers.

\n
\n", - "version" : 3 + "version" : 4 }, "relatedAlleles" : [], "relatedChemicals" : [ @@ -141468,7 +143030,7 @@ "objCls" : "Chemical", "id" : "PA166161216", "name" : "aripiprazole lauroxil", - "version" : 8 + "version" : 11 } ], "relatedGenes" : [ @@ -141477,7 +143039,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "FDA", @@ -141503,67 +143065,67 @@ "version" : 0 }, "userId" : "jmbarbarino", - "version" : 27 + "version" : 55 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166312302", - "name" : "Recommendation Annotation PA166312302", - "alternateDrugAvailable" : true, - "dosingInformation" : false, + "id" : "PA166312323", + "name" : "Recommendation Annotation PA166312323", + "alternateDrugAvailable" : false, + "dosingInformation" : true, "implications" : [], "lookupKey" : {"CYP2D6": "0.0"}, "otherPrescribingGuidance" : false, - "population" : "ARISTADA INITIO Label", + "population" : "ARISTADA Label", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166161216", "name" : "aripiprazole lauroxil", - "version" : 8 + "version" : 11 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166161219", "name" : "Annotation of FDA Label for aripiprazole lauroxil and CYP2D6", - "version" : 27 + "version" : 55 }, "text" : { - "id" : 1452216561, - "html" : "

"ARISTADA INITIO [aripiprazole lauroxil] is only available at a single strength as a single-dose pre-filled syringe, so dosage adjustments are not possible. Therefore, avoid use in patients who are known CYP2D6 poor metabolizers." See label for more information.

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The label states "Dosage adjustment is recommended in known CYP2D6 poor metabolizers due to high aripiprazole concentrations." Table 4 of the label contains information for a concomitant medicine that is a strong CYP3A4 inhibitor: "For patients known to be poor metabolizers of CYP2D6: Reduce dose to 441 mg from 662 mg, 882 mg, or 1064 mg. No dosage adjustment is necessary in patients taking 441 mg ARISTADA, if tolerated." See label for more information

\n", + "version" : 1 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312323", - "name" : "Recommendation Annotation PA166312323", - "alternateDrugAvailable" : false, - "dosingInformation" : true, + "id" : "PA166312302", + "name" : "Recommendation Annotation PA166312302", + "alternateDrugAvailable" : true, + "dosingInformation" : false, "implications" : [], "lookupKey" : {"CYP2D6": "0.0"}, "otherPrescribingGuidance" : false, - "population" : "ARISTADA Label", + "population" : "ARISTADA INITIO Label", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166161216", "name" : "aripiprazole lauroxil", - "version" : 8 + "version" : 11 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166161219", "name" : "Annotation of FDA Label for aripiprazole lauroxil and CYP2D6", - "version" : 27 + "version" : 55 }, "text" : { - "id" : 1452216582, - "html" : "

The label states "Dosage adjustment is recommended in known CYP2D6 poor metabolizers due to high aripiprazole concentrations." Table 4 of the label contains information for a concomitant medicine that is a strong CYP3A4 inhibitor: "For patients known to be poor metabolizers of CYP2D6: Reduce dose to 441 mg from 662 mg, 882 mg, or 1064 mg. No dosage adjustment is necessary in patients taking 441 mg ARISTADA, if tolerated." See label for more information

\n", + "id" : 1452216561, + "html" : "

"ARISTADA INITIO [aripiprazole lauroxil] is only available at a single strength as a single-dose pre-filled syringe, so dosage adjustments are not possible. Therefore, avoid use in patients who are known CYP2D6 poor metabolizers." See label for more information.

\n", "version" : 0 }, "version" : 0 @@ -141600,7 +143162,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 3, + "version" : 4, "year" : -1 } ], @@ -141658,14 +143220,14 @@ "id" : "PA27331", "symbol" : "CYB5R3", "name" : "cytochrome b5 reductase 3", - "version" : 13 + "version" : 80 }, { "objCls" : "Gene", "id" : "PA28469", "symbol" : "G6PD", "name" : "glucose-6-phosphate dehydrogenase", - "version" : 135 + "version" : 1326 } ], "prescribingMarkdown" : { @@ -141688,14 +143250,14 @@ "id" : "PA27331", "symbol" : "CYB5R3", "name" : "cytochrome b5 reductase 3", - "version" : 13 + "version" : 80 }, { "objCls" : "Gene", "id" : "PA28469", "symbol" : "G6PD", "name" : "glucose-6-phosphate dehydrogenase", - "version" : 135 + "version" : 1326 } ], "source" : "FDA", @@ -141718,10 +143280,10 @@ "textMarkdown" : { "id" : 1450400398, "html" : "

Excerpt from the articaine and epinephrine (ORABLOC) drug label:

\n
\n

Although all patients are at risk for methemoglobinemia, patients with glucose-6-phosphate dehydrogenase deficiency, congenital or idiopathic methemoglobinemia, cardiac or pulmonary compromise, infants under 6 months of age, and concurrent exposure to oxidizing agents or their metabolites are more susceptible to developing clinical manifestations of the condition. If local anesthetics must be used in these patients, close monitoring for symptoms and signs of methemoglobinemia is recommended.

\n
\n

NOTE: While the CYB5R3 gene is not explicitly stated in the drug label variants in this gene are associated with congenital methemoglobinemia I and II OMIM 250800.

\n

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the articaine and epinephrine drug label.

\n

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

\n", - "version" : 1 + "version" : 2 }, "userId" : "cfthorn", - "version" : 11 + "version" : 24 }, "recommendations" : [ { @@ -141745,7 +143307,7 @@ "objCls" : "Label Annotation", "id" : "PA166182741", "name" : "Annotation of FDA Label for articaine / epinephrine and CYB5R3, G6PD", - "version" : 11 + "version" : 24 }, "text" : { "id" : 1452245681, @@ -141775,7 +143337,7 @@ "objCls" : "Label Annotation", "id" : "PA166182741", "name" : "Annotation of FDA Label for articaine / epinephrine and CYB5R3, G6PD", - "version" : 11 + "version" : 24 }, "text" : { "id" : 1452216726, @@ -141805,7 +143367,7 @@ "objCls" : "Label Annotation", "id" : "PA166182741", "name" : "Annotation of FDA Label for articaine / epinephrine and CYB5R3, G6PD", - "version" : 11 + "version" : 24 }, "text" : { "id" : 1452216715, @@ -141846,7 +143408,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 4, + "version" : 5, "year" : -1 } ], @@ -141889,7 +143451,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "prescribingMarkdown" : { @@ -141903,7 +143465,7 @@ "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "relatedGenes" : [ @@ -141912,7 +143474,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "FDA", @@ -141938,7 +143500,7 @@ "version" : 0 }, "userId" : "jmbarbarino", - "version" : 30 + "version" : 57 }, "recommendations" : [ { @@ -141955,14 +143517,14 @@ "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104827", "name" : "Annotation of FDA Label for atomoxetine and CYP2D6", - "version" : 30 + "version" : 57 }, "text" : { "id" : 1452216391, @@ -142003,7 +143565,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 4, + "version" : 5, "year" : -1 } ], @@ -142035,7 +143597,7 @@ "date" : "2020-10-15T00:00:00-07:00", "description" : "Removing TPMT alleles and NUDT15 rsID because label does not specify them but rather refers to TPMT and NUDT15 deficiency", "type" : "Update", - "version" : 0 + "version" : 1 }, { "id" : 1452213600, @@ -142060,14 +143622,14 @@ "id" : "PA134963132", "symbol" : "NUDT15", "name" : "nudix hydrolase 15", - "version" : 11 + "version" : 39 }, { "objCls" : "Gene", "id" : "PA356", "symbol" : "TPMT", "name" : "thiopurine S-methyltransferase", - "version" : 7545 + "version" : 7628 } ], "prescribingMarkdown" : { @@ -142081,7 +143643,7 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "relatedGenes" : [ @@ -142090,14 +143652,14 @@ "id" : "PA134963132", "symbol" : "NUDT15", "name" : "nudix hydrolase 15", - "version" : 11 + "version" : 39 }, { "objCls" : "Gene", "id" : "PA356", "symbol" : "TPMT", "name" : "thiopurine S-methyltransferase", - "version" : 7545 + "version" : 7628 } ], "source" : "FDA", @@ -142123,34 +143685,34 @@ "version" : 1 }, "userId" : "jmbarbarino", - "version" : 33 + "version" : 72 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166310968", - "name" : "Recommendation Annotation PA166310968", + "id" : "PA166310941", + "name" : "Recommendation Annotation PA166310941", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "No Result"}, + "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104782", "name" : "Annotation of FDA Label for azathioprine and NUDT15, TPMT", - "version" : 33 + "version" : 72 }, "text" : { - "id" : 1452213567, + "id" : 1452213540, "html" : "

"Consider alternative therapy in patients with homozygous TPMT or NUDT15 deficiency." See label for more information.

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"Consider...reduced dosages in patients with heterozygous [TPMT or NUDT15] deficiency...Because of the risk of increased toxicity, dosage reduction is recommended in patients known to have heterozygous deficiency of TPMT or NUDT15." See label for more information.

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"Consider alternative therapy in patients with homozygous TPMT or NUDT15 deficiency." See label for more information.

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"Consider...reduced dosages in patients with heterozygous [TPMT or NUDT15] deficiency...Because of the risk of increased toxicity, dosage reduction is recommended in patients known to have heterozygous deficiency of TPMT or NUDT15." See label for more information.

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"Consider...reduced dosages in patients with heterozygous [TPMT or NUDT15] deficiency...Because of the risk of increased toxicity, dosage reduction is recommended in patients known to have heterozygous deficiency of TPMT or NUDT15." See label for more information.

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"Consider...reduced dosages in patients with heterozygous [TPMT or NUDT15] deficiency...Because of the risk of increased toxicity, dosage reduction is recommended in patients known to have heterozygous deficiency of TPMT or NUDT15." See label for more information.

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"Consider...reduced dosages in patients with heterozygous [TPMT or NUDT15] deficiency...Because of the risk of increased toxicity, dosage reduction is recommended in patients known to have heterozygous deficiency of TPMT or NUDT15." See label for more information.

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"Consider...reduced dosages in patients with heterozygous [TPMT or NUDT15] deficiency...Because of the risk of increased toxicity, dosage reduction is recommended in patients known to have heterozygous deficiency of TPMT or NUDT15." See label for more information.

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"Consider...reduced dosages in patients with heterozygous [TPMT or NUDT15] deficiency...Because of the risk of increased toxicity, dosage reduction is recommended in patients known to have heterozygous deficiency of TPMT or NUDT15." See label for more information.

\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166311487", + "name" : "Recommendation Annotation PA166311487", + "alternateDrugAvailable" : false, + "dosingInformation" : true, + "implications" : [], + "lookupKey" : {"TPMT": "No Result", "NUDT15": "Possible Intermediate Metabolizer"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA448515", + "name" : "azathioprine", + "version" : 57 + } + ], + "source" : { + "objCls" : "Label Annotation", + "id" : "PA166104782", + "name" : "Annotation of FDA Label for azathioprine and NUDT15, TPMT", + "version" : 72 + }, + "text" : { + "id" : 1452215666, + "html" : "

"Consider...reduced dosages in patients with heterozygous [TPMT or NUDT15] deficiency...Because of the risk of increased toxicity, dosage reduction is recommended in patients known to have heterozygous deficiency of TPMT or NUDT15." See label for more information.

\n", + "version" : 0 + }, + "version" : 0 } ], "url" : "https://www.pharmgkb.org/labelAnnotation/PA166104782" @@ -142968,7 +144530,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 4, + "version" : 5, "year" : -1 } ], @@ -143005,7 +144567,7 @@ "id" : "PA420", "symbol" : "UGT1A1", "name" : "UDP glucuronosyltransferase 1 family, polypeptide A1", - "version" : 6110 + "version" : 6350 } ], "prescribingMarkdown" : { @@ -143019,7 +144581,7 @@ "objCls" : "Chemical", "id" : "PA165971474", "name" : "belinostat", - "version" : 5 + "version" : 12 } ], "relatedGenes" : [ @@ -143028,7 +144590,7 @@ "id" : "PA420", "symbol" : "UGT1A1", "name" : "UDP glucuronosyltransferase 1 family, polypeptide A1", - "version" : 6110 + "version" : 6350 } ], "source" : "FDA", @@ -143054,7 +144616,7 @@ "version" : 1 }, "userId" : "jmbarbarino", - "version" : 38 + "version" : 69 }, "recommendations" : [ { @@ -143071,14 +144633,14 @@ "objCls" : "Chemical", "id" : "PA165971474", "name" : "belinostat", - "version" : 5 + "version" : 12 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166129553", "name" : "Annotation of FDA Label for belinostat and UGT1A1", - "version" : 38 + "version" : 69 }, "text" : { "id" : 1452217300, @@ -143086,6 +144648,36 @@ "version" : 0 }, "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166339761", + "name" : "Recommendation Annotation PA166339761", + "alternateDrugAvailable" : false, + "dosingInformation" : true, + "implications" : [], + "lookupKey" : {"UGT1A1": {"*80+*28": 2}}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA165971474", + "name" : "belinostat", + "version" : 12 + } + ], + "source" : { + "objCls" : "Label Annotation", + "id" : "PA166129553", + "name" : "Annotation of FDA Label for belinostat and UGT1A1", + "version" : 69 + }, + "text" : { + "id" : 1452486220, + "html" : "

"Reduce the starting dose of Beleodaq [belinostat] to 750 mg/m2 in patients known to be homozygous for the UGT1A1*28 allele to minimize dose limiting toxicities." See label for more information.

\n", + "version" : 0 + }, + "version" : 0 } ], "url" : "https://www.pharmgkb.org/labelAnnotation/PA166129553" @@ -143119,7 +144711,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 3, + "version" : 4, "year" : -1 } ], @@ -143170,14 +144762,14 @@ "id" : "PA124", "symbol" : "CYP2C19", "name" : "cytochrome P450 family 2 subfamily C member 19", - "version" : 7210 + "version" : 7266 }, { "objCls" : "Gene", "id" : "PA37189", "symbol" : "UGT2B17", "name" : "UDP glucuronosyltransferase family 2 member B17", - "version" : 11 + "version" : 34 } ], "prescribingMarkdown" : { @@ -143191,14 +144783,14 @@ "id" : "PA165980635", "symbol" : "CYP2C19*2", "name" : "*2", - "version" : 25 + "version" : 44 }, { "objCls" : "Haplotype", "id" : "PA165980636", "symbol" : "CYP2C19*3", "name" : "*3", - "version" : 25 + "version" : 44 } ], "relatedChemicals" : [ @@ -143206,7 +144798,7 @@ "objCls" : "Chemical", "id" : "PA166268761", "name" : "belzutifan", - "version" : 3 + "version" : 4 } ], "relatedGenes" : [ @@ -143215,14 +144807,14 @@ "id" : "PA124", "symbol" : "CYP2C19", "name" : "cytochrome P450 family 2 subfamily C member 19", - "version" : 7210 + "version" : 7266 }, { "objCls" : "Gene", "id" : "PA37189", "symbol" : "UGT2B17", "name" : "UDP glucuronosyltransferase family 2 member B17", - "version" : 11 + "version" : 34 } ], "source" : "FDA", @@ -143245,10 +144837,10 @@ "textMarkdown" : { "id" : 1451741247, "html" : "

Excerpts from the belzutifan (WELIREG) label:

\n
\n

Monitor for anemia before initiation of, and periodically throughout, treatment with WELIREG. Closely monitor patients who are dual UGT2B17 and CYP2C19 poor metabolizers due to potential increases in exposure that may increase the incidence or severity of anemia.

\n
\n
\n

Coadministration of WELIREG with inhibitors of UGT2B17 or CYP2C19 increases plasma exposure of belzutifan, which may increase the incidence and severity of adverse reactions of WELIREG. Monitor for anemia and hypoxia and reduce the dosage of WELIREG as recommended

\n
\n
\n

Pharmacogenomics\nPatients who are UGT2B17, CYP2C19, or dual UGT2B17 and CYP2C19 poor metabolizers have 2-, 1.6-, or 3.2-fold higher belzutifan steady state AUC0-24h (respectively) compared to patients who are UGT2B17 normal (extensive) metabolizers and CYP2C19 non-poor (ultrarapid, rapid, normal, and intermediate) metabolizers.\nUGT2B17 poor metabolizers who are homozygous for the UGT2B17*2 allele have no UGT2B17 enzyme activity. CYP2C19 poor metabolizers (such as *2/*2, *3/*3, *2/*3) have significantly reduced or absent CYP2C19 enzyme activity. Approximately 15% of White, 6% of Black or African American, and up to 77% of certain Asian populations are UGT2B17 poor metabolizers. Approximately 2% of White, 5% of Black or African American, and up to 19% of certain Asian populations are CYP2C19 poor metabolizers. Approximately 0.4% of White, 0.3% of Black or African American, and up to 15% of certain Asian populations are dual UGT2B17 and CYP2C19 poor metabolizers.

\n
\n

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the belzutifan drug label.

\n

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

\n", - "version" : 0 + "version" : 1 }, "userId" : "cfthorn", - "version" : 12 + "version" : 24 }, "recommendations" : [ { @@ -143257,9 +144849,7 @@ "name" : "Recommendation Annotation PA166308241", "alternateDrugAvailable" : false, "dosingInformation" : false, - "implications" : [ - "\"Patients who are dual UGT2B17 and CYP2C19 poor metabolizers have higher belzutifan exposures, which may increase the incidence and severity of adverse reactions of WELIREG [belzutifan].\"" - ], + "implications" : [], "lookupKey" : {"CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ @@ -143267,21 +144857,21 @@ "objCls" : "Chemical", "id" : "PA166268761", "name" : "belzutifan", - "version" : 3 + "version" : 4 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166268882", "name" : "Annotation of FDA Label for belzutifan and CYP2C19, UGT2B17", - "version" : 12 + "version" : 24 }, "text" : { "id" : 1452193120, - "html" : "

"Closely monitor for adverse reactions in patients who are dual UGT2B17 and CYP2C19 poor metabolizers." See label for more information.

\n", - "version" : 0 + "html" : "

The belzutifan (WELIREG) label states: "Closely monitor for adverse reactions in patients who are dual UGT2B17 and CYP2C19 poor metabolizers." "Patients who are dual UGT2B17 and CYP2C19 poor metabolizers have higher belzutifan exposures, which may increase the incidence and severity of adverse reactions of WELIREG (belzutifan)." See label for more information.

\n", + "version" : 2 }, - "version" : 0 + "version" : 8 }, { "objCls" : "Recommendation Annotation", @@ -143289,9 +144879,7 @@ "name" : "Recommendation Annotation PA166309882", "alternateDrugAvailable" : false, "dosingInformation" : false, - "implications" : [ - "\"Patients who are dual UGT2B17 and CYP2C19 poor metabolizers have higher belzutifan exposures, which may increase the incidence and severity of adverse reactions of WELIREG [belzutifan].\"" - ], + "implications" : [], "lookupKey" : {"CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ @@ -143299,21 +144887,21 @@ "objCls" : "Chemical", "id" : "PA166268761", "name" : "belzutifan", - "version" : 3 + "version" : 4 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166268882", "name" : "Annotation of FDA Label for belzutifan and CYP2C19, UGT2B17", - "version" : 12 + "version" : 24 }, "text" : { "id" : 1452208381, - "html" : "

"Closely monitor for adverse reactions in patients who are dual UGT2B17 and CYP2C19 poor metabolizers." See label for more information.

\n", - "version" : 0 + "html" : "

The belzutifan (WELIREG) label states: "Closely monitor for adverse reactions in patients who are dual UGT2B17 and CYP2C19 poor metabolizers." "Patients who are dual UGT2B17 and CYP2C19 poor metabolizers have higher belzutifan exposures, which may increase the incidence and severity of adverse reactions of WELIREG (belzutifan)." See label for more information.

\n", + "version" : 2 }, - "version" : 0 + "version" : 4 } ], "url" : "https://www.pharmgkb.org/labelAnnotation/PA166268882" @@ -143347,7 +144935,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 4, + "version" : 5, "year" : -1 } ], @@ -143384,13 +144972,13 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "prescribingMarkdown" : { "id" : 1450396271, "html" : "

Excerpt from the brexpiprazole (REXULTI) drug label:

\n
\n

Table 1: Dosage Adjustments of REXULTI for CYP2D6 Poor Metabolizers and for Concomitant Use with CYP3A4 and CYP2D6 Inhibitors and/or CYP3A4 Inducers

\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
FactorsAdjusted REXULTI Dosage
CYP2D6 poor metabolizersAdminister half of the usual dose
Known CYP2D6 poor metabolizers taking strong/moderate CYP3A4 inhibitorsAdminister a quarter of the usual dose
\n
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The FDA-approved drug label for brexpiprazole (REXULTI) states that known CYP2D6 poor metabolizers should have their usual dosage reduced by half, and that known CYP2D6 poor metabolizers who are also taking strong/moderate CYP3A4 inhibitors should be administered a quarter of the usual dose. However, the label does not mention genetic testing.

\n", - "version" : 1 + "version" : 2 }, "terms" : [], "testing" : { @@ -143433,7 +145021,7 @@ "version" : 0 }, "userId" : "jmbarbarino", - "version" : 33 + "version" : 58 }, "recommendations" : [ { @@ -143450,14 +145038,14 @@ "objCls" : "Chemical", "id" : "PA166160053", "name" : "brexpiprazole", - "version" : 5 + "version" : 8 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166160054", "name" : "Annotation of FDA Label for brexpiprazole and CYP2D6", - "version" : 33 + "version" : 58 }, "text" : { "id" : 1452216483, @@ -143498,7 +145086,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 4, + "version" : 5, "year" : -1 } ], @@ -143547,7 +145135,7 @@ "id" : "PA124", "symbol" : "CYP2C19", "name" : "cytochrome P450 family 2 subfamily C member 19", - "version" : 7210 + "version" : 7266 } ], "prescribingMarkdown" : { @@ -143561,7 +145149,7 @@ "objCls" : "Chemical", "id" : "PA166153491", "name" : "brivaracetam", - "version" : 5 + "version" : 6 } ], "relatedGenes" : [ @@ -143570,14 +145158,14 @@ "id" : "PA124", "symbol" : "CYP2C19", "name" : "cytochrome P450 family 2 subfamily C member 19", - "version" : 7210 + "version" : 7266 } ], "source" : "FDA", "summaryMarkdown" : { "id" : 1447991035, "html" : "

The FDA-approved drug label for brivaracetam (BRIVIACT) states that CYP2C19 intermediate or poor metabolizers may have increased levels of brivaracetam, and that poor metabolizers may require a dose reduction.

\n", - "version" : 0 + "version" : 2 }, "terms" : [], "testing" : { @@ -143596,7 +145184,7 @@ "version" : 0 }, "userId" : "jmbarbarino", - "version" : 37 + "version" : 64 }, "recommendations" : [ { @@ -143613,21 +145201,21 @@ "objCls" : "Chemical", "id" : "PA166153491", "name" : "brivaracetam", - "version" : 5 + "version" : 6 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166153492", "name" : "Annotation of FDA Label for brivaracetam and CYP2C19", - "version" : 37 + "version" : 64 }, "text" : { "id" : 1452157580, "html" : "

"CYP2C19 poor metabolizers and patients using inhibitors of CYP2C19 may require dose reduction." See label for more information.

\n", - "version" : 0 + "version" : 2 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", @@ -143643,21 +145231,21 @@ "objCls" : "Chemical", "id" : "PA166153491", "name" : "brivaracetam", - "version" : 5 + "version" : 6 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166153492", "name" : "Annotation of FDA Label for brivaracetam and CYP2C19", - "version" : 37 + "version" : 64 }, "text" : { "id" : 1452211580, "html" : "

"CYP2C19 poor metabolizers and patients using inhibitors of CYP2C19 may require dose reduction." See label for more information.

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The risks and benefits of Tegretol therapy should be weighed before considering Tegretol in patients known to be positive for HLA-A*3101.

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Retrospective case-control studies in patients of European, Korean, and Japanese ancestry have found a moderate association between the risk of developing hypersensitivity reactions and the presence of HLA-A*3101, an inherited allelic variant of the HLA-A gene, in patients using carbamazepine. These hypersensitivity reactions include SJS/TEN, maculopapular eruptions, and Drug Reaction with Eosinophilia and Systemic Symptoms (see DRESS/Multiorgan hypersensitivity below).

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The FDA-approved label for carbamazepine (TEGRETOL) states that a moderate association has been found between HLA-A*3101 and the risk of developing hypersensitivity reactions to carbamazepine, and the risks and benefits of Tegretol therapy should be weighed before considering Tegretol in patients known to be positive for HLA-A*3101. The label also states that screening of patients with ancestry in genetically at-risk populations (patients of Asian descent) for the presence of the HLA-B*1502 allele should be carried out prior to treatment due to a high risk of serious and possibly fatal dermatologic reactions.

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Excerpt from the carbamazepine (TEGRETOL) drug label:

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\n

Hypersensitivity Reactions and HLA-A*3101 Allele

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Retrospective case-control studies in patients of European, Korean, and Japanese ancestry have found a moderate association between the risk of developing hypersensitivity reactions and the presence of HLAA*3101, an inherited allelic variant of the HLA-A gene, in patients using carbamazepine. These hypersensitivity reactions include SJS/TEN, maculopapular eruptions, and Drug Reaction with Eosinophilia and Systemic Symptoms (see DRESS/Multiorgan hypersensitivity below).

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\n
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HLA-A*3101 is expected to be carried by more than 15% of patients of Japanese, Native American, Southern Indian (for example, Tamil Nadu), and some Arabic ancestry; up to about 10% in patients of Han Chinese, Korean, European, Latin American, and other Indian ancestry; and up to about 5% in African-Americans and patients of Thai, Taiwanese, and Chinese (Hong Kong) ancestry.

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The risks and benefits of Tegretol therapy should be weighed before considering Tegretol in patients known to be positive for HLA-A*3101.

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Application of HLA genotyping as a screening tool has important limitations and must never substitute for appropriate clinical vigilance and patient management. Many HLA-B*1502-positive and HLA-A*3101-positive patients treated with Tegretol will not develop SJS/TEN or other hypersensitivity reactions, and these reactions can still occur infrequently in HLA-B*1502-negative and HLA-A*3101-negative patients of any ethnicity. The role of other possible factors in the development of, and morbidity from, SJS/TEN and other hypersensitivity reactions, such as antiepileptic drug (AED) dose, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring, have not been studied.

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For the complete drug label text with sections containing pharmacogenetic information highlighted, see the carbamazepine drug label.

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*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

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The Tegretol (carbamazepine) label states: "The risks and benefits of Tegretol therapy should be weighed before considering Tegretol in patients known to be positive for HLA-A*3101." "Retrospective case-control studies in patients of European, Korean, and Japanese ancestry have found a moderate association between the risk of developing hypersensitivity reactions and the presence of HLA-A*3101, an inherited allelic variant of the HLA-A gene, in patients using carbamazepine. These hypersensitivity reactions include SJS/TEN, maculopapular eruptions, and Drug Reaction with Eosinophilia and Systemic Symptoms" See label for more information.

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Carisoprodol (SOMA) is skeletal muscle relaxant. The FDA-approved drug label for carisoprodol (SOMA) highlights information regarding CYP2C19 poor metabolizers.

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Excerpt from the carisoprodol drug label:

\n
\n

Patients with Reduced CYP2C19 Activity: SOMA should be used with caution in patients with reduced CYP2C19 activity. Published studies indicate that patients who are poor CYP2C19 metabolizers have a 4-fold increase in exposure to carisoprodol, and concomitant 50% reduced exposure to meprobamate compared to normal CYP2C19 metabolizers. The prevalence of poor metabolizers in Caucasians and African Americans is approximately 3-5% and in Asians is approximately 15-20%.

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For the complete drug label text with sections containing pharmacogenetic information highlighted, see the carisoprodol drug label.

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*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

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"Patients with Reduced CYP2C19 Activity: SOMA [carisoprodol] should be used with caution in patients with reduced CYP2C19 activity." See label for more information.

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"Patients with Reduced CYP2C19 Activity: SOMA [carisoprodol] should be used with caution in patients with reduced CYP2C19 activity." See label for more information.

\n", - "version" : 0 + "version" : 1 }, - "version" : 0 + "version" : 2 } ], "url" : "https://www.pharmgkb.org/labelAnnotation/PA166104832" @@ -144244,7 +146004,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 3, + "version" : 4, "year" : -1 } ], @@ -144295,14 +146055,14 @@ "id" : "PA27331", "symbol" : "CYB5R3", "name" : "cytochrome b5 reductase 3", - "version" : 13 + "version" : 80 }, { "objCls" : "Gene", "id" : "PA28469", "symbol" : "G6PD", "name" : "glucose-6-phosphate dehydrogenase", - "version" : 135 + "version" : 1326 } ], "prescribingMarkdown" : { @@ -144316,7 +146076,7 @@ "objCls" : "Chemical", "id" : "PA448866", "name" : "ceftriaxone", - "version" : 7 + "version" : 21 } ], "relatedGenes" : [ @@ -144325,14 +146085,14 @@ "id" : "PA27331", "symbol" : "CYB5R3", "name" : "cytochrome b5 reductase 3", - "version" : 13 + "version" : 80 }, { "objCls" : "Gene", "id" : "PA28469", "symbol" : "G6PD", "name" : "glucose-6-phosphate dehydrogenase", - "version" : 135 + "version" : 1326 } ], "source" : "FDA", @@ -144358,39 +146118,9 @@ "version" : 1 }, "userId" : "cfthorn", - "version" : 12 + "version" : 19 }, "recommendations" : [ - { - "objCls" : "Recommendation Annotation", - "id" : "PA166312418", - "name" : "Recommendation Annotation PA166312418", - "alternateDrugAvailable" : false, - "dosingInformation" : false, - "implications" : [], - "lookupKey" : {"G6PD": "Deficient"}, - "otherPrescribingGuidance" : true, - "relatedChemicals" : [ - { - "objCls" : "Chemical", - "id" : "PA448866", - "name" : "ceftriaxone", - "version" : 7 - } - ], - "source" : { - "objCls" : "Label Annotation", - "id" : "PA166182746", - "name" : "Annotation of FDA Label for ceftriaxone and CYB5R3, G6PD", - "version" : 12 - }, - "text" : { - "id" : 1452216717, - "html" : "

"Although all patients are at risk for methemoglobinemia, patients with glucose-6-phosphate dehydrogenase deficiency, ... are more susceptible to developing clinical manifestations of the condition. If local anesthetics must be used in these patients, close monitoring for symptoms and signs of methemoglobinemia is recommended." See label for more information.

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"Although all patients are at risk for methemoglobinemia, patients with glucose-6-phosphate dehydrogenase deficiency, ... are more susceptible to developing clinical manifestations of the condition. If local anesthetics must be used in these patients, close monitoring for symptoms and signs of methemoglobinemia is recommended." See label for more information.

\n", + "version" : 0 + }, + "version" : 0 } ], "url" : "https://www.pharmgkb.org/labelAnnotation/PA166182746" @@ -144483,7 +146243,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 5, + "version" : 6, "year" : -1 } ], @@ -144533,7 +146293,7 @@ "id" : "PA126", "symbol" : "CYP2C9", "name" : "cytochrome P450 family 2 subfamily C member 9", - "version" : 7877 + "version" : 7952 } ], "prescribingMarkdown" : { @@ -144547,7 +146307,7 @@ "id" : "PA165816544", "symbol" : "CYP2C9*3", "name" : "*3", - "version" : 25 + "version" : 55 } ], "relatedChemicals" : [ @@ -144555,7 +146315,7 @@ "objCls" : "Chemical", "id" : "PA448871", "name" : "celecoxib", - "version" : 22 + "version" : 43 } ], "relatedGenes" : [ @@ -144564,7 +146324,7 @@ "id" : "PA126", "symbol" : "CYP2C9", "name" : "cytochrome P450 family 2 subfamily C member 9", - "version" : 7877 + "version" : 7952 } ], "source" : "FDA", @@ -144587,37 +146347,37 @@ "textMarkdown" : { "id" : 1450342775, "html" : "

Excerpts from the celecoxib (CELEBREX) drug label:

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\n

Dosage and administration:

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Poor Metabolizers of CYP2C9 Substrates: Consider a dose reduction by 50% (or alternative management for JRA) in patients who are known or suspected to be CYP2C9 poor metabolizers.

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\n
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Poor Metabolizers of CYP2C9 Substrates:

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\n
\n

In patients who are known or suspected to be poor CYP2C9 metabolizers (i.e., CYP2C9*3/*3), based on genotype or previous history/experience with other CYP2C9 substrates (such as warfarin, phenytoin) administer CELEBREX starting with half the lowest recommended dose. Alternative management should be considered in JRA patients identified to be CYP2C9 poor metabolizers.

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Pharmacogenomics: CYP2C9 activity is reduced in individuals with genetic polymorphisms that lead to reduced enzyme activity, such as those homozygous for the CYP2C9*2 and CYP2C9*3 polymorphisms. Limited data from 4 published reports that included a total of 8 subjects with the homozygous CYP2C9*3/*3 genotype showed celecoxib systemic levels that were 3- to 7-fold higher in these subjects compared to subjects with CYP2C9*1/*1 or *I/*3 genotypes. The pharmacokinetics of celecoxib have not been evaluated in subjects with other CYP2C9 polymorphisms, such as *2, *5, *6, *9 and *11. It is estimated that the frequency of the homozygous *3/*3 genotype is 0.3% to 1.0% in various ethnic groups.

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For the complete drug label text with sections containing pharmacogenetic information highlighted, see the celecoxib drug label.

\n

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

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"Poor Metabolizers of CYP2C9 Substrates: Consider a dose reduction by 50% (or alternative management for JRA) in patients who are known or suspected to be CYP2C9 poor metabolizers." See label for more information.

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"Poor Metabolizers of CYP2C9 Substrates: Consider a dose reduction by 50% (or alternative management for JRA) in patients who are known or suspected to be CYP2C9 poor metabolizers." See label for more information.

\n", "version" : 0 }, @@ -144685,7 +146445,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 4, + "version" : 5, "year" : -1 } ], @@ -144721,7 +146481,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "prescribingMarkdown" : { @@ -144735,7 +146495,7 @@ "objCls" : "Chemical", "id" : "PA164754754", "name" : "cevimeline", - "version" : 6 + "version" : 21 } ], "relatedGenes" : [ @@ -144744,7 +146504,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "FDA", @@ -144770,7 +146530,7 @@ "version" : 1 }, "userId" : "whaleyr", - "version" : 32 + "version" : 50 }, "recommendations" : [ { @@ -144787,14 +146547,14 @@ "objCls" : "Chemical", "id" : "PA164754754", "name" : "cevimeline", - "version" : 6 + "version" : 21 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104787", "name" : "Annotation of FDA Label for cevimeline and CYP2D6", - "version" : 32 + "version" : 50 }, "text" : { "id" : 1452221380, @@ -144836,7 +146596,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 4, + "version" : 5, "year" : -1 } ], @@ -144907,7 +146667,7 @@ "id" : "PA28469", "symbol" : "G6PD", "name" : "glucose-6-phosphate dehydrogenase", - "version" : 135 + "version" : 1326 } ], "prescribingMarkdown" : { @@ -144921,7 +146681,7 @@ "objCls" : "Chemical", "id" : "PA448948", "name" : "chloroquine", - "version" : 14 + "version" : 48 } ], "relatedGenes" : [ @@ -144930,14 +146690,14 @@ "id" : "PA28469", "symbol" : "G6PD", "name" : "glucose-6-phosphate dehydrogenase", - "version" : 135 + "version" : 1326 } ], "source" : "FDA", "summaryMarkdown" : { "id" : 1450342785, "html" : "

The FDA-approved drug label for chloroquine (ARALAN) states that it may cause hemolysis in glucose-6-phosphate dehydrogenase (G6PD) deficient individuals. However, CDC guidelines from 2019 recommend chloroquine for malaria prophylaxis in patients who cannot be treated with primaquine or tafenoquine due to G6PD deficiency.

\n", - "version" : 2 + "version" : 3 }, "terms" : [], "testing" : { @@ -144953,37 +146713,37 @@ "textMarkdown" : { "id" : 1450342786, "html" : "

Excerpt from the chloroquine (ARALAN) drug label:

\n
\n

Chloroquine may cause hemolysis in glucose-6 phosphate dehydrogenase (G-6-PD) deficiency. Blood monitoring may be needed as hemolytic anemia may occur, in particular in association with other drugs that cause hemolysis.

\n
\n

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the chloroquine drug label.

\n

Excerpt from the CDC Treatment of Malaria: Guidelines for Clinicians (United States)

\n
\n

Patients with G6PD deficiency who are not expected to tolerate primaquine or tafenoquine should be put on chloroquine\nprophylaxis (300 mg)

\n
\n

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

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"Chloroquine may cause hemolysis in glucose-6 phosphate dehydrogenase (G-6-PD) deficiency. Blood monitoring may be needed as hemolytic anemia may occur, in particular in association with other drugs that cause hemolysis." See label for more information.

\n", "version" : 0 }, @@ -144991,29 +146751,29 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312763", - "name" : "Recommendation Annotation PA166312763", + "id" : "PA166312761", + "name" : "Recommendation Annotation PA166312761", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"G6PD": "Variable"}, + "lookupKey" : {"G6PD": "Deficient with CNSHA"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448948", "name" : "chloroquine", - "version" : 14 + "version" : 48 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104786", "name" : "Annotation of FDA Label for chloroquine and G6PD", - "version" : 33 + "version" : 55 }, "text" : { - "id" : 1452219102, + "id" : 1452219100, "html" : "

"Chloroquine may cause hemolysis in glucose-6 phosphate dehydrogenase (G-6-PD) deficiency. Blood monitoring may be needed as hemolytic anemia may occur, in particular in association with other drugs that cause hemolysis." See label for more information.

\n", "version" : 0 }, @@ -145021,29 +146781,29 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312761", - "name" : "Recommendation Annotation PA166312761", + "id" : "PA166312762", + "name" : "Recommendation Annotation PA166312762", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"G6PD": "Deficient with CNSHA"}, + "lookupKey" : {"G6PD": "Deficient"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448948", "name" : "chloroquine", - "version" : 14 + "version" : 48 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104786", "name" : "Annotation of FDA Label for chloroquine and G6PD", - "version" : 33 + "version" : 55 }, "text" : { - "id" : 1452219100, + "id" : 1452219101, "html" : "

"Chloroquine may cause hemolysis in glucose-6 phosphate dehydrogenase (G-6-PD) deficiency. Blood monitoring may be needed as hemolytic anemia may occur, in particular in association with other drugs that cause hemolysis." See label for more information.

\n", "version" : 0 }, @@ -145082,7 +146842,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 4, + "version" : 5, "year" : -1 } ], @@ -145132,13 +146892,13 @@ "id" : "PA28469", "symbol" : "G6PD", "name" : "glucose-6-phosphate dehydrogenase", - "version" : 135 + "version" : 1326 } ], "prescribingMarkdown" : { "id" : 1450379956, "html" : "

Excerpt from the chlorpropamide (DIABINESE) drug label:

\n
\n

Treatment of patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency with sulfonylurea agents can lead to hemolytic anemia. Because DIABINESE belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD deficiency and a non-sulfonylurea alternative should be considered.

\n
\n", - "version" : 2 + "version" : 4 }, "relatedAlleles" : [], "relatedChemicals" : [ @@ -145146,7 +146906,7 @@ "objCls" : "Chemical", "id" : "PA448966", "name" : "chlorpropamide", - "version" : 10 + "version" : 26 } ], "relatedGenes" : [ @@ -145155,7 +146915,7 @@ "id" : "PA28469", "symbol" : "G6PD", "name" : "glucose-6-phosphate dehydrogenase", - "version" : 135 + "version" : 1326 } ], "source" : "FDA", @@ -145178,37 +146938,37 @@ "textMarkdown" : { "id" : 1450342790, "html" : "

Chlorpropamide (DIABINESE) is a blood-glucose-lowering drug indicated for use in adults with type 2 diabetes mellitus as an adjunct to diet and exercise.

\n

Excerpt from the chlorpropamide (DIABINESE) drug label:

\n
\n

Hemolytic Anemia: Treatment of patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency with sulfonylurea agents can lead to hemolytic anemia. Because DIABINESE belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD deficiency and a non-sulfonylurea alternative should be considered.

\n
\n

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the chlorpropamide drug label.

\n

*Disclaimer: The contents of this page are the sole responsibility of PharmGKB.

\n", - "version" : 0 + "version" : 1 }, "userId" : "whaleyr", - "version" : 33 + "version" : 51 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166312304", - "name" : "Recommendation Annotation PA166312304", + "id" : "PA166315042", + "name" : "Recommendation Annotation PA166315042", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"G6PD": "Deficient with CNSHA"}, + "lookupKey" : {"G6PD": "Variable"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448966", "name" : "chlorpropamide", - "version" : 10 + "version" : 26 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166114910", "name" : "Annotation of FDA Label for chlorpropamide and G6PD", - "version" : 33 + "version" : 51 }, "text" : { - "id" : 1452216564, + "id" : 1452245581, "html" : "

"Because DIABINESE [chlorpropamide] belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD deficiency and a non-sulfonylurea alternative should be considered." See label for more information.

\n", "version" : 0 }, @@ -145216,29 +146976,29 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166315042", - "name" : "Recommendation Annotation PA166315042", + "id" : "PA166312304", + "name" : "Recommendation Annotation PA166312304", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"G6PD": "Variable"}, + "lookupKey" : {"G6PD": "Deficient with CNSHA"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448966", "name" : "chlorpropamide", - "version" : 10 + "version" : 26 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166114910", "name" : "Annotation of FDA Label for chlorpropamide and G6PD", - "version" : 33 + "version" : 51 }, "text" : { - "id" : 1452245581, + "id" : 1452216564, "html" : "

"Because DIABINESE [chlorpropamide] belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD deficiency and a non-sulfonylurea alternative should be considered." See label for more information.

\n", "version" : 0 }, @@ -145258,14 +147018,14 @@ "objCls" : "Chemical", "id" : "PA448966", "name" : "chlorpropamide", - "version" : 10 + "version" : 26 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166114910", "name" : "Annotation of FDA Label for chlorpropamide and G6PD", - "version" : 33 + "version" : 51 }, "text" : { "id" : 1452216565, @@ -145306,7 +147066,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 4, + "version" : 5, "year" : -1 } ], @@ -145356,7 +147116,7 @@ "id" : "PA124", "symbol" : "CYP2C19", "name" : "cytochrome P450 family 2 subfamily C member 19", - "version" : 7210 + "version" : 7266 } ], "prescribingMarkdown" : { @@ -145370,7 +147130,7 @@ "objCls" : "Chemical", "id" : "PA449015", "name" : "citalopram", - "version" : 21 + "version" : 49 } ], "relatedGenes" : [ @@ -145379,7 +147139,7 @@ "id" : "PA124", "symbol" : "CYP2C19", "name" : "cytochrome P450 family 2 subfamily C member 19", - "version" : 7210 + "version" : 7266 } ], "source" : "FDA", @@ -145402,10 +147162,10 @@ "textMarkdown" : { "id" : 1450342817, "html" : "

Citalopram (CELEXA) is an antidepressant drug of the selective serotonin reuptake inhibitor (SSRI) class.

\n

Excerpts from the citalopram (CELEXA) drug label:

\n
\n

In CYP2C19 poor metabolizers, citalopram steady state Cmax and AUC was increased by 68% and 107%, respectively. Celexa 20 mg/day is the maximum recommended dose in CYP2C19 poor metabolizers due to the risk of QT prolongation.

\n
\n
\n

The maximum dose should be limited to 20 mg/day in patients who are CYP2C19 poor metabolizers...

\n
\n

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the citalopram drug label.

\n

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

\n", - "version" : 2 + "version" : 3 }, "userId" : "jmbarbarino", - "version" : 40 + "version" : 91 }, "recommendations" : [ { @@ -145414,9 +147174,7 @@ "name" : "Recommendation Annotation PA166308322", "alternateDrugAvailable" : false, "dosingInformation" : true, - "implications" : [ - "CYP2C19 poor metabolizers have higher systemic concentration and adverse reaction risk (QT prolongation)." - ], + "implications" : [], "lookupKey" : {"CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ @@ -145424,21 +147182,21 @@ "objCls" : "Chemical", "id" : "PA449015", "name" : "citalopram", - "version" : 21 + "version" : 49 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104852", "name" : "Annotation of FDA Label for citalopram and CYP2C19", - "version" : 40 + "version" : 91 }, "text" : { "id" : 1452193821, - "html" : "

"Celexa [citalopram] 20 mg/day is the maximum recommended dose in CYP2C19 poor metabolizers due to the risk of QT prolongation." See label for more information.

\n", - "version" : 0 + "html" : "

The citalopram (CELEXA) label states: "Celexa 20 mg/day is the maximum recommended dose in CYP2C19 poor metabolizers due to the risk of QT prolongation" "In CYP2C19 poor metabolizers, citalopram steady state Cmax and AUC was increased by 68% and 107%, respectively." See label for more information.

\n", + "version" : 4 }, - "version" : 0 + "version" : 6 }, { "objCls" : "Recommendation Annotation", @@ -145446,9 +147204,7 @@ "name" : "Recommendation Annotation PA166308342", "alternateDrugAvailable" : false, "dosingInformation" : true, - "implications" : [ - "CYP2C19 poor metabolizers have higher systemic concentration and adverse reaction risk (QT prolongation)." - ], + "implications" : [], "lookupKey" : {"CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ @@ -145456,21 +147212,21 @@ "objCls" : "Chemical", "id" : "PA449015", "name" : "citalopram", - "version" : 21 + "version" : 49 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104852", "name" : "Annotation of FDA Label for citalopram and CYP2C19", - "version" : 40 + "version" : 91 }, "text" : { "id" : 1452193841, - "html" : "

"Celexa [citalopram] 20 mg/day is the maximum recommended dose in CYP2C19 poor metabolizers due to the risk of QT prolongation." See label for more information.

\n", - "version" : 0 + "html" : "

The citalopram (CELEXA) label states: "Celexa 20 mg/day is the maximum recommended dose in CYP2C19 poor metabolizers due to the risk of QT prolongation" "In CYP2C19 poor metabolizers, citalopram steady state Cmax and AUC was increased by 68% and 107%, respectively." See label for more information.

\n", + "version" : 3 }, - "version" : 0 + "version" : 5 } ], "url" : "https://www.pharmgkb.org/labelAnnotation/PA166104852" @@ -145504,7 +147260,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 4, + "version" : 5, "year" : -1 } ], @@ -145547,7 +147303,7 @@ "id" : "PA124", "symbol" : "CYP2C19", "name" : "cytochrome P450 family 2 subfamily C member 19", - "version" : 7210 + "version" : 7266 } ], "prescribingMarkdown" : { @@ -145561,7 +147317,7 @@ "objCls" : "Chemical", "id" : "PA10888", "name" : "clobazam", - "version" : 11 + "version" : 27 } ], "relatedGenes" : [ @@ -145570,7 +147326,7 @@ "id" : "PA124", "symbol" : "CYP2C19", "name" : "cytochrome P450 family 2 subfamily C member 19", - "version" : 7210 + "version" : 7266 } ], "source" : "FDA", @@ -145593,71 +147349,71 @@ "textMarkdown" : { "id" : 1450342822, "html" : "

Clobazam (ONFI) is indicated for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in patients 2 years of age or older.

\n

Excerpts from the clobazam (ONFI) label:

\n
\n

In CYP2C19 poor metabolizers, levels of N-desmethylclobazam, clobazam’s active metabolite, will be increased. Therefore, in patients known to be CYP2C19 poor metabolizers, the starting dose should be 5 mg/day and dose titration should proceed slowly according to weight, but to half the dose presented in Table 1, as tolerated. If necessary and based upon clinical response, an additional titration to the maximum dose (20 mg/day or 40 mg/day, depending on the weight group) may be started on day 21.

\n
\n

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the clobazam drug label.

\n

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

\n", - "version" : 0 + "version" : 1 }, "userId" : "jmbarbarino", - "version" : 30 + "version" : 70 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166307682", - "name" : "Recommendation Annotation PA166307682", + "id" : "PA166307681", + "name" : "Recommendation Annotation PA166307681", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA10888", "name" : "clobazam", - "version" : 11 + "version" : 27 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104884", "name" : "Annotation of FDA Label for clobazam and CYP2C19", - "version" : 30 + "version" : 70 }, "text" : { - "id" : 1452162041, + "id" : 1452162040, "html" : "

"In CYP2C19 poor metabolizers ... the starting dose should be 5 mg/day and dose titration should proceed slowly according to weight, but to half the dose presented in Table 1 [of the drug label], as tolerated. If necessary and based upon clinical response, an additional titration to the maximum dose (20 mg/day or 40 mg/day, depending on the weight group) may be started on day 21." See label for more information.

\n", - "version" : 0 + "version" : 2 }, - "version" : 0 + "version" : 4 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166307681", - "name" : "Recommendation Annotation PA166307681", + "id" : "PA166307682", + "name" : "Recommendation Annotation PA166307682", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA10888", "name" : "clobazam", - "version" : 11 + "version" : 27 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104884", "name" : "Annotation of FDA Label for clobazam and CYP2C19", - "version" : 30 + "version" : 70 }, "text" : { - "id" : 1452162040, + "id" : 1452162041, "html" : "

"In CYP2C19 poor metabolizers ... the starting dose should be 5 mg/day and dose titration should proceed slowly according to weight, but to half the dose presented in Table 1 [of the drug label], as tolerated. If necessary and based upon clinical response, an additional titration to the maximum dose (20 mg/day or 40 mg/day, depending on the weight group) may be started on day 21." See label for more information.

\n", - "version" : 0 + "version" : 3 }, - "version" : 0 + "version" : 4 } ], "url" : "https://www.pharmgkb.org/labelAnnotation/PA166104884" @@ -145691,7 +147447,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 4, + "version" : 5, "year" : -1 } ], @@ -145741,7 +147497,7 @@ "id" : "PA124", "symbol" : "CYP2C19", "name" : "cytochrome P450 family 2 subfamily C member 19", - "version" : 7210 + "version" : 7266 } ], "prescribingMarkdown" : { @@ -145755,7 +147511,7 @@ "objCls" : "Chemical", "id" : "PA449053", "name" : "clopidogrel", - "version" : 20 + "version" : 58 } ], "relatedGenes" : [ @@ -145764,14 +147520,14 @@ "id" : "PA124", "symbol" : "CYP2C19", "name" : "cytochrome P450 family 2 subfamily C member 19", - "version" : 7210 + "version" : 7266 } ], "source" : "FDA", "summaryMarkdown" : { "id" : 1447981538, "html" : "

The FDA-approved drug label for clopidogrel (Plavix) warns that patients who are CYP2C19 poor metabolizers may have diminished effectiveness of the drug as compared to patients with normal CYP2C19 function. The drug label says to consider use of a different platelet P2Y12 inhibitor in patients identified as CYP2C19 poor metabolizers.

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"Consider use of another platelet P2Y12 inhibitor in patients identified as CYP2C19 poor metabolizers." See label for more information.

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"Consider use of another platelet P2Y12 inhibitor in patients identified as CYP2C19 poor metabolizers." See label for more information.

\n", - "version" : 0 + "version" : 1 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/labelAnnotation/PA166104777" @@ -145885,7 +147641,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 4, + "version" : 5, "year" : -1 } ], @@ -145928,7 +147684,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "prescribingMarkdown" : { @@ -145942,7 +147698,7 @@ "objCls" : "Chemical", "id" : "PA449061", "name" : "clozapine", - "version" : 9 + "version" : 46 } ], "relatedGenes" : [ @@ -145951,7 +147707,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "FDA", @@ -145974,10 +147730,10 @@ "textMarkdown" : { "id" : 1450342829, "html" : "

Clozapine (CLOZARIL) is an atypical antipsychotic drug. It is approved for the treatment of severely ill patients with schizophrenia who fail to show an acceptable response to standard antipsychotic drug treatment.

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Excerpts from the clozapine (CLOZARIL) drug label:

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It may be necessary to reduce the CLOZARIL dose in patients with significant renal or hepatic impairment, or in CYP2D6 poor metabolizers...

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A subset (3%–10%) of the population has reduced activity of CYP2D6 (CYP2D6 poor metabolizers). These individuals may develop higher than expected plasma concentrations of clozapine when given usual doses.

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For the complete drug label text with sections containing pharmacogenetic information highlighted, see the clozapine drug label.

\n

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

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"Dose reduction may be necessary in patients who are CYP2D6 poor metabolizers." See label for more information.

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The clozapine (CLOZARIL) label states: "Dose reduction may be necessary in patients who are CYP2D6 poor metabolizers." "These individuals [CY2D6 poor metabolizers] may develop higher than expected plasma concentrations of clozapine when given usual doses." See label for more information.

\n", + "version" : 1 }, - "version" : 0 + "version" : 3 } ], "url" : "https://www.pharmgkb.org/labelAnnotation/PA166104815" @@ -146044,7 +147798,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 4, + "version" : 5, "year" : -1 } ], @@ -146105,13 +147859,13 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "prescribingMarkdown" : { "id" : 1450385851, "html" : "

Excerpts from the codeine drug label:

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Life-threatening respiratory depression and death have occurred in children who received codeine; most cases followed tonsillectomy and/or adenoidectomy and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a CYP2D6 polymorphism. Codeine Sulfate Tablets are contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy.

\n
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...individuals who are ultra-rapid metabolizers should not use Codeine Sulfate Tablets.

\n
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On April 20th 2017, the FDA released a safety announcement stating that they are restricting the use of codeine and tramadol in children, and recommending against the use of codeine and tramadol in breastfeeding mothers due to possible harm to their infants. Please refer to the link above for full details on the safety announcement.

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Codeine is an opioid analgesic pro-drug, typically used for pain relief. It is metabolized by CYP2D6 into morphine, which is the active drug form.

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Excerpts from the codeine drug label:

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Life-threatening respiratory depression and death have occurred in children who received codeine; most cases followed tonsillectomy and/or adenoidectomy and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a CYP2D6 polymorphism.

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Nursing Mothers...At least one death was reported in a nursing infant who was exposed to high levels of morphine in breast milk because the mother was an ultra-rapid metabolizer of codeine. Breastfeeding is not recommended during treatment with Codeine Sulfate Tablets.

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Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype (e.g., gene duplications denoted as *1/*1xN or *1/*2xN). The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 1 to 10% for Whites (European, North American), 3 to 4% for Blacks (African Americans), 1 to 2% for East Asians (Chinese, Japanese, Korean), and may be greater than 10% in certain racial/ethnic groups (i.e., Oceanian, Northern African, Middle Eastern, Ashkenazi Jews, Puerto Rican). These individuals convert codeine into its active metabolite, morphine, more rapidly and completely than other people. This rapid conversion results in higher than expected serum morphine levels. Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may have life-threatening or fatal respiratory depression or experience signs of overdose (such as extreme sleepiness, confusion, or shallow breathing). Therefore, individuals who are ultra-rapid metabolizers should not use Codeine Sulfate Tablets.

\n
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For the complete drug label text with sections containing pharmacogenetic information highlighted, see the codeine drug label.

\n

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

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"... individuals who are ultra-rapid metabolizers should not use Codeine Sulfate Tablets." See label for more information.

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"... individuals who are ultra-rapid metabolizers should not use Codeine Sulfate Tablets." See label for more information.

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"... individuals who are ultra-rapid metabolizers should not use Codeine Sulfate Tablets." See label for more information.

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"... individuals who are ultra-rapid metabolizers should not use Codeine Sulfate Tablets." See label for more information.

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"... individuals who are ultra-rapid metabolizers should not use Codeine Sulfate Tablets." See label for more information.

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"... individuals who are ultra-rapid metabolizers should not use Codeine Sulfate Tablets." See label for more information.

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"... individuals who are ultra-rapid metabolizers should not use Codeine Sulfate Tablets." See label for more information.

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"... individuals who are ultra-rapid metabolizers should not use Codeine Sulfate Tablets." See label for more information.

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"... individuals who are ultra-rapid metabolizers should not use Codeine Sulfate Tablets." See label for more information.

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"... individuals who are ultra-rapid metabolizers should not use Codeine Sulfate Tablets." See label for more information.

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"... individuals who are ultra-rapid metabolizers should not use Codeine Sulfate Tablets." See label for more information.

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Excerpt from the dabrafenib (TAFINLAR) drug label:

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TAFINLAR, which contains a sulfonamide moiety, confers a potential risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Monitor patients with G6PD deficiency for signs of hemolytic anemia while taking TAFINLAR.

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The drug label for dabrafenib (TAFINLAR) states that it is indicated, as a single agent or in combination with trametinib, for patients with certain types of cancer. The label also notes that patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency have a risk for developing hemolytic anemia, and that these patients should be closely observed when taking dabrafenib.

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Dabrafenib (TAFINLAR) contains a sulfonamide moeity, and therefore confers a risk for hemolytic anemia in patients with glucose-6-phospate dehydrogenase (G6PD) deficiency. G6PD deficiency is a condition caused by variants in the G6PD gene which can be determined by enzymatic or genetic tests, however the drug label does not specifically mention testing.

\n

Excerpt from the dabrafenib (TAFINLAR) drug label:

\n
\n

TAFINLAR, which contains a sulfonamide moiety, confers a potential risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Monitor patients with G6PD deficiency for signs of hemolytic anemia while taking TAFINLAR.

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For the complete drug label text with sections containing pharmacogenetic information highlighted, see the dabrafenib drug label

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*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

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The TAFINLAR (dabrafenib) label states: "TAFINLAR, which contains a sulfonamide moiety, confers a potential risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Monitor patients with G6PD deficiency for signs of hemolytic anemia while taking TAFINLAR." See label for more information.

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The TAFINLAR (dabrafenib) label states: "TAFINLAR, which contains a sulfonamide moiety, confers a potential risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Monitor patients with G6PD deficiency for signs of hemolytic anemia while taking TAFINLAR." See label for more information.

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The TAFINLAR (dabrafenib) label states: "TAFINLAR, which contains a sulfonamide moiety, confers a potential risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Monitor patients with G6PD deficiency for signs of hemolytic anemia while taking TAFINLAR." See label for more information.

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Specific variants in the RYR1 and CACNA1S genes are associated with risk of malignant hyperthermia in individuals administered potent inhalational anesthetics, including desflurane. The FDA-approved label for desflurane (SUPRANE) contraindicates it for individuals with known, or suspected, genetic predisposition to malignant hyperthermia.

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Excerpts from the FDA-approved desflurane (SUPRANE) drug label:

\n
\n

The use of SUPRANE is contraindicated in the following conditions...Malignant Hyperthermia: Malignant hyperthermia may occur, especially in individuals with known or suspected susceptibility based on genetic factors or family history. Discontinue triggering agents, administer intravenous dantrolene sodium, and apply supportive therapies.

\n
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In susceptible individuals, volatile anesthetic agents, including desflurane, may trigger malignant hyperthermia, a skeletal muscle hypermetabolic state leading to high oxygen demand. Fatal outcomes of malignant hyperthermia have been reported.

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The risk of developing malignant hyperthermia increases with the concomitant administration of succinylcholine and volatile anesthetic agents. SUPRANE can induce malignant hyperthermia in patients with known or suspected susceptibility based on genetic factors or family history, including those with certain inherited ryanodine receptor (RYR1) or dihydropyridine receptor (CACNA1S) variants.

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Pharmacogenomics: RYR1 and CACNA1S are polymorphic genes and multiple pathogenic variants have been associated with malignant hyperthermia susceptibility (MHS) in patients receiving volatile anesthetic agents, including SUPRANE. Case reports as well as exvivo studies have identified multiple variants in RYR1 and CACNA1S associated with\nMHS. Variant pathogenicity should be assessed based on prior clinical experience, functional studies, prevalence information, or other evidence (see Contraindications (4),\nWarnings and Precautions (5.1)).

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For the complete drug label text with sections containing pharmacogenetic information highlighted, see the desflurane drug label

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*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

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"The use of SUPRANE [desflurane] is contraindicated in...[cases of k]nown or suspected genetic susceptibility to malignant hyperthermia...SUPRANE [desflurane] can induce malignant hyperthermia in patients with known or suspected susceptibility based on genetic factors or family history, including those with certain inherited ryanodine receptor (RYR1) or dihydropyridine receptor (CACNA1S) variants. " See label for more information.

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"The use of SUPRANE [desflurane] is contraindicated in...[cases of k]nown or suspected genetic susceptibility to malignant hyperthermia...SUPRANE [desflurane] can induce malignant hyperthermia in patients with known or suspected susceptibility based on genetic factors or family history, including those with certain inherited ryanodine receptor (RYR1) or dihydropyridine receptor (CACNA1S) variants. " See label for more information.

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"The use of SUPRANE [desflurane] is contraindicated in...[cases of k]nown or suspected genetic susceptibility to malignant hyperthermia...SUPRANE [desflurane] can induce malignant hyperthermia in patients with known or suspected susceptibility based on genetic factors or family history, including those with certain inherited ryanodine receptor (RYR1) or dihydropyridine receptor (CACNA1S) variants. " See label for more information.

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"The use of SUPRANE [desflurane] is contraindicated in...[cases of k]nown or suspected genetic susceptibility to malignant hyperthermia...SUPRANE [desflurane] can induce malignant hyperthermia in patients with known or suspected susceptibility based on genetic factors or family history, including those with certain inherited ryanodine receptor (RYR1) or dihydropyridine receptor (CACNA1S) variants. " See label for more information.

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"The use of SUPRANE [desflurane] is contraindicated in...[cases of k]nown or suspected genetic susceptibility to malignant hyperthermia...SUPRANE [desflurane] can induce malignant hyperthermia in patients with known or suspected susceptibility based on genetic factors or family history, including those with certain inherited ryanodine receptor (RYR1) or dihydropyridine receptor (CACNA1S) variants. " See label for more information.

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"The use of SUPRANE [desflurane] is contraindicated in...[cases of k]nown or suspected genetic susceptibility to malignant hyperthermia...SUPRANE [desflurane] can induce malignant hyperthermia in patients with known or suspected susceptibility based on genetic factors or family history, including those with certain inherited ryanodine receptor (RYR1) or dihydropyridine receptor (CACNA1S) variants. " See label for more information.

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"The use of SUPRANE [desflurane] is contraindicated in...[cases of k]nown or suspected genetic susceptibility to malignant hyperthermia...SUPRANE [desflurane] can induce malignant hyperthermia in patients with known or suspected susceptibility based on genetic factors or family history, including those with certain inherited ryanodine receptor (RYR1) or dihydropyridine receptor (CACNA1S) variants. " See label for more information.

\n", "version" : 0 }, @@ -146915,7 +148900,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 4, + "version" : 5, "year" : -1 } ], @@ -146959,7 +148944,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "prescribingMarkdown" : { @@ -146973,7 +148958,7 @@ "objCls" : "Chemical", "id" : "PA166169881", "name" : "deutetrabenazine", - "version" : 7 + "version" : 13 } ], "relatedGenes" : [ @@ -146982,7 +148967,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "FDA", @@ -147005,10 +148990,10 @@ "textMarkdown" : { "id" : 1448821087, "html" : "

Excerpts from the deutetrabenazine (AUSTEDO) drug label:

\n
\n

Dosage Adjustment with Strong CYP2D6 Inhibitors: In patients receiving strong CYP2D6 inhibitors (e.g., quinidine, antidepressants such as paroxetine, fluoxetine, and bupropion), the total daily dosage of AUSTEDO should not exceed 36 mg (maximum single dose of 18 mg)

\n
\n
\n

Dosage Adjustment in Poor CYP2D6 Metabolizers: In patients who are poor CYP2D6 metabolizers, the total daily dosage of AUSTEDO should not\nexceed 36 mg (maximum single dose of 18 mg) (see Use in Specific Populations).

\n
\n
\n

Poor CYP2D6 Metabolizers: Although the pharmacokinetics of deutetrabenazine and its metabolites have not been systematically evaluated in patients who do not express the drug metabolizing enzyme, it is likely that the exposure to α-HTBZ and β-HTBZ would be increased similarly to taking a strong CYP2D6 inhibitor (approximately 3-fold). In patients who are CYP2D6 poor metabolizers, the daily dose of AUSTEDO should not exceed 36 mg (maximum single dose of 18 mg).

\n
\n
\n

Cardiac Electrophysiology: At the maximum recommended dose, AUSTEDO does not prolong the QT interval to any clinically relevant extent. An exposure-response analysis on QTc prolongation from a study in extensive or intermediate (EM) and poor CYP2D6 metabolizers (PM) showed that a clinicallyrelevant effect can be excluded at exposures following single doses of 24 and 48 mg of AUSTEDO.

\n
\n

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the deutetrabenazine drug label.

\n

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

\n", - "version" : 3 + "version" : 5 }, "userId" : "jmbarbarino", - "version" : 21 + "version" : 50 }, "recommendations" : [ { @@ -147025,14 +149010,14 @@ "objCls" : "Chemical", "id" : "PA166169881", "name" : "deutetrabenazine", - "version" : 7 + "version" : 13 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166169882", "name" : "Annotation of FDA Label for deutetrabenazine and CYP2D6", - "version" : 21 + "version" : 50 }, "text" : { "id" : 1452216584, @@ -147073,7 +149058,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 4, + "version" : 5, "year" : -1 } ], @@ -147123,7 +149108,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "prescribingMarkdown" : { @@ -147137,7 +149122,7 @@ "objCls" : "Chemical", "id" : "PA166175998", "name" : "dextromethorphan / quinidine", - "version" : 5 + "version" : 8 } ], "relatedGenes" : [ @@ -147146,7 +149131,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "FDA", @@ -147169,10 +149154,10 @@ "textMarkdown" : { "id" : 1450342992, "html" : "

NUEDEXTA is a combination of dextromethorphan and quinidine, used as a treatment for pseudobulbar affect (PBA). The quinidine component of NUEDEXTA is a CYP2D6 inhibitor used to increase the plasma availability of dextromethorphan. Dextromethorphan is metabolized by CYP2D6, while quinidine is a CYP2D6 inhibitor that is metabolized by CYP3A4.

\n

Excerpt from the dextromethorphan and quinidine (NUEDEXTA) label:

\n
\n

The quinidine component of NUEDEXTA is intended to inhibit CYP2D6 so that higher exposure to dextromethorphan can be achieved compared to when dextromethorphan is given alone. Approximately 7-10% of Caucasians and 3-8% of African Americans generally lack the capacity to metabolize CYP2D6 substrates and are classified as PMs. The quinidine component of NUEDEXTA is not expected to contribute to the effectiveness of NUEDEXTA in PMs, but adverse events of the quinidine are still possible. In those patients who may be at risk of significant toxicity due to quinidine, genotyping to determine if they are PMs should be considered prior to making the decision to treat with NUEDEXTA.

\n
\n
\n

Contraindications: Concomitant use with drugs that both prolong QT interval and are metabolized by CYP2D6 (e.g., thioridazine or pimozide).

\n
\n
\n

CYP2D6 substrates: Nuedexta inhibits CYP2D6. Accumulation of parent drug and/or failure of metabolite formation may decrease safety and/or ef\nof concomitant CYP2D6 metabolized drugs. Adjust dose of CYP2D6 substrate or use alternative treatment when clinically indicated.

\n
\n

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the dextromethorphan and quinidine drug label.

\n

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

\n", - "version" : 1 + "version" : 3 }, "userId" : "jmbarbarino", - "version" : 29 + "version" : 60 }, "recommendations" : [ { @@ -147189,21 +149174,21 @@ "objCls" : "Chemical", "id" : "PA166175998", "name" : "dextromethorphan / quinidine", - "version" : 5 + "version" : 8 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104886", "name" : "Annotation of FDA Label for dextromethorphan / quinidine and CYP2D6", - "version" : 29 + "version" : 60 }, "text" : { "id" : 1452221460, "html" : "

"The quinidine component of NUEDEXTA [dextromethorphan / quinidine] is not expected to contribute to the effectiveness of NUEDEXTA [dextromethorphan / quinidine] in PMs, but adverse events of the quinidine are still possible. In those patients who may be at risk of significant toxicity due to quinidine, genotyping to determine if they are PMs should be considered prior to making the decision to treat with NUEDEXTA [dextromethorphan / quinidine]." See label for more information.

\n", - "version" : 0 + "version" : 1 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/labelAnnotation/PA166104886" @@ -147237,7 +149222,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 4, + "version" : 5, "year" : -1 } ], @@ -147265,7 +149250,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "prescribingMarkdown" : { @@ -147288,14 +149273,14 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "FDA", "summaryMarkdown" : { "id" : 1451880180, "html" : "

The FDA-approved drug label for AUVELITY (dextromethorphan hydrobromide and bupropion hydrochloride) states that AUVELITY is indicated for the treatment of major depressive disorder (MDD) in adults. Dextromethorphan is a CYP2D6 substrate and bupropion is an aminoketone and CYP450 2D6 inhibitor. The recommended dosage for patients known to be poor CYP2D6 metabolizers is one tablet once daily in the morning, because these patients have higher dextromethorphan concentrations than extensive/intermediate CYP2D6 metabolizers.

\n", - "version" : 0 + "version" : 1 }, "terms" : [], "testing" : { @@ -147314,7 +149299,7 @@ "version" : 0 }, "userId" : "lgong", - "version" : 5 + "version" : 12 }, "recommendations" : [ { @@ -147338,14 +149323,14 @@ "objCls" : "Label Annotation", "id" : "PA166278361", "name" : "Annotation of FDA Label for dextromethorphan hydrobromide / bupropion hydrochloride and CYP2D6", - "version" : 5 + "version" : 12 }, "text" : { "id" : 1452216849, "html" : "

"The recommended dosage for patients known to be poor CYP2D6 metabolizers is one tablet once daily in the morning." See label for more information.

\n", - "version" : 0 + "version" : 1 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/labelAnnotation/PA166278361" @@ -147379,7 +149364,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 4, + "version" : 5, "year" : -1 } ], @@ -147408,7 +149393,7 @@ "id" : "PA126", "symbol" : "CYP2C9", "name" : "cytochrome P450 family 2 subfamily C member 9", - "version" : 7877 + "version" : 7952 } ], "prescribingMarkdown" : { @@ -147422,7 +149407,7 @@ "objCls" : "Chemical", "id" : "PA449421", "name" : "dronabinol", - "version" : 8 + "version" : 27 } ], "relatedGenes" : [ @@ -147431,7 +149416,7 @@ "id" : "PA126", "symbol" : "CYP2C9", "name" : "cytochrome P450 family 2 subfamily C member 9", - "version" : 7877 + "version" : 7952 } ], "source" : "FDA", @@ -147457,34 +149442,34 @@ "version" : 5 }, "userId" : "jmbarbarino", - "version" : 19 + "version" : 34 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166312026", - "name" : "Recommendation Annotation PA166312026", + "id" : "PA166312024", + "name" : "Recommendation Annotation PA166312024", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2C9": "1.0"}, + "lookupKey" : {"CYP2C9": "0.0"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449421", "name" : "dronabinol", - "version" : 8 + "version" : 27 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166163422", "name" : "Annotation of FDA Label for dronabinol and CYP2C9", - "version" : 19 + "version" : 34 }, "text" : { - "id" : 1452216225, + "id" : 1452216223, "html" : "

"Monitoring for increased adverse reactions is recommended in patients known to carry genetic variants associated with diminished CYP2C9 function." See label for more information.

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"Monitoring for increased adverse reactions is recommended in patients known to carry genetic variants associated with diminished CYP2C9 function." See label for more information.

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"Monitoring for increased adverse reactions is recommended in patients known to carry genetic variants associated with diminished CYP2C9 function." See label for more information.

\n", "version" : 0 }, @@ -147552,29 +149537,29 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312025", - "name" : "Recommendation Annotation PA166312025", + "id" : "PA166312027", + "name" : "Recommendation Annotation PA166312027", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2C9": "0.5"}, + "lookupKey" : {"CYP2C9": "1.5"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449421", "name" : "dronabinol", - "version" : 8 + "version" : 27 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166163422", "name" : "Annotation of FDA Label for dronabinol and CYP2C9", - "version" : 19 + "version" : 34 }, "text" : { - "id" : 1452216224, + "id" : 1452216226, "html" : "

"Monitoring for increased adverse reactions is recommended in patients known to carry genetic variants associated with diminished CYP2C9 function." See label for more information.

\n", "version" : 0 }, @@ -147613,7 +149598,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 6, + "version" : 7, "year" : 2018 } ], @@ -147650,7 +149635,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "prescribingMarkdown" : { @@ -147664,7 +149649,7 @@ "objCls" : "Chemical", "id" : "PA166123486", "name" : "eliglustat", - "version" : 5 + "version" : 6 } ], "relatedGenes" : [ @@ -147673,14 +149658,14 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "FDA", "summaryMarkdown" : { "id" : 1447982161, "html" : "

The FDA-approved drug label for eliglustat (CERDELGA) states that it is indicated for patients with Gaucher disease type 1. CYP2D6 intermediate and extensive metabolizers have a recommended dose of 84 mg twice daily, while poor metabolizers have a recommended dose of 84 mg once daily. The label notes that CYP2D6 ultra-rapid metabolizers may not achieve adequate concentrations of eliglustat to achieve a therapeutic effect.

\n", - "version" : 0 + "version" : 1 }, "terms" : [], "testing" : { @@ -147696,311 +149681,311 @@ "textMarkdown" : { "id" : 1450361340, "html" : "

Eliglustat (CERDELGA) is a glucosylceramide synthase inhibitor used for the long-term treatment of adult patients with Gaucher disease type 1.

\n

Excerpts from the eliglustat (CERDELGA) drug label:

\n
\n

CERDELGA is a glucosylceramide synthase inhibitor indicated for the long-term treatment of adult patients with Gaucher disease type 1 who are CYP2D6 extensive metabolizers (EMs), intermediate metabolizers (IMs) or poor metabolizers (PMs) as detected by an FDA-cleared test...CYP2D6 ultra-rapid metabolizers may not achieve adequate concentrations of CERDELGA to achieve a therapeutic effect.

\n
\n
\n

Select patients with Gaucher disease type 1 based on their CYP2D6 metabolizer status. It is recommended patient genotypes be established using an FDA-cleared test for determining CYP2D6 genotype.

\n
\n
\n

A specific dosage cannot be recommended for CYP2D6 indeterminate metabolizers...CYP2D6 EMs or IMs: 84 mg orally twice daily...CYP2D6 PMs: 84 mg orally once daily.

\n
\n

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the eliglustat drug label.

\n

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

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CYP2D6 normal metabolizers have a recommended dose of 84 mg orally twice daily.

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CYP2D6 poor metabolizers have a recommended dose of 84 mg once daily.

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"CYP2D6 ultra-rapid metabolizers may not achieve adequate concentrations of CERDELGA [eliglustat] to achieve a therapeutic effect." See label for more information.

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CYP2D6 IMs have a recommended dose of 84 mg orally twice daily.

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CYP2D6 normal metabolizers have a recommended dose of 84 mg orally twice daily.

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CYP2D6 IMs have a recommended dose of 84 mg orally twice daily.

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"CYP2D6 ultra-rapid metabolizers may not achieve adequate concentrations of CERDELGA [eliglustat] to achieve a therapeutic effect." See label for more information.

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CYP2D6 IMs have a recommended dose of 84 mg orally twice daily.

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"CYP2D6 ultra-rapid metabolizers may not achieve adequate concentrations of CERDELGA [eliglustat] to achieve a therapeutic effect." See label for more information.

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"CYP2D6 ultra-rapid metabolizers may not achieve adequate concentrations of CERDELGA [eliglustat] to achieve a therapeutic effect." See label for more information.

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CYP2D6 IMs have a recommended dose of 84 mg orally twice daily.

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"CYP2D6 ultra-rapid metabolizers may not achieve adequate concentrations of CERDELGA [eliglustat] to achieve a therapeutic effect." See label for more information.

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"CYP2D6 ultra-rapid metabolizers may not achieve adequate concentrations of CERDELGA [eliglustat] to achieve a therapeutic effect." See label for more information.

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CYP2D6 normal metabolizers have a recommended dose of 84 mg orally twice daily.

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"CYP2D6 ultra-rapid metabolizers may not achieve adequate concentrations of CERDELGA [eliglustat] to achieve a therapeutic effect." See label for more information.

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CYP2D6 normal metabolizers have a recommended dose of 84 mg orally twice daily.

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CYP2D6 normal metabolizers have a recommended dose of 84 mg orally twice daily.

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"CYP2D6 ultra-rapid metabolizers may not achieve adequate concentrations of CERDELGA [eliglustat] to achieve a therapeutic effect." See label for more information.

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CYP2D6 IMs have a recommended dose of 84 mg orally twice daily.

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CYP2D6 normal metabolizers have a recommended dose of 84 mg orally twice daily.

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"CYP2D6 ultra-rapid metabolizers may not achieve adequate concentrations of CERDELGA [eliglustat] to achieve a therapeutic effect." See label for more information.

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"CYP2D6 ultra-rapid metabolizers may not achieve adequate concentrations of CERDELGA [eliglustat] to achieve a therapeutic effect." See label for more information.

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"CYP2D6 ultra-rapid metabolizers may not achieve adequate concentrations of CERDELGA [eliglustat] to achieve a therapeutic effect." See label for more information.

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CYP2D6 IMs have a recommended dose of 84 mg orally twice daily.

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CYP2D6 poor metabolizers have a recommended dose of 84 mg once daily.

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"CYP2D6 ultra-rapid metabolizers may not achieve adequate concentrations of CERDELGA [eliglustat] to achieve a therapeutic effect." See label for more information.

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"CYP2D6 ultra-rapid metabolizers may not achieve adequate concentrations of CERDELGA [eliglustat] to achieve a therapeutic effect." See label for more information.

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CYP2D6 IMs have a recommended dose of 84 mg orally twice daily.

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"CYP2D6 ultra-rapid metabolizers may not achieve adequate concentrations of CERDELGA [eliglustat] to achieve a therapeutic effect." See label for more information.

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"CYP2D6 ultra-rapid metabolizers may not achieve adequate concentrations of CERDELGA [eliglustat] to achieve a therapeutic effect." See label for more information.

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CYP2D6 normal metabolizers have a recommended dose of 84 mg orally twice daily.

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CYP2D6 IMs have a recommended dose of 84 mg orally twice daily.

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"CYP2D6 ultra-rapid metabolizers may not achieve adequate concentrations of CERDELGA [eliglustat] to achieve a therapeutic effect." See label for more information.

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"Erdafitinib plasma concentrations were predicted to be higher in patients with the CYP2C9*3/*3 genotype. Monitor for increased adverse reactions in patients who are known or suspected to have CYP2C9*3/*3 genotype." See label for more information.

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Excerpt from the fluorouracil injection drug label:

\n
\n

Withhold or permanently discontinue fluorouracil based on clinical assessment of the onset, duration, and severity of the observed adverse events in patients with evidence of acute early-onset or unusually severe reactions, which may indicate complete DPD deficiency. No fluorouracil dose has been proven safe for patients with complete DPD deficiency. There are insufficient data to recommend a specific dose in patients with partial DPD deficiency.

\n
\n
\n

Consider testing for genetic variants of DPYD prior to initiating fluorouracil to reduce the risk of serious adverse reactions if the patient’s clinical status permits and based on clinical judgement. Serious adverse reactions may still occur even if no DPYD variants are identified.

\n
\n

Excerpt from the topical fluorouracil (CARAC) drug label:

\n
\n

CONTRAINDICATIONS...Carac should not be used in patients with dihydropyrimidine dehydrogenase (DPD) enzyme deficiency...

\n
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Fluorouracil is not recommended for use in patients known to have certain homozygous or compound heterozygous DPYD variants that result in complete dihydropyrimidine dehydrogenase (DPD) deficiency. Fluorouracil is available as both an injection and a topical cream (CARAC). These two formulations have different indications. Both FDA-approved labels contain information about the potential for severe toxicity in patients with DPD deficiency.

\n", - "version" : 1 + "html" : "

Fluorouracil is not recommended for use in patients known to have certain homozygous or compound heterozygous DPYD variants that result in complete dihydropyrimidine dehydrogenase (DPD) deficiency. Prescribers should consider testing for genetic variants of DPYD prior to initiating fluorouracil. Fluorouracil is available as both an injection and a topical cream (CARAC). These two formulations have different indications. Both FDA-approved labels contain information about the potential for severe toxicity in patients with DPD deficiency.

\n", + "version" : 2 }, "terms" : [], "testing" : { @@ -148640,10 +150657,10 @@ "textMarkdown" : { "id" : 1450361447, "html" : "

There are two label indications for fluroruracil linked from the FDA table of Pharmacogenomic Biomarkers in Drug Labeling: Fluorouracil injection is used in oncology for the treatment of various types of neoplasms, including colorectal neoplasms; Fluorouracil cream (CARAC) is used in dermatology to treat multiple actinic or solar keratoses of the face and anterior scalp.

\n

Excerpts from the fluorouracil injection drug label:

\n
\n

Serious Adverse Reactions from Dihydropyrimidine Dehydrogenase (DPD) Deficiency

\n
\n
\n

Patients with certain homozygous or compound heterozygous variants in the DPYD gene known to result in complete or near complete absence of DPD activity (complete\nDPD deficiency) are at increased risk for acute early-onset toxicity and serious, including fatal, adverse reactions due to fluorouracil (e.g., mucositis, diarrhea, neutropenia, and\nneurotoxicity). Patients with partial DPD activity (partial DPD deficiency) may also have increased risk of serious, including fatal, adverse reactions.

\n
\n
\n

Fluorouracil is not recommended for use in patients known to have certain homozygous or compound heterozygous DPYD variants that result in complete DPD deficiency.

\n
\n
\n

Withhold or permanently discontinue fluorouracil based on clinical assessment of the onset, duration, and severity of the observed adverse events in patients with evidence of acute early-onset or unusually severe reactions, which may indicate complete DPD deficiency. No fluorouracil dose has been proven safe for patients with complete DPD deficiency. There are insufficient data to recommend a specific dose in patients with partial DPD deficiency.

\n
\n
\n

Consider testing for genetic variants of DPYD prior to initiating fluorouracil to reduce the risk of serious adverse reactions if the patient’s clinical status permits and based on\nclinical judgement. Serious adverse reactions may still occur even if no DPYD variants are identified.

\n
\n
\n

An FDA-authorized test for the detection of genetic variants of DPYD to identify patients at risk of serious adverse reactions due to increased systemic exposure to fluorouracil is not currently available. Currently available tests used to identify DPYD variants may vary in accuracy and design (e.g., which DPYD variant(s) they identify).

\n
\n
\n

The DPYD gene encodes the enzyme DPD, which is responsible for the catabolism of >80% of fluorouracil. Approximately 3-5% of White populations have partial DPD\ndeficiency and 0.2% of White populations have complete DPD deficiency, which may be due to certain genetic no function or decreased function variants in DPYD resulting in\npartial to complete or near complete absence of enzyme activity. DPD deficiency is estimated to be more prevalent in Black or African American populations compared to\nWhite populations. Insufficient information is available to estimate the prevalence of DPD deficiency in other populations.

\n
\n
\n

Patients who are homozygous or compound heterozygous for no function DPYD variants (i.e., carry two no function DPYD variants) or are compound heterozygous for a no function DPYD variant plus a decreased function DPYD variant have complete DPD deficiency and are at increased risk for acute early-onset of toxicity and serious life-threatening, or fatal adverse reactions due to increased systemic exposure to fluorouracil. Partial DPD deficiency can result from the presence of either two decreased function DPYD variants or one normal function plus either a decreased function or a no function DPYD variant. Patients with partial DPD deficiency may also be at an increased risk for toxicity from fluorouracil.

\n
\n
\n

Four DPYD variants have been associated with impaired DPD activity in White populations, especially when present as homozygous or compound heterozygous variants: c.1905+1G>A (DPYD *2A), c.1679T>G (DPYD *13), c.2846A>T, and c.1129-5923C>G (Haplotype B3). DPYD*2A and DPYD*13 are no function variants, and c.2846A>T and c.1129-5923C>G are decreased function variants. The decreased function DPYD variant c.557A>G is observed in individuals of African ancestry. This is not a complete listing of all DPYD variants that may result in DPD deficiency.

\n
\n

Excerpts from the fluorouracil cream (CARAC) drug label:

\n
\n

CONTRAINDICATIONS...Carac should not be used in patients with dihydropyrimidine dehydrogenase (DPD) enzyme deficiency...

\n
\n
\n

One case of life-threatening systemic toxicity has been reported with the topical use of 5% fluorouracil in a patient with a complete absence of DPD enzyme activity... Although this case was observed with 5% fluorouracil cream, it is unknown whether patients with profound DPD enzyme deficiency would develop systemic toxicity with lower concentrations of topically applied fluorouracil.

\n
\n

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the fluorouracil injection drug label and the fluorouracil cream drug label.

\n

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

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"Increased Risk of Serious or Fatal Adverse Reactions in Patients with Low or Absent Dipyrimidine Dehydrogenase (DPD) Activity...Based on postmarketing reports, patients with certain homozygous or certain compound heterozygous mutations in the DPD gene that result in complete or near complete absence of DPD activity are at increased risk for acute early-onset of toxicity and severe, life-threatening, or fatal adverse reactions caused by fluorouracil (e.g., mucositis, diarrhea, neutropenia, and neurotoxicity). Patients with partial DPD activity may also have increased risk of severe, life-threatening, or fatal adverse reactions caused by fluorouracil...Withhold or permanently discontinue fluorouracil based on clinical assessment of the onset, duration and severity of the observed toxicities in patients with evidence of acute early-onset or unusually severe toxicity, which may indicate near complete or total absence of DPD activity. No fluorouracil dose has been proven safe for patients with complete absence of DPD activity. There is insufficient data to recommend a specific dose in patients with partial DPD activity as measured by any specific test." See label for more information.

\n", - "version" : 0 + "html" : "

The fluorouracil label states: "Withhold or permanently discontinue fluorouracil based on clinical assessment of the onset, duration, and severity of the observed adverse events in patients with evidence of acute early-onset or unusually severe reactions, which may indicate complete DPD deficiency. No fluorouracil dose has been proven safe for patients with complete DPD deficiency." "Patients who are homozygous or compound heterozygous for no function DPYD variants (i.e., carry two no function DPYD variants) ... have complete DPD deficiency and are at increased risk for acute early-onset of toxicity and serious life-threatening, or fatal adverse reactions due to increased systemic exposure to fluorouracil."

\n

The Carac (fluorouracil) label states: "Carac should not be used in patients with dihydropyrimidine dehydrogenase (DPD) enzyme deficiency..."

\n

See labels for more information.

\n", + "version" : 1 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -148690,24 +150707,181 @@ "objCls" : "Chemical", "id" : "PA128406956", "name" : "fluorouracil", - "version" : 17 + "version" : 84 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104807", "name" : "Annotation of FDA Label for fluorouracil and DPYD", - "version" : 33 + "version" : 86 }, "text" : { "id" : 1452213182, - "html" : "

"Increased Risk of Serious or Fatal Adverse Reactions in Patients with Low or Absent Dipyrimidine Dehydrogenase (DPD) Activity...Based on postmarketing reports, patients with certain homozygous or certain compound heterozygous mutations in the DPD gene that result in complete or near complete absence of DPD activity are at increased risk for acute early-onset of toxicity and severe, life-threatening, or fatal adverse reactions caused by fluorouracil (e.g., mucositis, diarrhea, neutropenia, and neurotoxicity). Patients with partial DPD activity may also have increased risk of severe, life-threatening, or fatal adverse reactions caused by fluorouracil...Withhold or permanently discontinue fluorouracil based on clinical assessment of the onset, duration and severity of the observed toxicities in patients with evidence of acute early-onset or unusually severe toxicity, which may indicate near complete or total absence of DPD activity. No fluorouracil dose has been proven safe for patients with complete absence of DPD activity. There is insufficient data to recommend a specific dose in patients with partial DPD activity as measured by any specific test." See label for more information.

\n", + "html" : "

The fluorouracil label states: "Withhold or permanently discontinue fluorouracil based on clinical assessment of the onset, duration, and severity of the observed adverse events in patients with evidence of acute early-onset or unusually severe reactions, which may indicate complete DPD deficiency. No fluorouracil dose has been proven safe for patients with complete DPD deficiency." "Patients who are ... compound heterozygous for a no function DPYD variant plus a decreased function DPYD variant have complete DPD deficiency and are at increased risk for acute early-onset of toxicity and serious life-threatening, or fatal adverse reactions due to increased systemic exposure to fluorouracil."

\n

The CARAC (fluorouracil) label states: "Carac should not be used in patients with dihydropyrimidine dehydrogenase (DPD) enzyme deficiency..."

\n

See labels for more information.

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QT Prolongation:

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\n
\n

Post-marketing cases of QT interval prolongation and ventricular arrhythmia including Torsades de Pointes have been reported in patients treated with PROZAC. PROZAC should be used with caution in patients with congenital long QT syndrome; a previous history of QT prolongation; a family history of long QT syndrome or sudden cardiac death; and other conditions that predispose to QT prolongation and ventricular arrhythmia. Such conditions include concomitant use of drugs that prolong the QT interval; hypokalemia or hypomagnesemia; recent myocardial infarction, uncompensated heart failure, bradyarrhythmias, and other significant arrhythmias; and conditions that predispose to increased fluoxetine exposure (overdose, hepatic impairment, use of CYP2D6 inhibitors, CYP2D6 poor metabolizer status, or use of other\nhighly protein-bound drugs).

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Fluoxetine (PROZAC) is a selective serotonin reuptake inhibitor (SSRI) indicated for the treatment of major depressive disorder, obsessive compulsive disorder, bulimia nervosa, and panic disorder. Fluoxetine is primarily metabolized by CYP2D6. It should be used used with caution in patients with congenital long QT syndrome; a previous history of QT prolongation and other conditions that predispose to QT prolongation and ventricular arrhythmia (which include conditions that predispose to increased fluoxetine exposure (overdose, hepatic impairment, use of CYP2D6 inhibitors, CYP2D6 poor metabolizer status, or use of other\nhighly protein-bound drugs).

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Excerpts from the fluoxetine (PROZAC) drug label:

\n
\n

QT Prolongation: Post-marketing cases of QT interval prolongation and ventricular arrhythmia including Torsades de Pointes have been reported in patients treated with PROZAC. PROZAC should be used with caution in patients with congenital long QT syndrome; a previous history of QT prolongation; a family history of long QT syndrome or sudden cardiac death; and other conditions that predispose to QT prolongation and ventricular arrhythmia. Such conditions include concomitant use of drugs that prolong the QT interval; hypokalemia or hypomagnesemia; recent myocardial infarction, uncompensated heart failure, bradyarrhythmias, and other significant arrhythmias; and conditions that predispose to increased fluoxetine exposure (overdose, hepatic impairment, use of CYP2D6 inhibitors, CYP2D6 poor metabolizer status, or use of other\nhighly protein-bound drugs). PROZAC is primarily metabolized by CYP2D6.

\n
\n
\n

Variability in Metabolism — A subset (about 7%) of the population has reduced activity of the drug metabolizing enzyme cytochrome P450 2D6 (CYP2D6). Such individuals are referred to as “poor metabolizers” of drugs such as debrisoquin, dextromethorphan, and the TCAs. In a study involving labeled and unlabeled enantiomers administered as a racemate, these individuals metabolized S- fluoxetine at a slower rate and thus achieved higher concentrations of S-fluoxetine. Consequently, concentrations of S-norfluoxetine at steady state were lower. The metabolism of R-fluoxetine in these poor metabolizers appears normal. When compared with normal metabolizers, the total sum at steady state of the plasma concentrations of the 4 active enantiomers was not significantly greater among poor metabolizers. Thus, the net pharmacodynamic activities were essentially the same. Alternative, nonsaturable pathways (non-2D6) also contribute to the metabolism of fluoxetine. This explains how fluoxetine achieves a steady-state concentration rather than increasing without limit.

\n
\n

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the fluoxetine drug label.

\n

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

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The PROZAC (fluoxetine) label states: "PROZAC should be used with caution in patients with ... other conditions that predispose to QT prolongation and ventricular arrhythmia. Such conditions include ... conditions that predispose to increased fluoxetine exposure (... CYP2D6 poor metabolizer status...)." See label for more information.

\n", "version" : 0 }, "version" : 0 } ], - "url" : "https://www.pharmgkb.org/labelAnnotation/PA166104807" + "url" : "https://www.pharmgkb.org/labelAnnotation/PA166104835" }, { "citations" : [ @@ -148739,7 +150913,7 @@ {"id":1452267781,"resource":"PharmGKB Tags","term":"Has No PGx","termId":"pgkbTags:1452267781"} ], "type" : "Drug Label", - "version" : 3, + "version" : 4, "year" : -1 }, { @@ -148770,7 +150944,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 2, + "version" : 3, "year" : -1 } ], @@ -148807,7 +150981,7 @@ "id" : "PA126", "symbol" : "CYP2C9", "name" : "cytochrome P450 family 2 subfamily C member 9", - "version" : 7877 + "version" : 7952 } ], "prescribingMarkdown" : { @@ -148821,7 +150995,7 @@ "objCls" : "Chemical", "id" : "PA449683", "name" : "flurbiprofen", - "version" : 12 + "version" : 35 } ], "relatedGenes" : [ @@ -148830,7 +151004,7 @@ "id" : "PA126", "symbol" : "CYP2C9", "name" : "cytochrome P450 family 2 subfamily C member 9", - "version" : 7877 + "version" : 7952 } ], "source" : "FDA", @@ -148853,10 +151027,10 @@ "textMarkdown" : { "id" : 1447981819, "html" : "

Flurbiprofen (ANSAID) is indicated for the relief of the signs and symptoms of rheumatoid arthritis and osteoarthritis.

\n

Excerpts from the flurbiprofen (ANSAID) label:

\n
\n

Poor Metabolizers of CYP2C9 Substrates: In patients who are known or suspected to be poor CYP2C9 metabolizers based on genotype or previous history/experience with other CYP2C9 substrates (such as warfarin and phenytoin), reduce the dose of flurbiprofen to avoid abnormally high plasma levels due to reduced metabolic clearance.

\n
\n

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the flurbiprofen drug label.

\n

Note: Flurbiprofen (OCUFEN) is indicated for the inhibition of intraoperative miosis. The drug label for flurbiprofen (OCUFEN) contains no information regarding CYP2C9 metabolizer status.

\n

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

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Excerpts from the FDA fosphenytoin (CEREBYX) label:

\n
\n

Studies in patients of Chinese ancestry have found a strong association between the risk of developing SJS/TEN and the presence of HLA-B*1502, an inherited allelic variant of the HLA B gene, in patients using carbamazepine. Limited evidence suggests that HLA-B*1502 may be a risk factor for the development of SJS/TEN in patients of Asian ancestry taking other antiepileptic drugs associated with SJS/TEN, including phenytoin. In addition, retrospective, case-control, genome-wide association studies in patients of southeast Asian ancestry have also identified an increased risk of SCARs in carriers of the decreased function CYP2C9*3 variant, which has also been associated with decreased clearance of phenytoin. Consider avoiding CEREBYX as an alternative to carbamazepine in patients who are positive for HLA-B*1502 or in CYP2C9*3 carriers. Should CEREBYX be utilized for CYP2C9*3 carriers, consider starting at the lower end of the dosage range

\n

The use of HLA-B*1502 or CYP2C9 genotyping has important limitations and must never substitute for appropriate clinical vigilance and patient management. The role of other possible factors in the development of, and morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring have not been studied.

\n
\n
\n

Use in Patients with Decreased CYP2C9 Function\nPatients who are intermediate or poor metabolizers of CYP2C9 substrates (e.g., *1/*3, *2/*2, *3/*3) may exhibit increased phenytoin serum concentrations compared to patients who are normal metabolizers (e.g., *1/*1). Thus, patients who are known to be intermediate or poor metabolizers may ultimately require lower doses to maintain similar steady-state concentrations compared to normal metabolizers. In patients who are known to be carriers of the decreased function CYP2C9*2 or *3 alleles (intermediate and poor metabolizers), consider starting at the low end of the dosage range and monitor serum concentrations to maintain total phenytoin concentrations of 10 to 20 mcg/mL. If early signs of dose-related central nervous system (CNS) toxicity develop, serum concentrations should be checked immediately.

\n
\n
\n

Phenytoin derived from administration of CEREBYX is extensively metabolized in the liver by the cytochrome P450 enzyme CYP2C9 and to a lesser extent by CYP2C19.

\n
\n

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the fosphenytoin drug label.

\n

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

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"Consider avoiding CEREBYX [fosphenytoin] as an alternative to carbamazepine in patients who are positive for HLA-B*1502 or in CYP2C9*3 carriers." See label for more information.

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"Consider avoiding CEREBYX [fosphenytoin] as an alternative to carbamazepine in patients who are positive for HLA-B*1502 or in CYP2C9*3 carriers. Should CEREBYX [fosphenytoin] be utilized for CYP2C9*3 carriers, consider starting at the lower end of the dosage range...[P]atients who are known to be intermediate or poor metabolizers may ultimately require lower doses to maintain similar steady-state concentrations compared to normal metabolizers. In patients who are known to be carriers of the decreased function CYP2C9*2 or *3 alleles (intermediate and poor metabolizers), consider starting at the low end of the dosage range and monitor serum concentrations to maintain total phenytoin concentrations of 10 to 20 mcg/mL." See label for more information.

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"Consider avoiding CEREBYX [fosphenytoin] as an alternative to carbamazepine in patients who are positive for HLA-B*1502 or in CYP2C9*3 carriers. Should CEREBYX [fosphenytoin] be utilized for CYP2C9*3 carriers, consider starting at the lower end of the dosage range...[P]atients who are known to be intermediate or poor metabolizers may ultimately require lower doses to maintain similar steady-state concentrations compared to normal metabolizers. In patients who are known to be carriers of the decreased function CYP2C9*2 or *3 alleles (intermediate and poor metabolizers), consider starting at the low end of the dosage range and monitor serum concentrations to maintain total phenytoin concentrations of 10 to 20 mcg/mL." See label for more information.

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"No dose adjustment is recommended in patients with a known CYP2D6 poor metabolizer genotype, but these patients should be closely monitored for adverse reactions." See label for more information.

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In case of known maternal history of ototoxicity due to aminoglycoside use or a known mitochondrial DNA variant in the patient, consider alternative treatments other than aminoglycosides unless the increased risk of permanent hearing loss is outweighed by the severity of infection and lack of safe and effective alternative therapies.

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Gentamicin is a water soluble antibiotic of the aminoglycoside group derived from Micromonospora purpurea.

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Cases of ototoxicity with aminoglycosides have been observed in patients with certain variants in the mitochondrially encoded 12S rRNA gene (MT-RNR1), particularly the m.1555A>G variant. In case of known maternal history of ototoxicity due to aminoglycoside use or a known mitochondrial DNA variant in the patient, consider alternative treatments other than aminoglycosides unless the increased risk of permanent hearing loss is outweighed by the severity of infection and lack of safe and effective alternative therapies.

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Excerpt from the gentamicin label:

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Cases of ototoxicity with aminoglycosides have been observed in patients with certain variants in the mitochondrially encoded 12S rRNA gene (MT-RNR1), particularly the\nm.1555A>G variant. Ototoxicity occurred in some patients even when their aminoglycoside serum levels were within the recommended range. Mitochondrial DNA variants are present in less than 1% of the general US population, and the proportion of the variant carriers who may develop ototoxicity as well as the severity of ototoxicity is unknown. In case of known maternal history of ototoxicity due to aminoglycoside use or a known mitochondrial DNA variant in the patient, consider alternative treatments other than aminoglycosides unless the increased risk of permanent hearing loss is outweighed by the severity of infection and lack of safe and effective alternative therapies.

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\n

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the gentamicin drug label.

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*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

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The gentamicin label states: "Cases of ototoxicity with aminoglycosides have been observed in patients with certain variants in the mitochondrially encoded 12S rRNA gene (MT-RNR1), particularly the m.1555A>G variant. ... In case of known maternal history of ototoxicity due to aminoglycoside use or a known mitochondrial DNA variant in the patient, consider alternative treatments other than aminoglycosides unless the increased risk of permanent hearing loss is outweighed by the severity of infection and lack of safe and effective alternative therapies." See label for more information.

\n", + "version" : 2 + }, + "version" : 2 + } + ], + "url" : "https://www.pharmgkb.org/labelAnnotation/PA166316381" + }, { "citations" : [ { @@ -149691,7 +152018,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 4, + "version" : 5, "year" : -1 } ], @@ -149716,7 +152043,7 @@ "date" : "2023-08-25T00:00:00-07:00", "description" : "Added \"Alternate Drug\" tab based on updated definition", "type" : "Update", - "version" : 0 + "version" : 1 } ], "indication" : false, @@ -149734,7 +152061,7 @@ "id" : "PA28469", "symbol" : "G6PD", "name" : "glucose-6-phosphate dehydrogenase", - "version" : 135 + "version" : 1326 } ], "prescribingMarkdown" : { @@ -149748,7 +152075,7 @@ "objCls" : "Chemical", "id" : "PA449761", "name" : "glimepiride", - "version" : 10 + "version" : 28 } ], "relatedGenes" : [ @@ -149757,7 +152084,7 @@ "id" : "PA28469", "symbol" : "G6PD", "name" : "glucose-6-phosphate dehydrogenase", - "version" : 135 + "version" : 1326 } ], "source" : "FDA", @@ -149780,10 +152107,10 @@ "textMarkdown" : { "id" : 1447981911, "html" : "

Glimepiride (AMARYL) is a blood-glucose-lowering drug indicated for use in adults with type 2 diabetes mellitus as an adjunct to diet and exercise.

\n

Excerpt from the glimepiride (AMARYL) drug label:

\n
\n

Hemolytic Anemia: Sulfonylureas can cause hemolytic anemia in patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency. Because AMARYL is a sulfonylurea, use caution in patients with G6PD deficiency and consider the use of a non-sulfonylurea alternative.

\n
\n

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the glimepiride drug label.

\n

*Disclaimer: The contents of this page are the sole responsibility of PharmGKB.

\n", - "version" : 11 + "version" : 10 }, "userId" : "whaleyr", - "version" : 33 + "version" : 51 }, "recommendations" : [ { @@ -149800,14 +152127,14 @@ "objCls" : "Chemical", "id" : "PA449761", "name" : "glimepiride", - "version" : 10 + "version" : 28 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166105147", "name" : "Annotation of FDA Label for glimepiride and G6PD", - "version" : 33 + "version" : 51 }, "text" : { "id" : 1452245560, @@ -149830,21 +152157,21 @@ "objCls" : "Chemical", "id" : "PA449761", "name" : "glimepiride", - "version" : 10 + "version" : 28 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166105147", "name" : "Annotation of FDA Label for glimepiride and G6PD", - "version" : 33 + "version" : 51 }, "text" : { "id" : 1452216547, "html" : "

"Because AMARYL [glimepiride] is a sulfonylurea, use caution in patients with G6PD deficiency and consider the use of a non-sulfonylurea alternative." See label for more information.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -149860,21 +152187,21 @@ "objCls" : "Chemical", "id" : "PA449761", "name" : "glimepiride", - "version" : 10 + "version" : 28 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166105147", "name" : "Annotation of FDA Label for glimepiride and G6PD", - "version" : 33 + "version" : 51 }, "text" : { "id" : 1452216581, "html" : "

"Because AMARYL [glimepiride] is a sulfonylurea, use caution in patients with G6PD deficiency and consider the use of a non-sulfonylurea alternative." See label for more information.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/labelAnnotation/PA166105147" @@ -149908,7 +152235,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 4, + "version" : 5, "year" : -1 } ], @@ -149951,13 +152278,13 @@ "id" : "PA28469", "symbol" : "G6PD", "name" : "glucose-6-phosphate dehydrogenase", - "version" : 135 + "version" : 1326 } ], "prescribingMarkdown" : { "id" : 1450399215, "html" : "

Excerpt from the glipizide (GLUCOTROL) drug label:

\n
\n

Because GLUCOTROL belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD deficiency and a non-sulfonylurea alternative should be considered.

\n
\n", - "version" : 2 + "version" : 3 }, "relatedAlleles" : [], "relatedChemicals" : [ @@ -149965,7 +152292,7 @@ "objCls" : "Chemical", "id" : "PA449762", "name" : "glipizide", - "version" : 10 + "version" : 27 } ], "relatedGenes" : [ @@ -149974,7 +152301,7 @@ "id" : "PA28469", "symbol" : "G6PD", "name" : "glucose-6-phosphate dehydrogenase", - "version" : 135 + "version" : 1326 } ], "source" : "FDA", @@ -149997,10 +152324,10 @@ "textMarkdown" : { "id" : 1447981913, "html" : "

Glipizide (GLUCOTROL) is a blood-glucose-lowering drug indicated for use in adults with type 2 diabetes mellitus as an adjunct to diet and exercise.

\n

Excerpt from the glipizide (GLUCOTROL) drug label:

\n
\n

Hemolytic Anemia: Treatment of patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency with sulfonylurea agents can lead to hemolytic anemia. Because GLUCOTROL belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD deficiency and a non-sulfonylurea alternative should be considered.

\n
\n

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the glipizide drug label.

\n

*Disclaimer: The contents of this page are the sole responsibility of PharmGKB.

\n", - "version" : 10 + "version" : 9 }, "userId" : "whaleyr", - "version" : 28 + "version" : 42 }, "recommendations" : [ { @@ -150017,14 +152344,14 @@ "objCls" : "Chemical", "id" : "PA449762", "name" : "glipizide", - "version" : 10 + "version" : 27 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166105148", "name" : "Annotation of FDA Label for glipizide and G6PD", - "version" : 28 + "version" : 42 }, "text" : { "id" : 1452245580, @@ -150047,14 +152374,14 @@ "objCls" : "Chemical", "id" : "PA449762", "name" : "glipizide", - "version" : 10 + "version" : 27 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166105148", "name" : "Annotation of FDA Label for glipizide and G6PD", - "version" : 28 + "version" : 42 }, "text" : { "id" : 1452216550, @@ -150077,14 +152404,14 @@ "objCls" : "Chemical", "id" : "PA449762", "name" : "glipizide", - "version" : 10 + "version" : 27 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166105148", "name" : "Annotation of FDA Label for glipizide and G6PD", - "version" : 28 + "version" : 42 }, "text" : { "id" : 1452216563, @@ -150125,7 +152452,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 4, + "version" : 5, "year" : -1 } ], @@ -150174,13 +152501,13 @@ "id" : "PA28469", "symbol" : "G6PD", "name" : "glucose-6-phosphate dehydrogenase", - "version" : 135 + "version" : 1326 } ], "prescribingMarkdown" : { "id" : 1450399093, "html" : "

Excerpt from the glibenclamide (GLYNASE PresTab) drug label:

\n
\n

Because GLYNASE PresTab belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD deficiency and a non-sulfonylurea alternative should be considered.

\n
\n", - "version" : 2 + "version" : 3 }, "relatedAlleles" : [], "relatedChemicals" : [ @@ -150188,7 +152515,7 @@ "objCls" : "Chemical", "id" : "PA449782", "name" : "glyburide", - "version" : 7 + "version" : 35 } ], "relatedGenes" : [ @@ -150197,7 +152524,7 @@ "id" : "PA28469", "symbol" : "G6PD", "name" : "glucose-6-phosphate dehydrogenase", - "version" : 135 + "version" : 1326 } ], "source" : "FDA", @@ -150223,34 +152550,34 @@ "version" : 9 }, "userId" : "whaleyr", - "version" : 32 + "version" : 53 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166312282", - "name" : "Recommendation Annotation PA166312282", + "id" : "PA166314981", + "name" : "Recommendation Annotation PA166314981", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"G6PD": "Deficient with CNSHA"}, + "lookupKey" : {"G6PD": "Variable"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449782", "name" : "glyburide", - "version" : 7 + "version" : 35 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104881", "name" : "Annotation of FDA Label for glyburide and G6PD", - "version" : 32 + "version" : 53 }, "text" : { - "id" : 1452216541, + "id" : 1452245520, "html" : "

"Because GLYNASE PresTab [glyburide] belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD deficiency and a non-sulfonylurea alternative should be considered." See label for more information.

\n", "version" : 0 }, @@ -150258,33 +152585,33 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166314981", - "name" : "Recommendation Annotation PA166314981", + "id" : "PA166312282", + "name" : "Recommendation Annotation PA166312282", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"G6PD": "Variable"}, + "lookupKey" : {"G6PD": "Deficient with CNSHA"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA449782", "name" : "glyburide", - "version" : 7 + "version" : 35 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104881", "name" : "Annotation of FDA Label for glyburide and G6PD", - "version" : 32 + "version" : 53 }, "text" : { - "id" : 1452245520, + "id" : 1452216541, "html" : "

"Because GLYNASE PresTab [glyburide] belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD deficiency and a non-sulfonylurea alternative should be considered." See label for more information.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -150300,21 +152627,21 @@ "objCls" : "Chemical", "id" : "PA449782", "name" : "glyburide", - "version" : 7 + "version" : 35 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104881", "name" : "Annotation of FDA Label for glyburide and G6PD", - "version" : 32 + "version" : 53 }, "text" : { "id" : 1452216542, "html" : "

"Because GLYNASE PresTab [glyburide] belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD deficiency and a non-sulfonylurea alternative should be considered." See label for more information.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/labelAnnotation/PA166104881" @@ -150348,7 +152675,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 3, + "version" : 4, "year" : -1 } ], @@ -150366,7 +152693,7 @@ "id" : 1450401313, "date" : "2019-05-17T00:00:00-07:00", "type" : "Create", - "version" : 0 + "version" : 1 }, { "id" : 1451091860, @@ -150405,7 +152732,7 @@ "id" : "PA28469", "symbol" : "G6PD", "name" : "glucose-6-phosphate dehydrogenase", - "version" : 135 + "version" : 1326 } ], "prescribingMarkdown" : { @@ -150419,7 +152746,7 @@ "objCls" : "Chemical", "id" : "PA164777036", "name" : "hydroxychloroquine", - "version" : 10 + "version" : 27 } ], "relatedGenes" : [ @@ -150428,14 +152755,14 @@ "id" : "PA28469", "symbol" : "G6PD", "name" : "glucose-6-phosphate dehydrogenase", - "version" : 135 + "version" : 1326 } ], "source" : "FDA", "summaryMarkdown" : { "id" : 1450401310, "html" : "

The FDA-approved drug label for hydroxychloroquine (PLAQUENIL) states that hemolysis was reported in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency and monitor for hemolytic anemia.

\n", - "version" : 3 + "version" : 4 }, "terms" : [], "testing" : { @@ -150454,34 +152781,34 @@ "version" : 4 }, "userId" : "katrin", - "version" : 16 + "version" : 27 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166312308", - "name" : "Recommendation Annotation PA166312308", + "id" : "PA166315082", + "name" : "Recommendation Annotation PA166315082", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"G6PD": "Deficient with CNSHA"}, + "lookupKey" : {"G6PD": "Variable"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA164777036", "name" : "hydroxychloroquine", - "version" : 10 + "version" : 27 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166182769", "name" : "Annotation of FDA Label for hydroxychloroquine and G6PD", - "version" : 16 + "version" : 27 }, "text" : { - "id" : 1452216569, + "id" : 1452245621, "html" : "

"Hemolytic Anemia Associated with G6PD Deficiency: Hemolysis has been reported in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Monitor for hemolytic anemia as this can occur, particularly in association with other drugs that cause hemolysis." See label for more information.

\n", "version" : 0 }, @@ -150501,14 +152828,14 @@ "objCls" : "Chemical", "id" : "PA164777036", "name" : "hydroxychloroquine", - "version" : 10 + "version" : 27 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166182769", "name" : "Annotation of FDA Label for hydroxychloroquine and G6PD", - "version" : 16 + "version" : 27 }, "text" : { "id" : 1452216587, @@ -150519,29 +152846,29 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166315082", - "name" : "Recommendation Annotation PA166315082", + "id" : "PA166312308", + "name" : "Recommendation Annotation PA166312308", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"G6PD": "Variable"}, + "lookupKey" : {"G6PD": "Deficient with CNSHA"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA164777036", "name" : "hydroxychloroquine", - "version" : 10 + "version" : 27 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166182769", "name" : "Annotation of FDA Label for hydroxychloroquine and G6PD", - "version" : 16 + "version" : 27 }, "text" : { - "id" : 1452245621, + "id" : 1452216569, "html" : "

"Hemolytic Anemia Associated with G6PD Deficiency: Hemolysis has been reported in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Monitor for hemolytic anemia as this can occur, particularly in association with other drugs that cause hemolysis." See label for more information.

\n", "version" : 0 }, @@ -150579,7 +152906,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 4, + "version" : 5, "year" : -1 } ], @@ -150615,7 +152942,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "prescribingMarkdown" : { @@ -150629,7 +152956,7 @@ "objCls" : "Chemical", "id" : "PA161199368", "name" : "iloperidone", - "version" : 7 + "version" : 11 } ], "relatedGenes" : [ @@ -150638,7 +152965,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "FDA", @@ -150661,10 +152988,10 @@ "textMarkdown" : { "id" : 1447981740, "html" : "

Excerpts from the iloperidone drug label:

\n
\n

The iloperidone metabolite P95 represents 47.9% of the AUC of iloperidone and its metabolites in plasma at steady-state for extensive metabolizers (EM) and 25% for poor metabolizers (PM). The active metabolite P88 accounts for 19.5% and 34.0% of total plasma exposure in EM and PM, respectively. Approximately 7% - 10% of Caucasians and 3% - 8% of black/African Americans lack the capacity to metabolize CYP2D6 substrates and are classified as poor metabolizers (PM), whereas the rest are intermediate, extensive or ultrarapid metabolizers.

\n
\n
\n

Similarly, PMs of CYP2D6 have higher exposure to iloperidone compared with EMs and PMs should have their dose reduced by one-half. Laboratory tests are available to identify CYP2D6 PMs.

\n
\n

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the iloperidone drug label.

\n

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

\n", - "version" : 11 + "version" : 15 }, "userId" : "jmbarbarino", - "version" : 27 + "version" : 47 }, "recommendations" : [ { @@ -150681,14 +153008,14 @@ "objCls" : "Chemical", "id" : "PA161199368", "name" : "iloperidone", - "version" : 7 + "version" : 11 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104887", "name" : "Annotation of FDA Label for iloperidone and CYP2D6", - "version" : 27 + "version" : 47 }, "text" : { "id" : 1452216460, @@ -150702,6 +153029,37 @@ }, { "citations" : [ + { + "id" : 15158882, + "title" : "Drugs@FDA: Drug Product Onivyde (IRINOTECAN HYDROCHLORIDE), Ipsen Biopharmaceuticals, Inc. - NDA207793/ORIG-1, 10/22/2015", + "_sameAs" : "https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=207793", + "authors" : [], + "crossReferences" : [ + { + "id" : 1452489281, + "resource" : "FDA Application", + "resourceId" : "NDA207793/ORIG-1", + "_url" : "https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=207793", + "version" : 0 + } + ], + "day" : 22, + "hasKeyword" : false, + "meshDiseases" : [], + "meshTerms" : [], + "month" : 10, + "nonHuman" : false, + "objCls" : "Literature", + "pediatric" : false, + "pgkbPublication" : false, + "pubDate" : "2015-10-22T00:00:00-07:00", + "terms" : [ + {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} + ], + "type" : "Drug Label", + "version" : 2, + "year" : 2015 + }, { "id" : 15102015, "title" : "Drugs@FDA: Drug Product Camptosar (irinotecan hydrochloride), NDA020571, Pharmacia and Upjohn Company LLC", @@ -150730,7 +153088,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 4, + "version" : 5, "year" : -1 } ], @@ -150756,15 +153114,30 @@ "description" : "Updated excerpts, attached most recent label and changed to testing recommended based on sentence in section 5.3 \"Consider UGT1A1 genotype testing for the *28 and *6 alleles to determine UGT1A1 metabolizer status.\"", "type" : "Update", "version" : 0 + }, + { + "id" : 1452489282, + "date" : "2024-05-31T14:30:59.810-07:00", + "description" : "added the Onivyde label source and prescribing info", + "type" : "Update", + "version" : 0 + }, + { + "id" : 1452492640, + "date" : "2024-06-04T16:43:09.564-07:00", + "description" : "added quote on other guidance from the CAMPTOSAR label to the Prescribing box", + "type" : "Update", + "version" : 0 } ], "indication" : false, "labelApplications" : [], "labelDocumentAvailable" : true, "literature" : [ + {"id":15158882,"title":"Drugs@FDA: Drug Product Onivyde (IRINOTECAN HYDROCHLORIDE), Ipsen Biopharmaceuticals, Inc. - NDA207793/ORIG-1, 10/22/2015","_sameAs":"https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=207793","crossReferences":[{"id":1452489281,"resource":"FDA Application","resourceId":"NDA207793/ORIG-1","_url":"https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=207793"}],"objCls":"Literature","pubDate":"2015-10-22T00:00:00-07:00","terms":[{"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"}],"type":"Drug Label"}, {"id":15102015,"title":"Drugs@FDA: Drug Product Camptosar (irinotecan hydrochloride), NDA020571, Pharmacia and Upjohn Company LLC","_sameAs":"https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=020571","crossReferences":[{"id":1450368469,"resource":"FDA Application","resourceId":"NDA020571","_url":"https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=020571"}],"notes":"CAMPTOSAR","objCls":"Literature","terms":[{"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"}],"type":"Drug Label"} ], - "otherPrescribingGuidance" : false, + "otherPrescribingGuidance" : true, "pediatric" : false, "pgxRelated" : true, "prescribingGenes" : [ @@ -150773,13 +153146,13 @@ "id" : "PA420", "symbol" : "UGT1A1", "name" : "UDP glucuronosyltransferase 1 family, polypeptide A1", - "version" : 6110 + "version" : 6350 } ], "prescribingMarkdown" : { "id" : 1450399556, - "html" : "

Excerpt from the irinotecan (CAMPTOSAR) label:

\n
\n

2.3 Dosage in Patients With Reduced UGT1A1 Activity\nWhen administered in combination with other agents, or as a single-agent, consider a reduction\nin the starting dose by at least one level of CAMPTOSAR for patients known to be homozygous\nfor the UGT1A1*28 or *6 alleles (*28/*28, *6/*6) or compound heterozygous for the\nUGT1A1*28 and *6 alleles (*6/*28). Subsequent dosage modifications may be required based on individual patient tolerance to treatment.

\n
\n", - "version" : 3 + "html" : "

Excerpt from the irinotecan (CAMPTOSAR) label:

\n
\n

2.3 Dosage in Patients With Reduced UGT1A1 Activity\nWhen administered in combination with other agents, or as a single-agent, consider a reduction in the starting dose by at least one level of CAMPTOSAR for patients known to be homozygous for the UGT1A1*28 or *6 alleles (*28/*28, *6/*6) or compound heterozygous for the UGT1A1*28 and *6 alleles (*6/*28). Subsequent dosage modifications may be required based on individual patient tolerance to treatment.

\n
\n
\n

Individuals who are heterozygous for either the UGT1A1*28 or *6 alleles (*1/*6, *1/*28) are UGT1A1 intermediate metabolizers and may also have an increased risk of severe or life-threatening neutropenia. Published studies have shown that individuals with UGT1A1*28 and *6 alleles may be at an increased risk of severe diarrhea.

\n
\n
\n

Closely monitor patients with UGT1A1*28 or *6 alleles for neutropenia during and after treatment with CAMPTOSAR.

\n
\n

Excerpt from the irinotecan (ONIVYDE) drug label:

\n
\n

The recommended starting dose of ONIVYDE in patients known to be homozygous for the UGT1A1*28 allele is 50 mg/m2 administered by intravenous infusion over 90 minutes. Increase the dose of ONIVYDE to 70 mg/m2 as tolerated in subsequent cycles.

\n
\n", + "version" : 5 }, "relatedAlleles" : [ { @@ -150787,14 +153160,14 @@ "id" : "PA166115842", "symbol" : "UGT1A1*28", "name" : "*28", - "version" : 16 + "version" : 34 }, { "objCls" : "Haplotype", "id" : "PA166115858", "symbol" : "UGT1A1*6", "name" : "*6", - "version" : 13 + "version" : 32 } ], "relatedChemicals" : [ @@ -150802,7 +153175,7 @@ "objCls" : "Chemical", "id" : "PA450085", "name" : "irinotecan", - "version" : 17 + "version" : 59 } ], "relatedGenes" : [ @@ -150811,14 +153184,14 @@ "id" : "PA420", "symbol" : "UGT1A1", "name" : "UDP glucuronosyltransferase 1 family, polypeptide A1", - "version" : 6110 + "version" : 6350 } ], "source" : "FDA", "summaryMarkdown" : { "id" : 1447981632, "html" : "

The FDA-approved drug label for irinotecan (CAMPTOSAR) states that a reduction in the starting dose by at least one level of CAMPTOSAR should be considered for patients known to be homozygous for the UGT1A1*28 allele, the UGT1A1*6 allele or compound heterozygotes. The label recommends to consider UGT1A1 genotype testing for the *28 and *6 alleles to determine UGT1A1 metabolizer\nstatus.

\n", - "version" : 2 + "version" : 6 }, "terms" : [], "testing" : { @@ -150833,13 +153206,43 @@ }, "textMarkdown" : { "id" : 1447981631, - "html" : "

Excerpts from the irinotecan (CAMPTOSAR) label:

\n
\n

5.3 Increased Risk of Neutropenia in Patients With Reduced UGT1A1 Activity\nPublished studies have shown that individuals who are homozygous for either the UGT1A1*28\nor *6 alleles (*28/*28, *6/*6) or who are compound or double heterozygous for the UGT1A1*28\nand *6 alleles (*6/*28) are at increased risk for severe or life-threatening neutropenia during\ntreatment with CAMPTOSAR. These individuals are UGT1A1 poor metabolizers and experience\nincreased systemic exposure to SN-38, an active metabolite of irinotecan. Individuals who are\nheterozygous for either the UGT1A1*28 or *6 alleles (*1/*28, *1/*6) are intermediate\nmetabolizers and may also have an increased risk of severe or life-threatening neutropenia.\n.\nConsider UGT1A1 genotype testing for the *28 and *6 alleles to determine UGT1A1 metabolizer\nstatus.

\n
\n
\n

When administering CAMPTOSAR, consider a reduction in the CAMPTOSAR starting dose by\nat least one level for patients known to be homozygous or compound heterozygous for the\nUGT1A1*28 and/or *6 alleles (*28/*28, *6/*6, *6/*28).\nClosely monitor patients with UGT1A1*28 or *6 alleles for neutropenia during and after\ntreatment with CAMPTOSAR. The precise dosage reduction in this patient population is not\nknown. Subsequent dosage modifications may be required based on individual patient tolerance\nto treatment

\n
\n
\n

2.3 Dosage in Patients With Reduced UGT1A1 Activity\nWhen administered in combination with other agents, or as a single-agent, consider a reduction\nin the starting dose by at least one level of CAMPTOSAR for patients known to be homozygous\nfor the UGT1A1*28 or *6 alleles (*28/*28, *6/*6) or compound heterozygous for the\nUGT1A1*28 and *6 alleles (*6/*28). Subsequent dosage modifications may be required based on individual patient tolerance to treatment.

\n
\n
\n

Irinotecan is subject to extensive metabolic conversion by various enzyme systems, including\nesterases that form an active metabolite SN-38, and UGT1A1 which mediates the\nglucuronidation of SN-38 to form an inactive metabolite. SN-38 glucuronide had 1/50 to 1/100\nthe activity of SN-38. Patients who are homozygous for either the UGT1A1*28 or *6 alleles, or\nwho are compound heterozygous for these alleles, have higher SN-38 AUC than patients with\nthe wild-type UGT1A1 alleles.

\n
\n
\n

12.5 Pharmacogenomics\nThe active metabolite SN-38 is further metabolized via UGT1A1. Genetic variants of the\nUGT1A1 gene such as the UGT1A1*28 (TA)7 and *6 alleles lead to reduced UGT1A1 enzyme\nexpression or activity and decreased function to a similar extent.\nIndividuals who are homozygous or compound (double) heterozygous for these alleles (e.g.,\n*28/*28, *6/*6, *6/*28) are UGT1A1 poor metabolizers and are at increased risk for severe or\nlife-threatening neutropenia from CAMPTOSAR due to elevated systemic exposure to SN-38. The UGT1A1*6/*6 genotype should not be confused with 6/6 genotype, which is sometimes\nused to represent the genotype of individuals who are wild type for UGT1A1*28. Individuals\nwho are heterozygous for either the UGT1A1*28 or *6 alleles (*1/*6, *1/*28) are UGT1A1\nintermediate metabolizers and may also have an increased risk of severe or life-threatening\nneutropenia.\nPublished studies have shown that individuals with UGT1A1*28 and *6 alleles may be at an\nincreased risk of severe diarrhea. The risk evidence appears greater in UGT1A1*28 and *6\nhomozygous patients and in those taking irinotecan doses > 125 mg/m2

\n
\n

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the irinotecan drug label.

\n

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

\n", - "version" : 13 + "html" : "

Excerpts from the irinotecan (CAMPTOSAR) label:

\n
\n

5.3 Increased Risk of Neutropenia in Patients With Reduced UGT1A1 Activity\nPublished studies have shown that individuals who are homozygous for either the UGT1A1*28\nor *6 alleles (*28/*28, *6/*6) or who are compound or double heterozygous for the UGT1A1*28\nand *6 alleles (*6/*28) are at increased risk for severe or life-threatening neutropenia during\ntreatment with CAMPTOSAR. These individuals are UGT1A1 poor metabolizers and experience\nincreased systemic exposure to SN-38, an active metabolite of irinotecan. Individuals who are\nheterozygous for either the UGT1A1*28 or *6 alleles (*1/*28, *1/*6) are intermediate\nmetabolizers and may also have an increased risk of severe or life-threatening neutropenia.

\n
\n
\n

Consider UGT1A1 genotype testing for the *28 and *6 alleles to determine UGT1A1 metabolizer\nstatus.

\n
\n
\n

When administering CAMPTOSAR, consider a reduction in the CAMPTOSAR starting dose by\nat least one level for patients known to be homozygous or compound heterozygous for the\nUGT1A1*28 and/or *6 alleles (*28/*28, *6/*6, *6/*28).\nClosely monitor patients with UGT1A1*28 or *6 alleles for neutropenia during and after\ntreatment with CAMPTOSAR. The precise dosage reduction in this patient population is not\nknown. Subsequent dosage modifications may be required based on individual patient tolerance\nto treatment

\n
\n
\n

2.3 Dosage in Patients With Reduced UGT1A1 Activity\nWhen administered in combination with other agents, or as a single-agent, consider a reduction\nin the starting dose by at least one level of CAMPTOSAR for patients known to be homozygous\nfor the UGT1A1*28 or *6 alleles (*28/*28, *6/*6) or compound heterozygous for the\nUGT1A1*28 and *6 alleles (*6/*28). Subsequent dosage modifications may be required based on individual patient tolerance to treatment.

\n
\n
\n

Irinotecan is subject to extensive metabolic conversion by various enzyme systems, including\nesterases that form an active metabolite SN-38, and UGT1A1 which mediates the\nglucuronidation of SN-38 to form an inactive metabolite. SN-38 glucuronide had 1/50 to 1/100\nthe activity of SN-38. Patients who are homozygous for either the UGT1A1*28 or *6 alleles, or\nwho are compound heterozygous for these alleles, have higher SN-38 AUC than patients with\nthe wild-type UGT1A1 alleles.

\n
\n
\n

12.5 Pharmacogenomics\nThe active metabolite SN-38 is further metabolized via UGT1A1. Genetic variants of the\nUGT1A1 gene such as the UGT1A1*28 (TA)7 and *6 alleles lead to reduced UGT1A1 enzyme\nexpression or activity and decreased function to a similar extent.\nIndividuals who are homozygous or compound (double) heterozygous for these alleles (e.g.,\n*28/*28, *6/*6, *6/*28) are UGT1A1 poor metabolizers and are at increased risk for severe or\nlife-threatening neutropenia from CAMPTOSAR due to elevated systemic exposure to SN-38. The UGT1A1*6/*6 genotype should not be confused with 6/6 genotype, which is sometimes\nused to represent the genotype of individuals who are wild type for UGT1A1*28. Individuals\nwho are heterozygous for either the UGT1A1*28 or *6 alleles (*1/*6, *1/*28) are UGT1A1\nintermediate metabolizers and may also have an increased risk of severe or life-threatening\nneutropenia.\nPublished studies have shown that individuals with UGT1A1*28 and *6 alleles may be at an\nincreased risk of severe diarrhea. The risk evidence appears greater in UGT1A1*28 and *6\nhomozygous patients and in those taking irinotecan doses > 125 mg/m2

\n
\n

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the irinotecan (CAMPTOSAR) drug label and the irinotecan (ONIVYDE) drug label.

\n

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

\n", + "version" : 17 }, "userId" : "jmbarbarino", - "version" : 30 + "version" : 68 }, "recommendations" : [ + { + "objCls" : "Recommendation Annotation", + "id" : "PA166339401", + "name" : "Recommendation Annotation PA166339401", + "alternateDrugAvailable" : false, + "dosingInformation" : true, + "implications" : [], + "lookupKey" : {"UGT1A1": {"*6": 2}}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA450085", + "name" : "irinotecan", + "version" : 59 + } + ], + "source" : { + "objCls" : "Label Annotation", + "id" : "PA166104831", + "name" : "Annotation of FDA Label for irinotecan and UGT1A1", + "version" : 68 + }, + "text" : { + "id" : 1452482200, + "html" : "

The CAMPTOSAR (irinotecan) label states: "When administered in combination with other agents, or as a single-agent, consider a reduction in the starting dose by at least one level of CAMPTOSAR for patients known to be homozygous\nfor the UGT1A1*28 or *6 alleles (*28/*28, *6/*6) or compound heterozygous for the UGT1A1*28 and *6 alleles (*6/*28)... Subsequent dosage modifications may be required based on individual patient tolerance to treatment"\nSee label for more information.

\n", + "version" : 2 + }, + "version" : 2 + }, { "objCls" : "Recommendation Annotation", "id" : "PA166312562", @@ -150854,21 +153257,171 @@ "objCls" : "Chemical", "id" : "PA450085", "name" : "irinotecan", - "version" : 17 + "version" : 59 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104831", "name" : "Annotation of FDA Label for irinotecan and UGT1A1", - "version" : 30 + "version" : 68 }, "text" : { "id" : 1452217281, - "html" : "

The CAMPTOSAR [irinotecan] label states "Individuals who are homozygous for the UGT1A1*28 allele (UGT1A1 7/7 genotype) are at increased risk for neutropenia following initiation of CAMPTOSAR [irinotecan] treatment...When administered in combination with other agents or as a single-agent, a reduction in the starting dose by at least one level of CAMPTOSAR should be considered for patients known to be homozygous for the UGT1A1*28 allele. However, the precise dose reduction in this patient population is not known and subsequent dose modifications should be considered based on individual patient tolerance to treatment."
\nThe ONIVYDE [irinotecan] label states "The recommended dose of ONIVYDE [irinotecan] is 70 mg/m2 administered by intravenous infusion over 90 minutes every 2 weeks...The recommended starting dose of ONIVYDE in patients known to be homozygous for the UGT1A1*28 allele is 50 mg/m2 administered by intravenous infusion over 90 minutes. Increase the dose of ONIVYDE to 70 mg/m2 as tolerated in subsequent cycles."
\nSee labels for more information.

\n", + "html" : "

The CAMPTOSAR [irinotecan] label states "Individuals who are homozygous for the UGT1A1*28 allele (UGT1A1 7/7 genotype) are at increased risk for neutropenia following initiation of CAMPTOSAR [irinotecan] treatment...When administered in combination with other agents or as a single-agent, a reduction in the starting dose by at least one level of CAMPTOSAR should be considered for patients known to be homozygous for the UGT1A1*28 allele. However, the precise dose reduction in this patient population is not known and subsequent dose modifications should be considered based on individual patient tolerance to treatment."
\nThe ONIVYDE [irinotecan] label states "The recommended starting dose of ONIVYDE in patients known to be homozygous for the UGT1A1*28 allele is 50 mg/m2 administered by intravenous infusion over 90 minutes. Increase the dose of ONIVYDE to 70 mg/m2 as tolerated in subsequent cycles."
\nSee labels for more information.

\n", + "version" : 3 + }, + "version" : 4 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166339421", + "name" : "Recommendation Annotation PA166339421", + "alternateDrugAvailable" : false, + "dosingInformation" : true, + "implications" : [], + "lookupKey" : {"UGT1A1": {"*6": 1, "*28": 1}}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA450085", + "name" : "irinotecan", + "version" : 59 + } + ], + "source" : { + "objCls" : "Label Annotation", + "id" : "PA166104831", + "name" : "Annotation of FDA Label for irinotecan and UGT1A1", + "version" : 68 + }, + "text" : { + "id" : 1452482220, + "html" : "

The CAMPTOSAR (irinotecan) label states: "When administered in combination with other agents, or as a single-agent, consider a reduction in the starting dose by at least one level of CAMPTOSAR for patients known to be homozygous\nfor the UGT1A1*28 or *6 alleles (*28/*28, *6/*6) or compound heterozygous for the UGT1A1*28 and *6 alleles (*6/*28)... Subsequent dosage modifications may be required based on individual patient tolerance to treatment"\nSee label for more information.

\n", "version" : 0 }, "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166340422", + "name" : "Recommendation Annotation PA166340422", + "alternateDrugAvailable" : false, + "dosingInformation" : false, + "implications" : [], + "lookupKey" : {"UGT1A1": {"*1": 1, "*80+*28": 1}}, + "otherPrescribingGuidance" : true, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA450085", + "name" : "irinotecan", + "version" : 59 + } + ], + "source" : { + "objCls" : "Label Annotation", + "id" : "PA166104831", + "name" : "Annotation of FDA Label for irinotecan and UGT1A1", + "version" : 68 + }, + "text" : { + "id" : 1452491381, + "html" : "

The CAMPTOSAR [irinotecan] label states "Individuals who are heterozygous for either the UGT1A1*28 or *6 alleles (*1/*6, *1/*28) are UGT1A1 intermediate metabolizers and may also have an increased risk of severe or life-threatening neutropenia. Published studies have shown that individuals with UGT1A1*28 and *6 alleles may be at an increased risk of severe diarrhea." "Closely monitor patients with UGT1A1*28 or *6 alleles for neutropenia during and after treatment with CAMPTOSAR." See label for more information.

\n", + "version" : 1 + }, + "version" : 1 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166340421", + "name" : "Recommendation Annotation PA166340421", + "alternateDrugAvailable" : false, + "dosingInformation" : false, + "implications" : [], + "lookupKey" : {"UGT1A1": {"*1": 1, "*28": 1}}, + "otherPrescribingGuidance" : true, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA450085", + "name" : "irinotecan", + "version" : 59 + } + ], + "source" : { + "objCls" : "Label Annotation", + "id" : "PA166104831", + "name" : "Annotation of FDA Label for irinotecan and UGT1A1", + "version" : 68 + }, + "text" : { + "id" : 1452491380, + "html" : "

The CAMPTOSAR [irinotecan] label states "Individuals who are heterozygous for either the UGT1A1*28 or *6 alleles (*1/*6, *1/*28) are UGT1A1 intermediate metabolizers and may also have an increased risk of severe or life-threatening neutropenia. Published studies have shown that individuals with UGT1A1*28 and *6 alleles may be at an increased risk of severe diarrhea." "Closely monitor patients with UGT1A1*28 or *6 alleles for neutropenia during and after treatment with CAMPTOSAR." See label for more information.

\n", + "version" : 1 + }, + "version" : 1 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166340382", + "name" : "Recommendation Annotation PA166340382", + "alternateDrugAvailable" : false, + "dosingInformation" : false, + "implications" : [], + "lookupKey" : {"UGT1A1": {"*1": 1, "*6": 1}}, + "otherPrescribingGuidance" : true, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA450085", + "name" : "irinotecan", + "version" : 59 + } + ], + "source" : { + "objCls" : "Label Annotation", + "id" : "PA166104831", + "name" : "Annotation of FDA Label for irinotecan and UGT1A1", + "version" : 68 + }, + "text" : { + "id" : 1452491341, + "html" : "

The CAMPTOSAR [irinotecan] label states "Individuals who are heterozygous for either the UGT1A1*28 or *6 alleles (*1/*6, *1/*28) are UGT1A1 intermediate metabolizers and may also have an increased risk of severe or life-threatening neutropenia. Published studies have shown that individuals with UGT1A1*28 and *6 alleles may be at an increased risk of severe diarrhea." "Closely monitor patients with UGT1A1*28 or *6 alleles for neutropenia during and after treatment with CAMPTOSAR." See label for more information.

\n", + "version" : 1 + }, + "version" : 1 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166339781", + "name" : "Recommendation Annotation PA166339781", + "alternateDrugAvailable" : false, + "dosingInformation" : true, + "implications" : [], + "lookupKey" : {"UGT1A1": {"*80+*28": 2}}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA450085", + "name" : "irinotecan", + "version" : 59 + } + ], + "source" : { + "objCls" : "Label Annotation", + "id" : "PA166104831", + "name" : "Annotation of FDA Label for irinotecan and UGT1A1", + "version" : 68 + }, + "text" : { + "id" : 1452486240, + "html" : "

The CAMPTOSAR [irinotecan] label states "Individuals who are homozygous for the UGT1A1*28 allele (UGT1A1 7/7 genotype) are at increased risk for neutropenia following initiation of CAMPTOSAR [irinotecan] treatment...When administered in combination with other agents or as a single-agent, a reduction in the starting dose by at least one level of CAMPTOSAR should be considered for patients known to be homozygous for the UGT1A1*28 allele. However, the precise dose reduction in this patient population is not known and subsequent dose modifications should be considered based on individual patient tolerance to treatment."
\nThe ONIVYDE [irinotecan] label states "The recommended starting dose of ONIVYDE in patients known to be homozygous for the UGT1A1*28 allele is 50 mg/m2 administered by intravenous infusion over 90 minutes. Increase the dose of ONIVYDE to 70 mg/m2 as tolerated in subsequent cycles."
\nSee labels for more information.

\n", + "version" : 1 + }, + "version" : 1 } ], "url" : "https://www.pharmgkb.org/labelAnnotation/PA166104831" @@ -150902,7 +153455,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 4, + "version" : 5, "year" : -1 } ], @@ -150959,14 +153512,14 @@ "id" : "PA85", "symbol" : "CACNA1S", "name" : "calcium voltage-gated channel subunit alpha1 S", - "version" : 19 + "version" : 59 }, { "objCls" : "Gene", "id" : "PA34896", "symbol" : "RYR1", "name" : "ryanodine receptor 1", - "version" : 131 + "version" : 7467 } ], "prescribingMarkdown" : { @@ -150980,7 +153533,7 @@ "objCls" : "Chemical", "id" : "PA450106", "name" : "isoflurane", - "version" : 7 + "version" : 33 } ], "relatedGenes" : [ @@ -150989,21 +153542,21 @@ "id" : "PA85", "symbol" : "CACNA1S", "name" : "calcium voltage-gated channel subunit alpha1 S", - "version" : 19 + "version" : 59 }, { "objCls" : "Gene", "id" : "PA34896", "symbol" : "RYR1", "name" : "ryanodine receptor 1", - "version" : 131 + "version" : 7467 } ], "source" : "FDA", "summaryMarkdown" : { "id" : 1447982449, "html" : "

The FDA-approved drug label for isoflurane (FORANE) warns that individuals with a genetic predisposition to malignant hyperthermia.

\n", - "version" : 4 + "version" : 5 }, "terms" : [], "testing" : { @@ -151019,37 +153572,37 @@ "textMarkdown" : { "id" : 1447982448, "html" : "

Isoflurane (FORANE) is a potent (volatile) inhalational anesthetic used to induce or maintain general anesthesia. Specific variants in the RYR1 and CACNA1S genes are associated with risk of malignant hyperthermia in individuals administered potent inhalational anesthetics, including isoflurane. Although the isoflurane drug label does not specifically mention genetic testing, the FDA-approved label for isoflurane contraindicates it for individuals with known, or suspected, genetic predisposition to malignant hyperthermia.

\n

Excerpts from the isoflurane (FORANE) drug label:

\n
\n

CONTRAINDICATIONS...with known or suspected genetic susceptibility to malignant hyperthermia.

\n
\n
\n

Malignant Hyperthermia: In susceptible individuals, volatile anesthetic agents, including isoflurane, may trigger malignant hyperthermia, a skeletal muscle hypermetabolic state leading to high oxygen demand. Fatal outcomes of malignant hyperthermia have been reported. The risk of developing malignant hyperthermia increases with the concomitant administration of succinylcholine and volatile anesthetic agents. FORANE can induce malignant hyperthermia in patients with known or suspected susceptibility based on genetic factors or family history, including those with certain inherited ryanodine receptor (RYR1) or dihydropyridine receptor (CACNA1S) variants.

\n
\n
\n

Pharmacogenomics: RYR1 and CACNA1S are polymorphic genes, and multiple pathogenic variants have been associated with malignant hyperthermia susceptibility (MHS) in patients receiving volatile anesthetic agents, including FORANE. Case reports as well as ex-vivo studies have identified multiple variants in RYR1 and CACNA1S associated with MHS. Variant pathogenicity should be assessed based on prior clinical experience, functional studies, prevalence information, or other evidence.

\n
\n

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the isoflurane drug label

\n

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

\n", - "version" : 13 + "version" : 15 }, "userId" : "jmbarbarino", - "version" : 30 + "version" : 68 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166312623", - "name" : "Recommendation Annotation PA166312623", + "id" : "PA166312622", + "name" : "Recommendation Annotation PA166312622", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"RYR1": "Uncertain Susceptibility", "CACNA1S": "Uncertain Susceptibility"}, + "lookupKey" : {"RYR1": "Uncertain Susceptibility", "CACNA1S": "No Result"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450106", "name" : "isoflurane", - "version" : 7 + "version" : 33 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166129517", "name" : "Annotation of FDA Label for isoflurane and CACNA1S, RYR1", - "version" : 30 + "version" : 68 }, "text" : { - "id" : 1452218682, + "id" : 1452218681, "html" : "

"CONTRAINDICATIONS...with known or suspected genetic susceptibility to malignant hyperthermia...FORANE [isoflurane] can induce malignant hyperthermia in patients with known or suspected susceptibility based on genetic factors or family history, including those with certain inherited ryanodine receptor (RYR1) or dihydropyridine receptor (CACNA1S) variants." See label for more information.

\n", "version" : 0 }, @@ -151057,29 +153610,29 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166311844", - "name" : "Recommendation Annotation PA166311844", + "id" : "PA166312623", + "name" : "Recommendation Annotation PA166312623", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"RYR1": "No Result", "CACNA1S": "Malignant Hyperthermia Susceptibility"}, + "lookupKey" : {"RYR1": "Uncertain Susceptibility", "CACNA1S": "Uncertain Susceptibility"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450106", "name" : "isoflurane", - "version" : 7 + "version" : 33 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166129517", "name" : "Annotation of FDA Label for isoflurane and CACNA1S, RYR1", - "version" : 30 + "version" : 68 }, "text" : { - "id" : 1452216043, + "id" : 1452218682, "html" : "

"CONTRAINDICATIONS...with known or suspected genetic susceptibility to malignant hyperthermia...FORANE [isoflurane] can induce malignant hyperthermia in patients with known or suspected susceptibility based on genetic factors or family history, including those with certain inherited ryanodine receptor (RYR1) or dihydropyridine receptor (CACNA1S) variants." See label for more information.

\n", "version" : 0 }, @@ -151099,14 +153652,14 @@ "objCls" : "Chemical", "id" : "PA450106", "name" : "isoflurane", - "version" : 7 + "version" : 33 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166129517", "name" : "Annotation of FDA Label for isoflurane and CACNA1S, RYR1", - "version" : 30 + "version" : 68 }, "text" : { "id" : 1452218670, @@ -151117,29 +153670,29 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166311861", - "name" : "Recommendation Annotation PA166311861", + "id" : "PA166311843", + "name" : "Recommendation Annotation PA166311843", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"RYR1": "Uncertain Susceptibility", "CACNA1S": "Malignant Hyperthermia Susceptibility"}, + "lookupKey" : {"RYR1": "Malignant Hyperthermia Susceptibility", "CACNA1S": "Malignant Hyperthermia Susceptibility"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450106", "name" : "isoflurane", - "version" : 7 + "version" : 33 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166129517", "name" : "Annotation of FDA Label for isoflurane and CACNA1S, RYR1", - "version" : 30 + "version" : 68 }, "text" : { - "id" : 1452216060, + "id" : 1452216042, "html" : "

"CONTRAINDICATIONS...with known or suspected genetic susceptibility to malignant hyperthermia...FORANE [isoflurane] can induce malignant hyperthermia in patients with known or suspected susceptibility based on genetic factors or family history, including those with certain inherited ryanodine receptor (RYR1) or dihydropyridine receptor (CACNA1S) variants." See label for more information.

\n", "version" : 0 }, @@ -151147,29 +153700,29 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166311863", - "name" : "Recommendation Annotation PA166311863", + "id" : "PA166311844", + "name" : "Recommendation Annotation PA166311844", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"RYR1": "Malignant Hyperthermia Susceptibility", "CACNA1S": "Uncertain Susceptibility"}, + "lookupKey" : {"RYR1": "No Result", "CACNA1S": "Malignant Hyperthermia Susceptibility"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450106", "name" : "isoflurane", - "version" : 7 + "version" : 33 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166129517", "name" : "Annotation of FDA Label for isoflurane and CACNA1S, RYR1", - "version" : 30 + "version" : 68 }, "text" : { - "id" : 1452216062, + "id" : 1452216043, "html" : "

"CONTRAINDICATIONS...with known or suspected genetic susceptibility to malignant hyperthermia...FORANE [isoflurane] can induce malignant hyperthermia in patients with known or suspected susceptibility based on genetic factors or family history, including those with certain inherited ryanodine receptor (RYR1) or dihydropyridine receptor (CACNA1S) variants." See label for more information.

\n", "version" : 0 }, @@ -151177,29 +153730,29 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312622", - "name" : "Recommendation Annotation PA166312622", + "id" : "PA166311861", + "name" : "Recommendation Annotation PA166311861", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"RYR1": "Uncertain Susceptibility", "CACNA1S": "No Result"}, + "lookupKey" : {"RYR1": "Uncertain Susceptibility", "CACNA1S": "Malignant Hyperthermia Susceptibility"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450106", "name" : "isoflurane", - "version" : 7 + "version" : 33 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166129517", "name" : "Annotation of FDA Label for isoflurane and CACNA1S, RYR1", - "version" : 30 + "version" : 68 }, "text" : { - "id" : 1452218681, + "id" : 1452216060, "html" : "

"CONTRAINDICATIONS...with known or suspected genetic susceptibility to malignant hyperthermia...FORANE [isoflurane] can induce malignant hyperthermia in patients with known or suspected susceptibility based on genetic factors or family history, including those with certain inherited ryanodine receptor (RYR1) or dihydropyridine receptor (CACNA1S) variants." See label for more information.

\n", "version" : 0 }, @@ -151207,29 +153760,29 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166311843", - "name" : "Recommendation Annotation PA166311843", + "id" : "PA166311862", + "name" : "Recommendation Annotation PA166311862", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"RYR1": "Malignant Hyperthermia Susceptibility", "CACNA1S": "Malignant Hyperthermia Susceptibility"}, + "lookupKey" : {"RYR1": "Malignant Hyperthermia Susceptibility", "CACNA1S": "No Result"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450106", "name" : "isoflurane", - "version" : 7 + "version" : 33 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166129517", "name" : "Annotation of FDA Label for isoflurane and CACNA1S, RYR1", - "version" : 30 + "version" : 68 }, "text" : { - "id" : 1452216042, + "id" : 1452216061, "html" : "

"CONTRAINDICATIONS...with known or suspected genetic susceptibility to malignant hyperthermia...FORANE [isoflurane] can induce malignant hyperthermia in patients with known or suspected susceptibility based on genetic factors or family history, including those with certain inherited ryanodine receptor (RYR1) or dihydropyridine receptor (CACNA1S) variants." See label for more information.

\n", "version" : 0 }, @@ -151237,29 +153790,29 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166311862", - "name" : "Recommendation Annotation PA166311862", + "id" : "PA166311863", + "name" : "Recommendation Annotation PA166311863", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"RYR1": "Malignant Hyperthermia Susceptibility", "CACNA1S": "No Result"}, + "lookupKey" : {"RYR1": "Malignant Hyperthermia Susceptibility", "CACNA1S": "Uncertain Susceptibility"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450106", "name" : "isoflurane", - "version" : 7 + "version" : 33 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166129517", "name" : "Annotation of FDA Label for isoflurane and CACNA1S, RYR1", - "version" : 30 + "version" : 68 }, "text" : { - "id" : 1452216061, + "id" : 1452216062, "html" : "

"CONTRAINDICATIONS...with known or suspected genetic susceptibility to malignant hyperthermia...FORANE [isoflurane] can induce malignant hyperthermia in patients with known or suspected susceptibility based on genetic factors or family history, including those with certain inherited ryanodine receptor (RYR1) or dihydropyridine receptor (CACNA1S) variants." See label for more information.

\n", "version" : 0 }, @@ -151297,7 +153850,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 4, + "version" : 5, "year" : -1 } ], @@ -151390,7 +153943,7 @@ "id" : "PA166164959", "symbol" : "rs11971167", "name" : "rs11971167", - "version" : 6 + "version" : 8 }, { "objCls" : "Variant", @@ -151411,21 +153964,21 @@ "id" : "PA166157529", "symbol" : "rs121908755", "name" : "rs121908755", - "version" : 5 + "version" : 8 }, { "objCls" : "Variant", "id" : "PA166157530", "symbol" : "rs121908757", "name" : "rs121908757", - "version" : 5 + "version" : 6 }, { "objCls" : "Variant", "id" : "PA166157532", "symbol" : "rs121909013", "name" : "rs121909013", - "version" : 5 + "version" : 6 }, { "objCls" : "Variant", @@ -151439,7 +153992,7 @@ "id" : "PA166157533", "symbol" : "rs121909041", "name" : "rs121909041", - "version" : 5 + "version" : 6 }, { "objCls" : "Variant", @@ -151467,7 +154020,7 @@ "id" : "PA166157534", "symbol" : "rs193922525", "name" : "rs193922525", - "version" : 5 + "version" : 6 }, { "objCls" : "Variant", @@ -151488,7 +154041,7 @@ "id" : "PA166157537", "symbol" : "rs267606723", "name" : "rs267606723", - "version" : 6 + "version" : 7 }, { "objCls" : "Variant", @@ -151551,14 +154104,14 @@ "id" : "PA166157511", "symbol" : "rs74503330", "name" : "rs74503330", - "version" : 5 + "version" : 6 }, { "objCls" : "Variant", "id" : "PA166162705", "symbol" : "rs74551128", "name" : "rs74551128", - "version" : 5 + "version" : 6 }, { "objCls" : "Variant", @@ -151572,7 +154125,7 @@ "id" : "PA166157516", "symbol" : "rs75527207", "name" : "rs75527207", - "version" : 5 + "version" : 6 }, { "objCls" : "Variant", @@ -151628,7 +154181,7 @@ "id" : "PA166157521", "symbol" : "rs80282562", "name" : "rs80282562", - "version" : 5 + "version" : 6 } ], "relatedChemicals" : [ @@ -151636,7 +154189,7 @@ "objCls" : "Chemical", "id" : "PA165950341", "name" : "ivacaftor", - "version" : 6 + "version" : 16 } ], "relatedGenes" : [ @@ -151645,14 +154198,14 @@ "id" : "PA109", "symbol" : "CFTR", "name" : "cystic fibrosis transmembrane conductance regulator", - "version" : 18 + "version" : 5399 } ], "source" : "FDA", "summaryMarkdown" : { "id" : 1447981757, "html" : "

Ivacaftor (KALYDECO) is indicated for the treatment of patients with cystic fibrosis (CF) who have a mutation in the CFTR gene that is responsive to ivacaftor based on clinical or in vitro data. Genetic testing is required prior to initiating treatment with ivacaftor if a patient's CFTR genotype is not known.

\n", - "version" : 11 + "version" : 27 }, "terms" : [], "testing" : { @@ -151668,10 +154221,10 @@ "textMarkdown" : { "id" : 1447981756, "html" : "

Please refer to Table 3 in the drug label PDF (downloadable below) for a full list of mutations that are responsive to ivacaftor.

\n

Excerpts from the ivacaftor (KALYDECO) drug label:

\n
\n

KALYDECO is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator indicated for the treatment of cystic fibrosis (CF) in patients age 1 month and older who have at least one mutation in the CFTR gene that is responsive to ivacaftor based on clinical and/or in vitro assay data. (12.1, 14)

\n
\n
\n

If the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of a CFTR mutation followed by verification with bi-directional sequencing when recommended by the mutation test instructions for use.

\n
\n

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the ivacaftor drug label.

\n

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

\n", - "version" : 14 + "version" : 30 }, "userId" : "jmbarbarino", - "version" : 42 + "version" : 93 }, "recommendations" : [ { @@ -151688,14 +154241,14 @@ "objCls" : "Chemical", "id" : "PA165950341", "name" : "ivacaftor", - "version" : 6 + "version" : 16 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104890", "name" : "Annotation of FDA Label for ivacaftor and CFTR", - "version" : 42 + "version" : 93 }, "text" : { "id" : 1452216000, @@ -151736,7 +154289,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 4, + "version" : 5, "year" : -1 } ], @@ -151765,7 +154318,7 @@ "id" : "PA126", "symbol" : "CYP2C9", "name" : "cytochrome P450 family 2 subfamily C member 9", - "version" : 7877 + "version" : 7952 } ], "prescribingMarkdown" : { @@ -151779,7 +154332,7 @@ "objCls" : "Chemical", "id" : "PA166160006", "name" : "lesinurad", - "version" : 5 + "version" : 6 } ], "relatedGenes" : [ @@ -151788,7 +154341,7 @@ "id" : "PA126", "symbol" : "CYP2C9", "name" : "cytochrome P450 family 2 subfamily C member 9", - "version" : 7877 + "version" : 7952 } ], "source" : "FDA", @@ -151814,34 +154367,34 @@ "version" : 11 }, "userId" : "jmbarbarino", - "version" : 27 + "version" : 43 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166311982", - "name" : "Recommendation Annotation PA166311982", + "id" : "PA166311981", + "name" : "Recommendation Annotation PA166311981", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2C9": "0.5"}, + "lookupKey" : {"CYP2C9": "0.0"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166160006", "name" : "lesinurad", - "version" : 5 + "version" : 6 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166160007", "name" : "Annotation of FDA Label for lesinurad and CYP2C9", - "version" : 27 + "version" : 43 }, "text" : { - "id" : 1452216181, + "id" : 1452216180, "html" : "

"ZURAMPIC [lesinurad] should be used with caution in patients taking moderate inhibitors of CYP2C9 (eg, fluconazole, amiodarone), and in CYP2C9 poor metabolizers." See label for more information.

\n", "version" : 0 }, @@ -151849,29 +154402,29 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166311981", - "name" : "Recommendation Annotation PA166311981", + "id" : "PA166311982", + "name" : "Recommendation Annotation PA166311982", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2C9": "0.0"}, + "lookupKey" : {"CYP2C9": "0.5"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166160006", "name" : "lesinurad", - "version" : 5 + "version" : 6 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166160007", "name" : "Annotation of FDA Label for lesinurad and CYP2C9", - "version" : 27 + "version" : 43 }, "text" : { - "id" : 1452216180, + "id" : 1452216181, "html" : "

"ZURAMPIC [lesinurad] should be used with caution in patients taking moderate inhibitors of CYP2C9 (eg, fluconazole, amiodarone), and in CYP2C9 poor metabolizers." See label for more information.

\n", "version" : 0 }, @@ -151909,7 +154462,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 3, + "version" : 4, "year" : -1 } ], @@ -151960,13 +154513,13 @@ "id" : "PA28469", "symbol" : "G6PD", "name" : "glucose-6-phosphate dehydrogenase", - "version" : 135 + "version" : 1326 } ], "prescribingMarkdown" : { "id" : 1450400234, "html" : "

Excerpt from the Lidocaine and tetracaine (SYNERA) drug label:

\n
\n

Although all patients are at risk for methemoglobinemia, patients with glucose-6-phosphate dehydrogenase deficiency, congenital or idiopathic methemoglobinemia, cardiac or pulmonary compromise, infants under 6 months of age, and concurrent exposure to oxidizing agents or their metabolites are more susceptible to developing clinical manifestations of the condition. If local anesthetics must be used in these patients, close monitoring for symptoms and signs of methemoglobinemia is recommended.

\n
\n", - "version" : 2 + "version" : 3 }, "relatedAlleles" : [], "relatedChemicals" : [ @@ -151974,7 +154527,7 @@ "objCls" : "Chemical", "id" : "PA166182735", "name" : "lidocaine and tetracaine", - "version" : 5 + "version" : 6 } ], "relatedGenes" : [ @@ -151983,14 +154536,14 @@ "id" : "PA28469", "symbol" : "G6PD", "name" : "glucose-6-phosphate dehydrogenase", - "version" : 135 + "version" : 1326 } ], "source" : "FDA", "summaryMarkdown" : { "id" : 1450400232, "html" : "

The FDA-approved drug label for lidocaine and tetracaine (SYNERA) states that caution should be used in patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency due to the risk for methemoglobinemia. Close monitoring for symptoms and signs of methemoglobinemia is recommended in this subset of patients.

\n", - "version" : 0 + "version" : 2 }, "terms" : [], "testing" : { @@ -152009,34 +154562,34 @@ "version" : 3 }, "userId" : "lgong", - "version" : 11 + "version" : 23 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166312426", - "name" : "Recommendation Annotation PA166312426", + "id" : "PA166315122", + "name" : "Recommendation Annotation PA166315122", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"G6PD": "Deficient"}, + "lookupKey" : {"G6PD": "Variable"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166182735", "name" : "lidocaine and tetracaine", - "version" : 5 + "version" : 6 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166182737", "name" : "Annotation of FDA Label for lidocaine and tetracaine and G6PD", - "version" : 11 + "version" : 23 }, "text" : { - "id" : 1452216725, + "id" : 1452245661, "html" : "

"Although all patients are at risk for methemoglobinemia, patients with glucose-6-phosphate dehydrogenase deficiency, ... are more susceptible to developing clinical manifestations of the condition. If local anesthetics must be used in these patients, close monitoring for symptoms and signs of methemoglobinemia is recommended." See label for more information.

\n", "version" : 0 }, @@ -152056,14 +154609,14 @@ "objCls" : "Chemical", "id" : "PA166182735", "name" : "lidocaine and tetracaine", - "version" : 5 + "version" : 6 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166182737", "name" : "Annotation of FDA Label for lidocaine and tetracaine and G6PD", - "version" : 11 + "version" : 23 }, "text" : { "id" : 1452216679, @@ -152074,29 +154627,29 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166315122", - "name" : "Recommendation Annotation PA166315122", + "id" : "PA166312426", + "name" : "Recommendation Annotation PA166312426", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"G6PD": "Variable"}, + "lookupKey" : {"G6PD": "Deficient"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA166182735", "name" : "lidocaine and tetracaine", - "version" : 5 + "version" : 6 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166182737", "name" : "Annotation of FDA Label for lidocaine and tetracaine and G6PD", - "version" : 11 + "version" : 23 }, "text" : { - "id" : 1452245661, + "id" : 1452216725, "html" : "

"Although all patients are at risk for methemoglobinemia, patients with glucose-6-phosphate dehydrogenase deficiency, ... are more susceptible to developing clinical manifestations of the condition. If local anesthetics must be used in these patients, close monitoring for symptoms and signs of methemoglobinemia is recommended." See label for more information.

\n", "version" : 0 }, @@ -152134,7 +154687,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 4, + "version" : 5, "year" : -1 } ], @@ -152163,7 +154716,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "prescribingMarkdown" : { @@ -152177,7 +154730,7 @@ "objCls" : "Chemical", "id" : "PA164744510", "name" : "lofexidine", - "version" : 6 + "version" : 19 } ], "relatedGenes" : [ @@ -152186,7 +154739,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "FDA", @@ -152212,7 +154765,7 @@ "version" : 1 }, "userId" : "jmbarbarino", - "version" : 14 + "version" : 23 }, "recommendations" : [ { @@ -152229,21 +154782,21 @@ "objCls" : "Chemical", "id" : "PA164744510", "name" : "lofexidine", - "version" : 6 + "version" : 19 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166179848", "name" : "Annotation of FDA Label for lofexidine and CYP2D6", - "version" : 14 + "version" : 23 }, "text" : { "id" : 1452203820, "html" : "

"Monitor adverse events such as orthostatic hypotension and bradycardia in known CYP2D6 poor metabolizers." See label for more information.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/labelAnnotation/PA166179848" @@ -152277,7 +154830,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 4, + "version" : 5, "year" : -1 } ], @@ -152314,7 +154867,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "prescribingMarkdown" : { @@ -152328,7 +154881,7 @@ "objCls" : "Chemical", "id" : "PA450338", "name" : "meclizine", - "version" : 6 + "version" : 21 } ], "relatedGenes" : [ @@ -152337,7 +154890,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "FDA", @@ -152363,7 +154916,7 @@ "version" : 1 }, "userId" : "jmbarbarino", - "version" : 13 + "version" : 22 }, "recommendations" : [ { @@ -152372,9 +154925,7 @@ "name" : "Recommendation Annotation PA166309563", "alternateDrugAvailable" : false, "dosingInformation" : false, - "implications" : [ - "\"The genetic polymorphism of CYP2D6 that results in poor-, intermediate-, extensive-, and ultrarapid metabolizer phenotypes could contribute to large inter-individual variability in meclizine exposure.\"" - ], + "implications" : [], "lookupKey" : {"CYP2D6": "2.75"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ @@ -152382,149 +154933,141 @@ "objCls" : "Chemical", "id" : "PA450338", "name" : "meclizine", - "version" : 6 + "version" : 21 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166180000", "name" : "Annotation of FDA Label for meclizine and CYP2D6", - "version" : 13 + "version" : 22 }, "text" : { "id" : 1452204002, - "html" : "

"... when ANTIVERT® [meclizine] is administered to patients with CYP2D6 polymorphism, monitor for adverse reactions and clinical effect accordingly." See label for more information.

\n", - "version" : 0 + "html" : "

The meclizine (ANTIVERT) label states: "... when ANTIVERT® is administered to patients with CYP2D6 polymorphism, monitor for adverse reactions and clinical effect accordingly." "The genetic polymorphism of CYP2D6 that results in poor-, intermediate-, extensive-, and ultrarapid metabolizer phenotypes could contribute to large inter-individual variability in meclizine exposure." See label for more information.

\n", + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166309565", - "name" : "Recommendation Annotation PA166309565", + "id" : "PA166309562", + "name" : "Recommendation Annotation PA166309562", "alternateDrugAvailable" : false, "dosingInformation" : false, - "implications" : [ - "\"... when ANTIVERT® \\[meclizine\\] is administered to patients with CYP2D6 polymorphism, monitor for adverse reactions and clinical effect accordingly.\" See label for more information." - ], - "lookupKey" : {"CYP2D6": "4.0"}, + "implications" : [], + "lookupKey" : {"CYP2D6": "2.5"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450338", "name" : "meclizine", - "version" : 6 + "version" : 21 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166180000", "name" : "Annotation of FDA Label for meclizine and CYP2D6", - "version" : 13 + "version" : 22 }, "text" : { - "id" : 1452204004, - "html" : "

"... when ANTIVERT® [meclizine] is administered to patients with CYP2D6 polymorphism, monitor for adverse reactions and clinical effect accordingly." See label for more information.

\n", - "version" : 0 + "id" : 1452204001, + "html" : "

The meclizine (ANTIVERT) label states: "... when ANTIVERT® is administered to patients with CYP2D6 polymorphism, monitor for adverse reactions and clinical effect accordingly." "The genetic polymorphism of CYP2D6 that results in poor-, intermediate-, extensive-, and ultrarapid metabolizer phenotypes could contribute to large inter-individual variability in meclizine exposure." See label for more information.

\n", + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166309541", - "name" : "Recommendation Annotation PA166309541", + "id" : "PA166309561", + "name" : "Recommendation Annotation PA166309561", "alternateDrugAvailable" : false, "dosingInformation" : false, - "implications" : [ - "\"The genetic polymorphism of CYP2D6 that results in poor-, intermediate-, extensive-, and ultrarapid metabolizer phenotypes could contribute to large inter-individual variability in meclizine exposure.\"" - ], - "lookupKey" : {"CYP2D6": "1.25"}, + "implications" : [], + "lookupKey" : {"CYP2D6": "2.25"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450338", "name" : "meclizine", - "version" : 6 + "version" : 21 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166180000", "name" : "Annotation of FDA Label for meclizine and CYP2D6", - "version" : 13 + "version" : 22 }, "text" : { - "id" : 1452203980, - "html" : "

"... when ANTIVERT® [meclizine] is administered to patients with CYP2D6 polymorphism, monitor for adverse reactions and clinical effect accordingly." See label for more information.

\n", - "version" : 0 + "id" : 1452204000, + "html" : "

The meclizine (ANTIVERT) label states: "... when ANTIVERT® is administered to patients with CYP2D6 polymorphism, monitor for adverse reactions and clinical effect accordingly." "The genetic polymorphism of CYP2D6 that results in poor-, intermediate-, extensive-, and ultrarapid metabolizer phenotypes could contribute to large inter-individual variability in meclizine exposure." See label for more information.

\n", + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166309567", - "name" : "Recommendation Annotation PA166309567", + "id" : "PA166309572", + "name" : "Recommendation Annotation PA166309572", "alternateDrugAvailable" : false, "dosingInformation" : false, - "implications" : [ - "\"The genetic polymorphism of CYP2D6 that results in poor-, intermediate-, extensive-, and ultrarapid metabolizer phenotypes could contribute to large inter-individual variability in meclizine exposure.\"" - ], - "lookupKey" : {"CYP2D6": "≥3.25"}, + "implications" : [], + "lookupKey" : {"CYP2D6": "≥6.0"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450338", "name" : "meclizine", - "version" : 6 + "version" : 21 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166180000", "name" : "Annotation of FDA Label for meclizine and CYP2D6", - "version" : 13 + "version" : 22 }, "text" : { - "id" : 1452204006, - "html" : "

"... when ANTIVERT® [meclizine] is administered to patients with CYP2D6 polymorphism, monitor for adverse reactions and clinical effect accordingly." See label for more information.

\n", - "version" : 0 + "id" : 1452204011, + "html" : "

The meclizine (ANTIVERT) label states: "... when ANTIVERT® is administered to patients with CYP2D6 polymorphism, monitor for adverse reactions and clinical effect accordingly." "The genetic polymorphism of CYP2D6 that results in poor-, intermediate-, extensive-, and ultrarapid metabolizer phenotypes could contribute to large inter-individual variability in meclizine exposure." See label for more information.

\n", + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166309543", - "name" : "Recommendation Annotation PA166309543", + "id" : "PA166309571", + "name" : "Recommendation Annotation PA166309571", "alternateDrugAvailable" : false, "dosingInformation" : false, - "implications" : [ - "\"The genetic polymorphism of CYP2D6 that results in poor-, intermediate-, extensive-, and ultrarapid metabolizer phenotypes could contribute to large inter-individual variability in meclizine exposure.\"" - ], - "lookupKey" : {"CYP2D6": "1.75"}, + "implications" : [], + "lookupKey" : {"CYP2D6": "≥5.0"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450338", "name" : "meclizine", - "version" : 6 + "version" : 21 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166180000", "name" : "Annotation of FDA Label for meclizine and CYP2D6", - "version" : 13 + "version" : 22 }, "text" : { - "id" : 1452203982, - "html" : "

"... when ANTIVERT® [meclizine] is administered to patients with CYP2D6 polymorphism, monitor for adverse reactions and clinical effect accordingly." See label for more information.

\n", - "version" : 0 + "id" : 1452204010, + "html" : "

The meclizine (ANTIVERT) label states: "... when ANTIVERT® is administered to patients with CYP2D6 polymorphism, monitor for adverse reactions and clinical effect accordingly." "The genetic polymorphism of CYP2D6 that results in poor-, intermediate-, extensive-, and ultrarapid metabolizer phenotypes could contribute to large inter-individual variability in meclizine exposure." See label for more information.

\n", + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", @@ -152532,9 +155075,7 @@ "name" : "Recommendation Annotation PA166309569", "alternateDrugAvailable" : false, "dosingInformation" : false, - "implications" : [ - "\"The genetic polymorphism of CYP2D6 that results in poor-, intermediate-, extensive-, and ultrarapid metabolizer phenotypes could contribute to large inter-individual variability in meclizine exposure.\"" - ], + "implications" : [], "lookupKey" : {"CYP2D6": "≥3.75"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ @@ -152542,341 +155083,321 @@ "objCls" : "Chemical", "id" : "PA450338", "name" : "meclizine", - "version" : 6 + "version" : 21 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166180000", "name" : "Annotation of FDA Label for meclizine and CYP2D6", - "version" : 13 + "version" : 22 }, "text" : { "id" : 1452204008, - "html" : "

"... when ANTIVERT® [meclizine] is administered to patients with CYP2D6 polymorphism, monitor for adverse reactions and clinical effect accordingly." See label for more information.

\n", - "version" : 0 + "html" : "

The meclizine (ANTIVERT) label states: "... when ANTIVERT® is administered to patients with CYP2D6 polymorphism, monitor for adverse reactions and clinical effect accordingly." "The genetic polymorphism of CYP2D6 that results in poor-, intermediate-, extensive-, and ultrarapid metabolizer phenotypes could contribute to large inter-individual variability in meclizine exposure." See label for more information.

\n", + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166309521", - "name" : "Recommendation Annotation PA166309521", + "id" : "PA166309568", + "name" : "Recommendation Annotation PA166309568", "alternateDrugAvailable" : false, "dosingInformation" : false, - "implications" : [ - "\"The genetic polymorphism of CYP2D6 that results in poor-, intermediate-, extensive-, and ultrarapid metabolizer phenotypes could contribute to large inter-individual variability in meclizine exposure.\"" - ], - "lookupKey" : {"CYP2D6": "1.0"}, + "implications" : [], + "lookupKey" : {"CYP2D6": "≥3.5"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450338", "name" : "meclizine", - "version" : 6 + "version" : 21 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166180000", "name" : "Annotation of FDA Label for meclizine and CYP2D6", - "version" : 13 + "version" : 22 }, "text" : { - "id" : 1452203960, - "html" : "

"... when ANTIVERT® [meclizine] is administered to patients with CYP2D6 polymorphism, monitor for adverse reactions and clinical effect accordingly." See label for more information.

\n", - "version" : 0 + "id" : 1452204007, + "html" : "

The meclizine (ANTIVERT) label states: "... when ANTIVERT® is administered to patients with CYP2D6 polymorphism, monitor for adverse reactions and clinical effect accordingly." "The genetic polymorphism of CYP2D6 that results in poor-, intermediate-, extensive-, and ultrarapid metabolizer phenotypes could contribute to large inter-individual variability in meclizine exposure." See label for more information.

\n", + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166309481", - "name" : "Recommendation Annotation PA166309481", + "id" : "PA166309567", + "name" : "Recommendation Annotation PA166309567", "alternateDrugAvailable" : false, "dosingInformation" : false, - "implications" : [ - "\"The genetic polymorphism of CYP2D6 that results in poor-, intermediate-, extensive-, and ultrarapid metabolizer phenotypes could contribute to large inter-individual variability in meclizine exposure.\"" - ], - "lookupKey" : {"CYP2D6": "0.25"}, + "implications" : [], + "lookupKey" : {"CYP2D6": "≥3.25"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450338", "name" : "meclizine", - "version" : 6 + "version" : 21 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166180000", "name" : "Annotation of FDA Label for meclizine and CYP2D6", - "version" : 13 + "version" : 22 }, "text" : { - "id" : 1452203920, - "html" : "

"... when ANTIVERT® [meclizine] is administered to patients with CYP2D6 polymorphism, monitor for adverse reactions and clinical effect accordingly." See label for more information.

\n", - "version" : 0 + "id" : 1452204006, + "html" : "

The meclizine (ANTIVERT) label states: "... when ANTIVERT® is administered to patients with CYP2D6 polymorphism, monitor for adverse reactions and clinical effect accordingly." "The genetic polymorphism of CYP2D6 that results in poor-, intermediate-, extensive-, and ultrarapid metabolizer phenotypes could contribute to large inter-individual variability in meclizine exposure." See label for more information.

\n", + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166309501", - "name" : "Recommendation Annotation PA166309501", + "id" : "PA166309566", + "name" : "Recommendation Annotation PA166309566", "alternateDrugAvailable" : false, "dosingInformation" : false, - "implications" : [ - "\"The genetic polymorphism of CYP2D6 that results in poor-, intermediate-, extensive-, and ultrarapid metabolizer phenotypes could contribute to large inter-individual variability in meclizine exposure.\"" - ], - "lookupKey" : {"CYP2D6": "0.75"}, + "implications" : [], + "lookupKey" : {"CYP2D6": "≥3.0"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450338", "name" : "meclizine", - "version" : 6 + "version" : 21 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166180000", "name" : "Annotation of FDA Label for meclizine and CYP2D6", - "version" : 13 + "version" : 22 }, "text" : { - "id" : 1452203940, - "html" : "

"... when ANTIVERT® [meclizine] is administered to patients with CYP2D6 polymorphism, monitor for adverse reactions and clinical effect accordingly." See label for more information.

\n", - "version" : 0 + "id" : 1452204005, + "html" : "

The meclizine (ANTIVERT) label states: "... when ANTIVERT® is administered to patients with CYP2D6 polymorphism, monitor for adverse reactions and clinical effect accordingly." "The genetic polymorphism of CYP2D6 that results in poor-, intermediate-, extensive-, and ultrarapid metabolizer phenotypes could contribute to large inter-individual variability in meclizine exposure." See label for more information.

\n", + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166309571", - "name" : "Recommendation Annotation PA166309571", + "id" : "PA166309565", + "name" : "Recommendation Annotation PA166309565", "alternateDrugAvailable" : false, "dosingInformation" : false, - "implications" : [ - "\"The genetic polymorphism of CYP2D6 that results in poor-, intermediate-, extensive-, and ultrarapid metabolizer phenotypes could contribute to large inter-individual variability in meclizine exposure.\"" - ], - "lookupKey" : {"CYP2D6": "≥5.0"}, + "implications" : [], + "lookupKey" : {"CYP2D6": "4.0"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450338", "name" : "meclizine", - "version" : 6 + "version" : 21 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166180000", "name" : "Annotation of FDA Label for meclizine and CYP2D6", - "version" : 13 + "version" : 22 }, "text" : { - "id" : 1452204010, - "html" : "

"... when ANTIVERT® [meclizine] is administered to patients with CYP2D6 polymorphism, monitor for adverse reactions and clinical effect accordingly." See label for more information.

\n", - "version" : 0 + "id" : 1452204004, + "html" : "

The meclizine (ANTIVERT) label states: "... when ANTIVERT® is administered to patients with CYP2D6 polymorphism, monitor for adverse reactions and clinical effect accordingly." "The genetic polymorphism of CYP2D6 that results in poor-, intermediate-, extensive-, and ultrarapid metabolizer phenotypes could contribute to large inter-individual variability in meclizine exposure." See label for more information.

\n", + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166309562", - "name" : "Recommendation Annotation PA166309562", + "id" : "PA166309564", + "name" : "Recommendation Annotation PA166309564", "alternateDrugAvailable" : false, "dosingInformation" : false, - "implications" : [ - "\"The genetic polymorphism of CYP2D6 that results in poor-, intermediate-, extensive-, and ultrarapid metabolizer phenotypes could contribute to large inter-individual variability in meclizine exposure.\"" - ], - "lookupKey" : {"CYP2D6": "2.5"}, + "implications" : [], + "lookupKey" : {"CYP2D6": "3.0"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450338", "name" : "meclizine", - "version" : 6 + "version" : 21 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166180000", "name" : "Annotation of FDA Label for meclizine and CYP2D6", - "version" : 13 + "version" : 22 }, "text" : { - "id" : 1452204001, - "html" : "

"... when ANTIVERT® [meclizine] is administered to patients with CYP2D6 polymorphism, monitor for adverse reactions and clinical effect accordingly." See label for more information.

\n", - "version" : 0 + "id" : 1452204003, + "html" : "

The meclizine (ANTIVERT) label states: "... when ANTIVERT® is administered to patients with CYP2D6 polymorphism, monitor for adverse reactions and clinical effect accordingly." "The genetic polymorphism of CYP2D6 that results in poor-, intermediate-, extensive-, and ultrarapid metabolizer phenotypes could contribute to large inter-individual variability in meclizine exposure." See label for more information.

\n", + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166309564", - "name" : "Recommendation Annotation PA166309564", + "id" : "PA166309543", + "name" : "Recommendation Annotation PA166309543", "alternateDrugAvailable" : false, "dosingInformation" : false, - "implications" : [ - "\"The genetic polymorphism of CYP2D6 that results in poor-, intermediate-, extensive-, and ultrarapid metabolizer phenotypes could contribute to large inter-individual variability in meclizine exposure.\"" - ], - "lookupKey" : {"CYP2D6": "3.0"}, + "implications" : [], + "lookupKey" : {"CYP2D6": "1.75"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450338", "name" : "meclizine", - "version" : 6 + "version" : 21 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166180000", "name" : "Annotation of FDA Label for meclizine and CYP2D6", - "version" : 13 + "version" : 22 }, "text" : { - "id" : 1452204003, - "html" : "

"... when ANTIVERT® [meclizine] is administered to patients with CYP2D6 polymorphism, monitor for adverse reactions and clinical effect accordingly." See label for more information.

\n", - "version" : 0 + "id" : 1452203982, + "html" : "

The meclizine (ANTIVERT) label states: "... when ANTIVERT® is administered to patients with CYP2D6 polymorphism, monitor for adverse reactions and clinical effect accordingly." "The genetic polymorphism of CYP2D6 that results in poor-, intermediate-, extensive-, and ultrarapid metabolizer phenotypes could contribute to large inter-individual variability in meclizine exposure." See label for more information.

\n", + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166309566", - "name" : "Recommendation Annotation PA166309566", + "id" : "PA166309542", + "name" : "Recommendation Annotation PA166309542", "alternateDrugAvailable" : false, "dosingInformation" : false, - "implications" : [ - "\"... when ANTIVERT® \\[meclizine\\] is administered to patients with CYP2D6 polymorphism, monitor for adverse reactions and clinical effect accordingly.\" See label for more information." - ], - "lookupKey" : {"CYP2D6": "≥3.0"}, + "implications" : [], + "lookupKey" : {"CYP2D6": "1.5"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450338", "name" : "meclizine", - "version" : 6 + "version" : 21 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166180000", "name" : "Annotation of FDA Label for meclizine and CYP2D6", - "version" : 13 + "version" : 22 }, "text" : { - "id" : 1452204005, - "html" : "

"... when ANTIVERT® [meclizine] is administered to patients with CYP2D6 polymorphism, monitor for adverse reactions and clinical effect accordingly." See label for more information.

\n", - "version" : 0 + "id" : 1452203981, + "html" : "

The meclizine (ANTIVERT) label states: "... when ANTIVERT® is administered to patients with CYP2D6 polymorphism, monitor for adverse reactions and clinical effect accordingly." "The genetic polymorphism of CYP2D6 that results in poor-, intermediate-, extensive-, and ultrarapid metabolizer phenotypes could contribute to large inter-individual variability in meclizine exposure." See label for more information.

\n", + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166309542", - "name" : "Recommendation Annotation PA166309542", + "id" : "PA166309541", + "name" : "Recommendation Annotation PA166309541", "alternateDrugAvailable" : false, "dosingInformation" : false, - "implications" : [ - "\"The genetic polymorphism of CYP2D6 that results in poor-, intermediate-, extensive-, and ultrarapid metabolizer phenotypes could contribute to large inter-individual variability in meclizine exposure.\"" - ], - "lookupKey" : {"CYP2D6": "1.5"}, + "implications" : [], + "lookupKey" : {"CYP2D6": "1.25"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450338", "name" : "meclizine", - "version" : 6 + "version" : 21 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166180000", "name" : "Annotation of FDA Label for meclizine and CYP2D6", - "version" : 13 + "version" : 22 }, "text" : { - "id" : 1452203981, - "html" : "

"... when ANTIVERT® [meclizine] is administered to patients with CYP2D6 polymorphism, monitor for adverse reactions and clinical effect accordingly." See label for more information.

\n", - "version" : 0 + "id" : 1452203980, + "html" : "

The meclizine (ANTIVERT) label states: "... when ANTIVERT® is administered to patients with CYP2D6 polymorphism, monitor for adverse reactions and clinical effect accordingly." "The genetic polymorphism of CYP2D6 that results in poor-, intermediate-, extensive-, and ultrarapid metabolizer phenotypes could contribute to large inter-individual variability in meclizine exposure." See label for more information.

\n", + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166309568", - "name" : "Recommendation Annotation PA166309568", + "id" : "PA166309521", + "name" : "Recommendation Annotation PA166309521", "alternateDrugAvailable" : false, "dosingInformation" : false, - "implications" : [ - "\"The genetic polymorphism of CYP2D6 that results in poor-, intermediate-, extensive-, and ultrarapid metabolizer phenotypes could contribute to large inter-individual variability in meclizine exposure.\"" - ], - "lookupKey" : {"CYP2D6": "≥3.5"}, + "implications" : [], + "lookupKey" : {"CYP2D6": "1.0"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450338", "name" : "meclizine", - "version" : 6 + "version" : 21 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166180000", "name" : "Annotation of FDA Label for meclizine and CYP2D6", - "version" : 13 + "version" : 22 }, "text" : { - "id" : 1452204007, - "html" : "

"... when ANTIVERT® [meclizine] is administered to patients with CYP2D6 polymorphism, monitor for adverse reactions and clinical effect accordingly." See label for more information.

\n", - "version" : 0 + "id" : 1452203960, + "html" : "

The meclizine (ANTIVERT) label states: "... when ANTIVERT® is administered to patients with CYP2D6 polymorphism, monitor for adverse reactions and clinical effect accordingly." "The genetic polymorphism of CYP2D6 that results in poor-, intermediate-, extensive-, and ultrarapid metabolizer phenotypes could contribute to large inter-individual variability in meclizine exposure." See label for more information.

\n", + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166309544", - "name" : "Recommendation Annotation PA166309544", + "id" : "PA166309501", + "name" : "Recommendation Annotation PA166309501", "alternateDrugAvailable" : false, "dosingInformation" : false, - "implications" : [ - "\"The genetic polymorphism of CYP2D6 that results in poor-, intermediate-, extensive-, and ultrarapid metabolizer phenotypes could contribute to large inter-individual variability in meclizine exposure.\"" - ], - "lookupKey" : {"CYP2D6": "2.0"}, + "implications" : [], + "lookupKey" : {"CYP2D6": "0.75"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450338", "name" : "meclizine", - "version" : 6 + "version" : 21 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166180000", "name" : "Annotation of FDA Label for meclizine and CYP2D6", - "version" : 13 + "version" : 22 }, "text" : { - "id" : 1452203983, - "html" : "

"... when ANTIVERT® [meclizine] is administered to patients with CYP2D6 polymorphism, monitor for adverse reactions and clinical effect accordingly." See label for more information.

\n", - "version" : 0 + "id" : 1452203940, + "html" : "

The meclizine (ANTIVERT) label states: "... when ANTIVERT® is administered to patients with CYP2D6 polymorphism, monitor for adverse reactions and clinical effect accordingly." "The genetic polymorphism of CYP2D6 that results in poor-, intermediate-, extensive-, and ultrarapid metabolizer phenotypes could contribute to large inter-individual variability in meclizine exposure." See label for more information.

\n", + "version" : 1 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", @@ -152884,9 +155405,7 @@ "name" : "Recommendation Annotation PA166309482", "alternateDrugAvailable" : false, "dosingInformation" : false, - "implications" : [ - "\"The genetic polymorphism of CYP2D6 that results in poor-, intermediate-, extensive-, and ultrarapid metabolizer phenotypes could contribute to large inter-individual variability in meclizine exposure.\"" - ], + "implications" : [], "lookupKey" : {"CYP2D6": "0.5"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ @@ -152894,149 +155413,141 @@ "objCls" : "Chemical", "id" : "PA450338", "name" : "meclizine", - "version" : 6 + "version" : 21 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166180000", "name" : "Annotation of FDA Label for meclizine and CYP2D6", - "version" : 13 + "version" : 22 }, "text" : { "id" : 1452203921, - "html" : "

"... when ANTIVERT® [meclizine] is administered to patients with CYP2D6 polymorphism, monitor for adverse reactions and clinical effect accordingly." See label for more information.

\n", - "version" : 0 + "html" : "

The meclizine (ANTIVERT) label states: "... when ANTIVERT® is administered to patients with CYP2D6 polymorphism, monitor for adverse reactions and clinical effect accordingly." "The genetic polymorphism of CYP2D6 that results in poor-, intermediate-, extensive-, and ultrarapid metabolizer phenotypes could contribute to large inter-individual variability in meclizine exposure." See label for more information.

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"... when ANTIVERT® [meclizine] is administered to patients with CYP2D6 polymorphism, monitor for adverse reactions and clinical effect accordingly." See label for more information.

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The meclizine (ANTIVERT) label states: "... when ANTIVERT® is administered to patients with CYP2D6 polymorphism, monitor for adverse reactions and clinical effect accordingly." "The genetic polymorphism of CYP2D6 that results in poor-, intermediate-, extensive-, and ultrarapid metabolizer phenotypes could contribute to large inter-individual variability in meclizine exposure." See label for more information.

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"... when ANTIVERT® [meclizine] is administered to patients with CYP2D6 polymorphism, monitor for adverse reactions and clinical effect accordingly." See label for more information.

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The meclizine (ANTIVERT) label states: "... when ANTIVERT® is administered to patients with CYP2D6 polymorphism, monitor for adverse reactions and clinical effect accordingly." "The genetic polymorphism of CYP2D6 that results in poor-, intermediate-, extensive-, and ultrarapid metabolizer phenotypes could contribute to large inter-individual variability in meclizine exposure." See label for more information.

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"... when ANTIVERT® [meclizine] is administered to patients with CYP2D6 polymorphism, monitor for adverse reactions and clinical effect accordingly." See label for more information.

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The meclizine (ANTIVERT) label states: "... when ANTIVERT® is administered to patients with CYP2D6 polymorphism, monitor for adverse reactions and clinical effect accordingly." "The genetic polymorphism of CYP2D6 that results in poor-, intermediate-, extensive-, and ultrarapid metabolizer phenotypes could contribute to large inter-individual variability in meclizine exposure." See label for more information.

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"... when ANTIVERT® [meclizine] is administered to patients with CYP2D6 polymorphism, monitor for adverse reactions and clinical effect accordingly." See label for more information.

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The meclizine (ANTIVERT) label states: "... when ANTIVERT® is administered to patients with CYP2D6 polymorphism, monitor for adverse reactions and clinical effect accordingly." "The genetic polymorphism of CYP2D6 that results in poor-, intermediate-, extensive-, and ultrarapid metabolizer phenotypes could contribute to large inter-individual variability in meclizine exposure." See label for more information.

\n", + "version" : 1 }, - "version" : 0 + "version" : 2 } ], "url" : "https://www.pharmgkb.org/labelAnnotation/PA166180000" @@ -153071,7 +155582,7 @@ {"id":1452267781,"resource":"PharmGKB Tags","term":"Has No PGx","termId":"pgkbTags:1452267781"} ], "type" : "Drug Label", - "version" : 2, + "version" : 3, "year" : -1 }, { @@ -153102,7 +155613,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 2, + "version" : 3, "year" : -1 }, { @@ -153133,7 +155644,7 @@ {"id":1452267781,"resource":"PharmGKB Tags","term":"Has No PGx","termId":"pgkbTags:1452267781"} ], "type" : "Drug Label", - "version" : 2, + "version" : 3, "year" : -1 } ], @@ -153179,13 +155690,13 @@ "id" : "PA126", "symbol" : "CYP2C9", "name" : "cytochrome P450 family 2 subfamily C member 9", - "version" : 7877 + "version" : 7952 } ], "prescribingMarkdown" : { "id" : 1450400588, "html" : "

Excerpt from meloxicam FDA drug label:

\n
\n

In patients who are known or suspected to be poor CYP2C9 metabolizers based on genotype or previous history/experience with other CYP2C9 substrates (such as warfarin or phenytoin), consider dose reduction, as these patients may have abnormally high plasma levels of meloxicam due to reduced metabolic clearance. Monitor these patients for adverse effects.

\n
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Meloxicam (QMIIZ ODT) is a non-steroidal anti-inflammatory drug indicated for treatment of osteoarthritis and rheumatoid arthritis in adults, and juvenile rheumatoid arthritis, pauciarticular and polyarticular course, in pediatric patients weighing greater than or equal to 60 kg.

\n

Excerpts from meloxicam FDA drug label:

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\n

Poor Metabolizers of CYP2C9 Substrates\nIn patients who are known or suspected to be poor CYP2C9 metabolizers based on genotype or\nprevious history/experience with other CYP2C9 substrates (such as warfarin or phenytoin),\nconsider dose reduction, as these patients may have abnormally high plasma levels of meloxicam\ndue to reduced metabolic clearance. Monitor these patients for adverse effects.

\n
\n
\n

Pharmacogenomics\nCYP2C9 activity is reduced in individuals with genetic variants such as CYP2C9*2 and\nCYP2C9*3 polymorphisms. Limited data from three published reports showed that meloxicam\nAUC was substantially higher in individuals with reduced CYP2C9 activity, particularly in poor\nmetabolizers (e.g., *3/*3), compared to normal metabolizers (*1/*1). The frequency of CYP2C9\npoor metabolizer genotypes varies based on racial/ethnic background but is generally present in\n<5% of the population.

\n
\n

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the meloxicam drug label.

\n

Note: Meloxicam (MOBIC) is indicated for the treatment of osteoarthritis, rheumatoid arthritis and juvenile rheumatoid arthritis in patients weighing greater than or equal to 60kg. Meloxicam (VIVLODEX) is indicated for management of osteoarthritis pain. The drug labels for meloxicam (MOBIC) and meloxicam (VIVLODEX) contain no information regarding dose reduction based on CYP2C9 metabolizer status.

\n

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

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The FDA-approved drug label for mepivacaine states that patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency and congenital methemoglobinemia may be more susceptible to developing clinical manifestations of methemoglobinemia. Close monitoring for symptoms and signs of methemoglobinemia is recommended in this subset of patients.

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"version" : 13 + "version" : 27 }, "text" : { "id" : 1452216741, @@ -153545,33 +156056,65 @@ "citations" : [ { "id" : 15101945, - "title" : "Drugs@FDA: Drug Product PURIXAN (Purixan), NDA205919, Nova Laboratories, Ltd", + "title" : "Drugs@FDA: Drug Product PURINETHOL (Mercaptopurine), Quinn Pharmaceuticals - NDA009053/SUPPL-40, 12/29/2020", + "_sameAs" : "https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=009053", + "authors" : [], + "crossReferences" : [ + { + "id" : 1452495063, + "resource" : "FDA Application", + "resourceId" : "NDA009053/SUPPL-40", + "_url" : "https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=009053", + "version" : 0 + } + ], + "day" : 29, + "hasKeyword" : false, + "meshDiseases" : [], + "meshTerms" : [], + "month" : 12, + "nonHuman" : false, + "objCls" : "Literature", + "pediatric" : false, + "pgkbPublication" : false, + "pubDate" : "2020-12-29T00:00:00-08:00", + "terms" : [ + {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} + ], + "type" : "Drug Label", + "version" : 7, + "year" : 2020 + }, + { + "id" : 15159242, + "title" : "Drugs@FDA: Drug Product PURIXAN (mercaptopurine), Nova Laboratories, Ltd - 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{"id":15101945,"title":"Drugs@FDA: Drug Product PURIXAN (Purixan), NDA205919, Nova Laboratories, Ltd","_sameAs":"https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=205919","crossReferences":[{"id":1449758575,"resource":"FDA Application","resourceId":"NDA205919","_url":"https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=205919"}],"objCls":"Literature","terms":[{"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"}],"type":"Drug Label"} + {"id":15101945,"title":"Drugs@FDA: Drug Product PURINETHOL (Mercaptopurine), Quinn Pharmaceuticals - NDA009053/SUPPL-40, 12/29/2020","_sameAs":"https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=009053","crossReferences":[{"id":1452495063,"resource":"FDA Application","resourceId":"NDA009053/SUPPL-40","_url":"https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=009053"}],"objCls":"Literature","pubDate":"2020-12-29T00:00:00-08:00","terms":[{"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"}],"type":"Drug Label"}, + {"id":15159242,"title":"Drugs@FDA: Drug Product PURIXAN (mercaptopurine), Nova Laboratories, Ltd - 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Safety and effectiveness of PURIXAN has been established in pediatric patients. Use of PURIXAN in pediatrics is supported by evidence from the published literature and clinical experience. Symptomatic hypoglycemia has been reported in pediatric patients with ALL receiving mercaptopurine. Reported cases were in pediatrics less than 6 years or with a low body mass index.

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Wide inter individual variations in systemic exposure is observed. Following oral administration of 50 mg/m2\nmercaptopurine in 10 children, median plasma concentrations 1 hour post dose was 0.35 (range 0.03 to 1.03) μM and median AUC1–5hours was 56 (range 23 to 65) μM·min. Tmax ranged from 1 to 3 hours.

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Excerpts from the mercaptopurine (PURIXAN) drug label:

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Dosage Modifications in Patients with TPMT and NUDT15 Deficiency:

\n
\n
\n

Consider testing for TPMT and NUDT15 deficiency in patients who experience severe myelosuppression or repeated episodes of myelosuppression

\n
\n
\n

Homozygous Deficiency in either TPMT or NUDT15: Patients with homozygous deficiency of either enzyme typically require 10% or less of the recommended dosage. Reduce the recommended starting dosage of PURINETHOL in patients who are known to have homozygous TPMT or NUDT15 deficiency.

\n
\n
\n

Heterozygous Deficiency in TPMT and/or NUDT15: Reduce the PURINETHOL dose based on tolerability. Most patients with heterozygous TPMT or NUDT15 deficiency tolerate the recommended dosage, but some require a dose reduction based on adverse reactions. Patients who are heterozygous for both TPMT and NUDT15 may require more substantial dose reductions.

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Excerpts from the mercaptopurine (PURIXAN) drug label:

\n
\n

Homozygous Deficiency in either TPMT or NUDT15:\nPatients with homozygous deficiency of either enzyme typically require 10% or less of the recommended dosage. Reduce the recommended starting dosage of PURIXAN in patients who are known to have homozygous TPMT or NUDT15 deficiency.

\n
\n
\n

Heterozygous Deficiency in TPMT and/or NUDT15:\nReduce the PURIXAN dosage based on tolerability. Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended dosage, but some require dose reduction based on adverse reactions. Patients who are heterozygous for both TPMT and NUDT15 may require more substantial dose reductions.

\n
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The FDA-approved drug label for mercaptopurine (PURIXAN) states that patients with severe myelosuppression should be evaluated for TPMT or NUDT15 deficiency, and that patients with homozygous TPMT or NUDT15 deficiency may require dose reductions.

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The FDA-approved drug labels for mercaptopurine (PURIXAN and PURINETHOL) state that patients with severe myelosuppression should be evaluated for TPMT or NUDT15 deficiency, and that patients with homozygous TPMT or NUDT15 deficiency may require dose reductions.

\n

The FDA Table of Pharmacogenomic Biomarkers in Drug Labeling lists two different labels for mercaptopurine, mercaptopurine oral suspension (PURIXAN) and mercaptopurine tablets (PURINETHOL).

\n", + "version" : 4 }, "terms" : [], "testing" : { @@ -153708,822 +156264,822 @@ }, "textMarkdown" : { "id" : 1447981601, - "html" : "

Mercaptopurine (PURIXAN) is indicated for the treatment of acute lymphoblastic leukemia (ALL). Excerpts from the mercaptopurine (PURIXAN) drug label:

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\n

Evaluate thiopurine S-methyltransferase (TPMT) and nucleotide diphosphatase (NUDT15) status in patients with severe myelosuppression or repeated episodes or myelosuppression

\n
\n
\n

Dosage Modifications in Patients with TPMT and NUDT15 Deficiency:

\n
\n
\n

Consider testing for TPMT and NUDT15 deficiency in patients who experience severe myelosuppression or repeated episodes of myelosuppression

\n
\n
\n

Homozygous Deficiency in either TPMT or NUDT15: Patients with homozygous deficiency of either enzyme typically require 10% or less of the recommended dosage. Reduce the recommended starting dosage of PURINETHOL in patients who are known to have homozygous TPMT or NUDT15 deficiency.

\n
\n
\n

Heterozygous Deficiency in TPMT and/or NUDT15: Reduce the PURINETHOL dose based on tolerability. Most patients with heterozygous TPMT or NUDT15 deficiency tolerate the recommended dosage, but some require a dose reduction based on adverse reactions. Patients who are heterozygous for both TPMT and NUDT15 may require more substantial dose reductions.

\n
\n
\n

Myelosuppression: Monitor complete blood count (CBC) and adjust the dose of PURINETHOL for excessive myelosuppression. Consider testing in\npatients with severe myelosuppression or repeated episodes of myelosuppression for thiopurine S-methyltransferase (TPMT) or nucleotide\ndiphosphatase (NUDT15) deficiency. Patients with homozygous or homozygous TPMT or NUDT15 deficiency may require a dose reduction.

\n
\n
\n

Pharmacogenomics: Several published studies indicate that patients with reduced TPMT or NUDT15 activity receiving usual doses of mercaptopurine, accumulate excessive cellular concentrations of active 6-TGNs, and are at higher risk for severe myelosuppression. In a study of 1028 children with ALL, the approximate tolerated mercaptopurine dosage for patients with TPMT and/or NUDT15 deficiency on mercaptopurine maintenance therapy (as a percentage of the planned dosage) was as follows: heterozygous for either TPMT or NUDT15, 50-90%; heterozygous for both TPMT and NUDT15, 30-50%; homozygous for either TPMT or NUDT15, 5-10%.

\n
\n
\n

Approximately 0.3% (1:300) of patients of European or African ancestry have two loss-of-function alleles of the TPMT gene and have little or no TPMT activity (homozygous deficient or poor metabolizers), and approximately 10% of patients have one loss-of-function TPMT allele leading to intermediate TPMT activity (heterozygous deficient or intermediate metabolizers). The TPMT*2, TPMT*3A, and TPMT*3C alleles account for about 95% of individuals with reduced levels of TPMT activity.

\n
\n
\n

NUDT15 deficiency is detected in <1% of patients of European or African ancestry. Among patients of East Asian ancestry (i.e., Chinese, Japanese, Vietnamese), 2% have two loss-of-function alleles of the NUDT15 gene, and approximately 21% have one loss-of-function allele. The p.R139C variant of NUDT15 (present on the *2 and *3 alleles) is the most commonly observed, but other less common loss-of-function NUDT15 alleles have been observed.

\n
\n
\n

Consider all clinical information when interpreting results from phenotypic testing used to determine the level of thiopurine nucleotides or TPMT activity in erythrocytes, since some coadministered drugs can influence measurement of TPMT activity in blood and blood from recent transfusions will misrepresent a patient’s actual TPMT activity.

\n
\n

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the mercaptopurine drug label.

\n

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

\n", - "version" : 10 + "html" : "

Mercaptopurine is indicated for the treatment of acute lymphoblastic leukemia (ALL). Excerpts from the mercaptopurine (PURIXAN) drug label:

\n
\n

Evaluate thiopurine S-methyltransferase (TPMT) and nucleotide diphosphatase (NUDT15) status in patients in patients with severe myelosuppression or repeated episodes of myelosuppression

\n
\n
\n

Dosage Modifications in Patients with TPMT and NUDT15 Deficiency

\n
\n
\n

Consider testing for TPMT and NUDT15 deficiency in patients who experience severe myelosuppression or repeated episodes of myelosuppression

\n
\n
\n

Homozygous Deficiency in either TPMT or NUDT15: Patients with homozygous deficiency of either enzyme typically require 10% or less of the recommended dosage. Reduce the recommended starting dosage of PURIXAN in patients who are known to have homozygous TPMT or NUDT15 deficiency.

\n
\n
\n

Heterozygous Deficiency in TPMT and/or NUDT15: Reduce the PURIXAN dosage based on tolerability. Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended dosage, but some require dose reduction based on adverse reactions. Patients who are heterozygous for both TPMT and NUDT15 may require more substantial dose reductions.

\n
\n
\n

Consider testing for thiopurine S-methyltransferase (TPMT) or nucleotide diphosphatase (NUDT15) deficiency in patients with severe myelosuppression or repeated episodes of myelosuppression. TPMT genotyping or phenotyping (red blood cell TPMT activity) and NUDT15 genotyping can identify patients who have reduced activity of these enzymes. Patients with homozygous TPMT or NUDT15 deficiency may require a dose reduction

\n
\n
\n

Pharmacogenomics

\n
\n
\n

Several published studies indicate that patients with reduced TPMT or NUDT15 activity receiving usual doses of mercaptopurine, accumulate excessive cellular concentrations of active 6-TGNs, and are at higher risk for severe myelosuppression [see Warnings and Precautions (5.1)]. In a study of 1028 children with ALL, the approximate tolerated mercaptopurine dosage for patients with TPMT and/or NUDT15 deficiency on mercaptopurine maintenance therapy (as a percentage of the planned dosage) was as follows: heterozygous for either TPMT or NUDT15, 50-90%; heterozygous for both TPMT and NUDT15, 30-50%; homozygous for either TPMT or NUDT15, 5-10%.

\n
\n
\n

Approximately 0.3% (1:300) of patients of European or African ancestry have two loss-of-function alleles of the TPMT gene and have little or no TMPT activity (homozygous deficient or poor metabolizers), and approximately 10% of patients have one loss-of-function TPMT allele leading to intermediate TPMT activity (heterozygous deficient or intermediate metabolizers). The TPMT*2, TPMT*3A, and TPMT*3C alleles account for about 95% of individuals with reduced levels of TPMT activity.

\n
\n
\n

NUDT15 deficiency is detected in <1% of patients of European or African ancestry. Among patients of East Asian ancestry (i.e., Chinese, Japanese, Vietnamese), 2% have two loss-of-function alleles of the NUDT15 gene, and approximately 21% have one loss-of-function allele. The p.R139C variant of NUDT15 (present on the *2 and *3 alleles) is the most commonly observed, but other less common loss-of-function NUDT15 alleles have been observed.

\n
\n
\n

Consider all clinical information when interpreting results from phenotypic testing used to determine the level of thiopurine nucleotides or TPMT activity in erythrocytes, since some coadministered drugs can influence measurement of TPMT activity in blood, and blood from recent transfusions will misrepresent a patient’s actual TPMT activity

\n
\n

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the mercaptopurine (PURIXAN) drug label or the mercaptopurine (PURINETHOL) drug label.

\n

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

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The mercaptopurine (PURIXAN) label states: "Heterozygous Deficiency in TPMT and/or NUDT15 … Reduce the PURIXAN dosage based on tolerability. Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended dosage, but some require dose reduction based on adverse reactions. Patients who are heterozygous for both TPMT and NUDT15 may require more substantial dose reductions.” See label for more information.

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The mercaptopurine (PURIXAN) label states: "Heterozygous Deficiency in TPMT and/or NUDT15 … Reduce the PURIXAN dosage based on tolerability. Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended dosage, but some require dose reduction based on adverse reactions. Patients who are heterozygous for both TPMT and NUDT15 may require more substantial dose reductions.” See label for more information.

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The mercaptopurine (PURIXAN) label states: "Heterozygous Deficiency in TPMT and/or NUDT15 … Reduce the PURIXAN dosage based on tolerability. Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended dosage, but some require dose reduction based on adverse reactions. Patients who are heterozygous for both TPMT and NUDT15 may require more substantial dose reductions.” See label for more information.

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The mercaptopurine (PURIXAN) label states: "Heterozygous Deficiency in TPMT and/or NUDT15 … Reduce the PURIXAN dosage based on tolerability. Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended dosage, but some require dose reduction based on adverse reactions. Patients who are heterozygous for both TPMT and NUDT15 may require more substantial dose reductions.” See label for more information.

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The mercaptopurine (PURIXAN) label states: "Heterozygous Deficiency in TPMT and/or NUDT15 … Reduce the PURIXAN dosage based on tolerability. Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended dosage, but some require dose reduction based on adverse reactions. Patients who are heterozygous for both TPMT and NUDT15 may require more substantial dose reductions.” See label for more information.

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"Homozygous deficiency in either TPMT or NUDT15...Patients with homozygous deficiency of either enzyme typically require 10% or less of the standard PURIXAN dosage. Reduce initial dosage in patients who are known to have homozygous TPMT or NUDT15 deficiency." See label for more information.

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The mercaptopurine (PURIXAN) label states: "Heterozygous Deficiency in TPMT and/or NUDT15 … Reduce the PURIXAN dosage based on tolerability. Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended dosage, but some require dose reduction based on adverse reactions. Patients who are heterozygous for both TPMT and NUDT15 may require more substantial dose reductions.” See label for more information.

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The mercaptopurine (PURIXAN) label states: "Heterozygous Deficiency in TPMT and/or NUDT15 … Reduce the PURIXAN dosage based on tolerability. Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended dosage, but some require dose reduction based on adverse reactions. Patients who are heterozygous for both TPMT and NUDT15 may require more substantial dose reductions.” See label for more information.

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The mercaptopurine (PURIXAN) label states: "Heterozygous Deficiency in TPMT and/or NUDT15 … Reduce the PURIXAN dosage based on tolerability. Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended dosage, but some require dose reduction based on adverse reactions. Patients who are heterozygous for both TPMT and NUDT15 may require more substantial dose reductions.” See label for more information.

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The mercaptopurine (PURIXAN) label states: "Heterozygous Deficiency in TPMT and/or NUDT15 … Reduce the PURIXAN dosage based on tolerability. Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended dosage, but some require dose reduction based on adverse reactions. Patients who are heterozygous for both TPMT and NUDT15 may require more substantial dose reductions.” See label for more information.

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The mercaptopurine (PURIXAN) label states: "Heterozygous Deficiency in TPMT and/or NUDT15 … Reduce the PURIXAN dosage based on tolerability. Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended dosage, but some require dose reduction based on adverse reactions. Patients who are heterozygous for both TPMT and NUDT15 may require more substantial dose reductions.” See label for more information.

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The mercaptopurine (PURIXAN) label states: "Heterozygous Deficiency in TPMT and/or NUDT15 … Reduce the PURIXAN dosage based on tolerability. Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended dosage, but some require dose reduction based on adverse reactions. Patients who are heterozygous for both TPMT and NUDT15 may require more substantial dose reductions.” See label for more information.

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"Heterozygous deficiency in TPMT and/or NUDT15...Reduce the PURIXAN dosage based on tolerability. Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended mercaptopurine doses, but some require dose reduction based on toxicities. Patients who are heterozygous for both TPMT and NUDT15 may require more substantial dosage reductions." See label for more information.

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The mercaptopurine (PURIXAN) label states: "Homozygous Deficiency in either TPMT or NUDT15 … Patients with homozygous deficiency of either enzyme typically require 10% or less of the recommended dosage. Reduce the recommended starting dosage of PURIXAN in patients who are known to have homozygous TPMT or NUDT15 deficiency." See label for more information.

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"Homozygous deficiency in either TPMT or NUDT15...Patients with homozygous deficiency of either enzyme typically require 10% or less of the standard PURIXAN dosage. Reduce initial dosage in patients who are known to have homozygous TPMT or NUDT15 deficiency." See label for more information.

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The mercaptopurine (PURIXAN) label states: "Homozygous Deficiency in either TPMT or NUDT15 … Patients with homozygous deficiency of either enzyme typically require 10% or less of the recommended dosage. Reduce the recommended starting dosage of PURIXAN in patients who are known to have homozygous TPMT or NUDT15 deficiency." See label for more information.

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"Heterozygous deficiency in TPMT and/or NUDT15...Reduce the PURIXAN dosage based on tolerability. Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended mercaptopurine doses, but some require dose reduction based on toxicities. Patients who are heterozygous for both TPMT and NUDT15 may require more substantial dosage reductions." See label for more information.

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The mercaptopurine (PURIXAN) label states: "Homozygous Deficiency in either TPMT or NUDT15 … Patients with homozygous deficiency of either enzyme typically require 10% or less of the recommended dosage. Reduce the recommended starting dosage of PURIXAN in patients who are known to have homozygous TPMT or NUDT15 deficiency." See label for more information.

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"Homozygous deficiency in either TPMT or NUDT15...Patients with homozygous deficiency of either enzyme typically require 10% or less of the standard PURIXAN dosage. Reduce initial dosage in patients who are known to have homozygous TPMT or NUDT15 deficiency." See label for more information.

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The mercaptopurine (PURIXAN) label states: "Homozygous Deficiency in either TPMT or NUDT15 … Patients with homozygous deficiency of either enzyme typically require 10% or less of the recommended dosage. Reduce the recommended starting dosage of PURIXAN in patients who are known to have homozygous TPMT or NUDT15 deficiency." See label for more information.

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"Homozygous deficiency in either TPMT or NUDT15...Patients with homozygous deficiency of either enzyme typically require 10% or less of the standard PURIXAN dosage. Reduce initial dosage in patients who are known to have homozygous TPMT or NUDT15 deficiency." See label for more information.

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The mercaptopurine (PURIXAN) label states: "Homozygous Deficiency in either TPMT or NUDT15 … Patients with homozygous deficiency of either enzyme typically require 10% or less of the recommended dosage. Reduce the recommended starting dosage of PURIXAN in patients who are known to have homozygous TPMT or NUDT15 deficiency." See label for more information.

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"Heterozygous deficiency in TPMT and/or NUDT15...Reduce the PURIXAN dosage based on tolerability. Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended mercaptopurine doses, but some require dose reduction based on toxicities. Patients who are heterozygous for both TPMT and NUDT15 may require more substantial dosage reductions." See label for more information.

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The mercaptopurine (PURIXAN) label states: "Homozygous Deficiency in either TPMT or NUDT15 … Patients with homozygous deficiency of either enzyme typically require 10% or less of the recommended dosage. Reduce the recommended starting dosage of PURIXAN in patients who are known to have homozygous TPMT or NUDT15 deficiency." See label for more information.

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"Heterozygous deficiency in TPMT and/or NUDT15...Reduce the PURIXAN dosage based on tolerability. Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended mercaptopurine doses, but some require dose reduction based on toxicities. Patients who are heterozygous for both TPMT and NUDT15 may require more substantial dosage reductions." See label for more information.

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The mercaptopurine (PURIXAN) label states: "Homozygous Deficiency in either TPMT or NUDT15 … Patients with homozygous deficiency of either enzyme typically require 10% or less of the recommended dosage. Reduce the recommended starting dosage of PURIXAN in patients who are known to have homozygous TPMT or NUDT15 deficiency." See label for more information.

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"Heterozygous deficiency in TPMT and/or NUDT15...Reduce the PURIXAN dosage based on tolerability. Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended mercaptopurine doses, but some require dose reduction based on toxicities. Patients who are heterozygous for both TPMT and NUDT15 may require more substantial dosage reductions." See label for more information.

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The mercaptopurine (PURIXAN) label states: "Homozygous Deficiency in either TPMT or NUDT15 … Patients with homozygous deficiency of either enzyme typically require 10% or less of the recommended dosage. Reduce the recommended starting dosage of PURIXAN in patients who are known to have homozygous TPMT or NUDT15 deficiency." See label for more information.

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"Homozygous deficiency in either TPMT or NUDT15...Patients with homozygous deficiency of either enzyme typically require 10% or less of the standard PURIXAN dosage. Reduce initial dosage in patients who are known to have homozygous TPMT or NUDT15 deficiency." See label for more information.

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The mercaptopurine (PURIXAN) label states: "Homozygous Deficiency in either TPMT or NUDT15 … Patients with homozygous deficiency of either enzyme typically require 10% or less of the recommended dosage. Reduce the recommended starting dosage of PURIXAN in patients who are known to have homozygous TPMT or NUDT15 deficiency." See label for more information.

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"Heterozygous deficiency in TPMT and/or NUDT15...Reduce the PURIXAN dosage based on tolerability. Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended mercaptopurine doses, but some require dose reduction based on toxicities. Patients who are heterozygous for both TPMT and NUDT15 may require more substantial dosage reductions." See label for more information.

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The mercaptopurine (PURIXAN) label states: "Homozygous Deficiency in either TPMT or NUDT15 … Patients with homozygous deficiency of either enzyme typically require 10% or less of the recommended dosage. Reduce the recommended starting dosage of PURIXAN in patients who are known to have homozygous TPMT or NUDT15 deficiency." See label for more information.

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"Heterozygous deficiency in TPMT and/or NUDT15...Reduce the PURIXAN dosage based on tolerability. Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended mercaptopurine doses, but some require dose reduction based on toxicities. Patients who are heterozygous for both TPMT and NUDT15 may require more substantial dosage reductions." See label for more information.

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The mercaptopurine (PURIXAN) label states: "Homozygous Deficiency in either TPMT or NUDT15 … Patients with homozygous deficiency of either enzyme typically require 10% or less of the recommended dosage. Reduce the recommended starting dosage of PURIXAN in patients who are known to have homozygous TPMT or NUDT15 deficiency." See label for more information.

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"Homozygous deficiency in either TPMT or NUDT15...Patients with homozygous deficiency of either enzyme typically require 10% or less of the standard PURIXAN dosage. Reduce initial dosage in patients who are known to have homozygous TPMT or NUDT15 deficiency." See label for more information.

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The mercaptopurine (PURIXAN) label states: "Heterozygous Deficiency in TPMT and/or NUDT15 … Reduce the PURIXAN dosage based on tolerability. Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended dosage, but some require dose reduction based on adverse reactions. Patients who are heterozygous for both TPMT and NUDT15 may require more substantial dose reductions.” See label for more information.

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"Heterozygous deficiency in TPMT and/or NUDT15...Reduce the PURIXAN dosage based on tolerability. Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended mercaptopurine doses, but some require dose reduction based on toxicities. Patients who are heterozygous for both TPMT and NUDT15 may require more substantial dosage reductions." See label for more information.

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The mercaptopurine (PURIXAN) label states: "Heterozygous Deficiency in TPMT and/or NUDT15 … Reduce the PURIXAN dosage based on tolerability. Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended dosage, but some require dose reduction based on adverse reactions. Patients who are heterozygous for both TPMT and NUDT15 may require more substantial dose reductions.” See label for more information.

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"Homozygous deficiency in either TPMT or NUDT15...Patients with homozygous deficiency of either enzyme typically require 10% or less of the standard PURIXAN dosage. Reduce initial dosage in patients who are known to have homozygous TPMT or NUDT15 deficiency." See label for more information.

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The mercaptopurine (PURIXAN) label states: "Heterozygous Deficiency in TPMT and/or NUDT15 … Reduce the PURIXAN dosage based on tolerability. Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended dosage, but some require dose reduction based on adverse reactions. Patients who are heterozygous for both TPMT and NUDT15 may require more substantial dose reductions.” See label for more information.

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"Heterozygous deficiency in TPMT and/or NUDT15...Reduce the PURIXAN dosage based on tolerability. Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended mercaptopurine doses, but some require dose reduction based on toxicities. Patients who are heterozygous for both TPMT and NUDT15 may require more substantial dosage reductions." See label for more information.

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The mercaptopurine (PURIXAN) label states: "Heterozygous Deficiency in TPMT and/or NUDT15 … Reduce the PURIXAN dosage based on tolerability. Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended dosage, but some require dose reduction based on adverse reactions. Patients who are heterozygous for both TPMT and NUDT15 may require more substantial dose reductions.” See label for more information.

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"Homozygous deficiency in either TPMT or NUDT15...Patients with homozygous deficiency of either enzyme typically require 10% or less of the standard PURIXAN dosage. Reduce initial dosage in patients who are known to have homozygous TPMT or NUDT15 deficiency." See label for more information.

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The mercaptopurine (PURIXAN) label states: "Heterozygous Deficiency in TPMT and/or NUDT15 … Reduce the PURIXAN dosage based on tolerability. Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended dosage, but some require dose reduction based on adverse reactions. Patients who are heterozygous for both TPMT and NUDT15 may require more substantial dose reductions.” See label for more information.

\n", + "version" : 1 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/labelAnnotation/PA166104810" @@ -154557,7 +157113,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 4, + "version" : 5, "year" : -1 } ], @@ -154593,7 +157149,7 @@ "id" : "PA28469", "symbol" : "G6PD", "name" : "glucose-6-phosphate dehydrogenase", - "version" : 135 + "version" : 1326 } ], "prescribingMarkdown" : { @@ -154607,7 +157163,7 @@ "objCls" : "Chemical", "id" : "PA450457", "name" : "methylene blue", - "version" : 8 + "version" : 14 } ], "relatedGenes" : [ @@ -154616,7 +157172,7 @@ "id" : "PA28469", "symbol" : "G6PD", "name" : "glucose-6-phosphate dehydrogenase", - "version" : 135 + "version" : 1326 } ], "source" : "FDA", @@ -154639,37 +157195,37 @@ "textMarkdown" : { "id" : 1447981730, "html" : "

Excerpt from the methylene blue (PROVAYBLUE) drug label:

\n
\n

Treatment of patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency with PROVAYBLUE(R) may result in severe hemolysis and severe anemia. PROVAYBLUE(R) is contraindicated for use in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency.

\n
\n

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the methylene blue drug label.

\n

*Disclaimer: The contents of this page are the sole responsibility of PharmGKB.

\n", - "version" : 10 + "version" : 12 }, "userId" : "jmbarbarino", - "version" : 29 + "version" : 48 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166312242", - "name" : "Recommendation Annotation PA166312242", + "id" : "PA166314962", + "name" : "Recommendation Annotation PA166314962", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"G6PD": "Deficient"}, + "lookupKey" : {"G6PD": "Variable"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450457", "name" : "methylene blue", - "version" : 8 + "version" : 14 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104878", "name" : "Annotation of FDA Label for methylene blue and G6PD", - "version" : 29 + "version" : 48 }, "text" : { - "id" : 1452216501, + "id" : 1452245501, "html" : "

"PROVAYBLUE [methylene blue] is contraindicated for use in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency." See label for more information.

\n", "version" : 0 }, @@ -154677,29 +157233,29 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312241", - "name" : "Recommendation Annotation PA166312241", + "id" : "PA166312242", + "name" : "Recommendation Annotation PA166312242", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"G6PD": "Deficient with CNSHA"}, + "lookupKey" : {"G6PD": "Deficient"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450457", "name" : "methylene blue", - "version" : 8 + "version" : 14 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104878", "name" : "Annotation of FDA Label for methylene blue and G6PD", - "version" : 29 + "version" : 48 }, "text" : { - "id" : 1452216500, + "id" : 1452216501, "html" : "

"PROVAYBLUE [methylene blue] is contraindicated for use in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency." See label for more information.

\n", "version" : 0 }, @@ -154707,33 +157263,33 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166314962", - "name" : "Recommendation Annotation PA166314962", + "id" : "PA166312241", + "name" : "Recommendation Annotation PA166312241", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"G6PD": "Variable"}, + "lookupKey" : {"G6PD": "Deficient with CNSHA"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450457", "name" : "methylene blue", - "version" : 8 + "version" : 14 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104878", "name" : "Annotation of FDA Label for methylene blue and G6PD", - "version" : 29 + "version" : 48 }, "text" : { - "id" : 1452245501, + "id" : 1452216500, "html" : "

"PROVAYBLUE [methylene blue] is contraindicated for use in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency." See label for more information.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/labelAnnotation/PA166104878" @@ -154767,7 +157323,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 4, + "version" : 5, "year" : -1 } ], @@ -154796,13 +157352,13 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "prescribingMarkdown" : { "id" : 1450399708, "html" : "

Excerpt from the metoclopramide (REGLAN) drug label:

\n
\n

Reduce the Reglan dosage in patients who are poor CYP2D6 metabolizers.

\n
\n", - "version" : 2 + "version" : 3 }, "relatedAlleles" : [], "relatedChemicals" : [ @@ -154810,7 +157366,7 @@ "objCls" : "Chemical", "id" : "PA450475", "name" : "metoclopramide", - "version" : 8 + "version" : 32 } ], "relatedGenes" : [ @@ -154819,7 +157375,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "FDA", @@ -154845,7 +157401,7 @@ "version" : 2 }, "userId" : "jmbarbarino", - "version" : 15 + "version" : 26 }, "recommendations" : [ { @@ -154862,21 +157418,21 @@ "objCls" : "Chemical", "id" : "PA450475", "name" : "metoclopramide", - "version" : 8 + "version" : 32 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166178750", "name" : "Annotation of FDA Label for metoclopramide and CYP2D6", - "version" : 15 + "version" : 26 }, "text" : { "id" : 1452216680, "html" : "

"Reduce the Reglan [metoclopramide] dosage in patients who are poor CYP2D6 metabolizers." Table 1 of the label gives the recommended dosage in patients with gastroesophageal reflux who are CYP2D6 poor metabolizers: "5 mg four times daily (thirty minutes before each meal and at bedtime), or 10 mg taken three times daily" with a maximum recommended daily dosage of 30 mg. Table 2 of the label gives the recommended dosage in patients with acute and recurrent diabetic gastroparesis who are CYP2D6 poor metabolizers: "5 mg four times daily (thirty minutes before each meal and at bedtime)" with a maximum recommended daily dosage of 20 mg. See label for more information.

\n", - "version" : 0 + "version" : 2 }, - "version" : 0 + "version" : 2 } ], "url" : "https://www.pharmgkb.org/labelAnnotation/PA166178750" @@ -154910,7 +157466,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 4, + "version" : 5, "year" : -1 } ], @@ -154952,7 +157508,7 @@ "id" : "PA28469", "symbol" : "G6PD", "name" : "glucose-6-phosphate dehydrogenase", - "version" : 135 + "version" : 1326 } ], "prescribingMarkdown" : { @@ -154966,7 +157522,7 @@ "objCls" : "Chemical", "id" : "PA166163260", "name" : "moviprep", - "version" : 5 + "version" : 11 } ], "relatedGenes" : [ @@ -154975,7 +157531,7 @@ "id" : "PA28469", "symbol" : "G6PD", "name" : "glucose-6-phosphate dehydrogenase", - "version" : 135 + "version" : 1326 } ], "source" : "FDA", @@ -154998,10 +157554,10 @@ "textMarkdown" : { "id" : 1447981770, "html" : "

Although the MoviPrep (polyethylene glycol 3350, sodium sulfate, sodium chloride, potassium chloride, ascorbic acid, sodium ascorbate) drug label does not specifically mention genetic testing, the FDA highlight information regarding G6PD deficient individuals within the Warnings and Precautions section.

\n

Excerpt from the MoviPrep drug label:

\n
\n

Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency. Since MoviPrep contains sodium ascorbate and ascorbic acid, MoviPrep should be used with caution in patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency, especially G-6-PD deficiency patients with an active infection, with a history of hemolysis, or taking concomitant medications known to precipitate hemolytic reactions.

\n
\n

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the moviprep drug label.

\n

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

\n", - "version" : 11 + "version" : 12 }, "userId" : "jmbarbarino", - "version" : 35 + "version" : 54 }, "recommendations" : [ { @@ -155018,14 +157574,14 @@ "objCls" : "Chemical", "id" : "PA166163260", "name" : "moviprep", - "version" : 5 + "version" : 11 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104897", "name" : "Annotation of FDA Label for moviprep and G6PD", - "version" : 35 + "version" : 54 }, "text" : { "id" : 1452245541, @@ -155048,14 +157604,14 @@ "objCls" : "Chemical", "id" : "PA166163260", "name" : "moviprep", - "version" : 5 + "version" : 11 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104897", "name" : "Annotation of FDA Label for moviprep and G6PD", - "version" : 35 + "version" : 54 }, "text" : { "id" : 1452216545, @@ -155078,14 +157634,14 @@ "objCls" : "Chemical", "id" : "PA166163260", "name" : "moviprep", - "version" : 5 + "version" : 11 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104897", "name" : "Annotation of FDA Label for moviprep and G6PD", - "version" : 35 + "version" : 54 }, "text" : { "id" : 1452216544, @@ -155127,7 +157683,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 4, + "version" : 5, "year" : -1 } ], @@ -155169,7 +157725,7 @@ "id" : "PA28469", "symbol" : "G6PD", "name" : "glucose-6-phosphate dehydrogenase", - "version" : 135 + "version" : 1326 } ], "prescribingMarkdown" : { @@ -155183,7 +157739,7 @@ "objCls" : "Chemical", "id" : "PA164746384", "name" : "nalidixic acid", - "version" : 6 + "version" : 17 } ], "relatedGenes" : [ @@ -155192,7 +157748,7 @@ "id" : "PA28469", "symbol" : "G6PD", "name" : "glucose-6-phosphate dehydrogenase", - "version" : 135 + "version" : 1326 } ], "source" : "FDA", @@ -155218,34 +157774,34 @@ "version" : 10 }, "userId" : "whaleyr", - "version" : 32 + "version" : 45 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166312284", - "name" : "Recommendation Annotation PA166312284", + "id" : "PA166315001", + "name" : "Recommendation Annotation PA166315001", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"G6PD": "Deficient"}, + "lookupKey" : {"G6PD": "Variable"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA164746384", "name" : "nalidixic acid", - "version" : 6 + "version" : 17 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104891", "name" : "Annotation of FDA Label for nalidixic acid and G6PD", - "version" : 32 + "version" : 45 }, "text" : { - "id" : 1452216543, + "id" : 1452245540, "html" : "

"Caution should be observed in patients with glucose-6-phosphate dehydrogenase deficiency." See label for more information.

\n", "version" : 0 }, @@ -155265,14 +157821,14 @@ "objCls" : "Chemical", "id" : "PA164746384", "name" : "nalidixic acid", - "version" : 6 + "version" : 17 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104891", "name" : "Annotation of FDA Label for nalidixic acid and G6PD", - "version" : 32 + "version" : 45 }, "text" : { "id" : 1452216560, @@ -155283,29 +157839,29 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166315001", - "name" : "Recommendation Annotation PA166315001", + "id" : "PA166312284", + "name" : "Recommendation Annotation PA166312284", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"G6PD": "Variable"}, + "lookupKey" : {"G6PD": "Deficient"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA164746384", "name" : "nalidixic acid", - "version" : 6 + "version" : 17 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104891", "name" : "Annotation of FDA Label for nalidixic acid and G6PD", - "version" : 32 + "version" : 45 }, "text" : { - "id" : 1452245540, + "id" : 1452216543, "html" : "

"Caution should be observed in patients with glucose-6-phosphate dehydrogenase deficiency." See label for more information.

\n", "version" : 0 }, @@ -155343,7 +157899,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 3, + "version" : 4, "year" : -1 } ], @@ -155379,7 +157935,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "prescribingMarkdown" : { @@ -155402,7 +157958,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "FDA", @@ -155428,7 +157984,7 @@ "version" : 0 }, "userId" : "cfthorn", - "version" : 8 + "version" : 13 }, "recommendations" : [ { @@ -155452,14 +158008,14 @@ "objCls" : "Label Annotation", "id" : "PA166225161", "name" : "Annotation of FDA Label for oliceridine and CYP2D6", - "version" : 8 + "version" : 13 }, "text" : { "id" : 1452216713, "html" : "

"In patients who are known or suspected to be poor CYP2D6 metabolizers, based on genotype or\nprevious history/experience with other CYP2D6 substrates, less frequent dosing of OLINVYK [oliceridine]\nmay be required. These patients should be closely monitored, and subsequent doses should be\nbased on the patient’s severity of pain and response to treatment." See label for more information

\n", - "version" : 0 + "version" : 1 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/labelAnnotation/PA166225161" @@ -155493,7 +158049,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 4, + "version" : 5, "year" : -1 } ], @@ -155536,13 +158092,13 @@ "id" : "PA35056", "symbol" : "HLA-B", "name" : "major histocompatibility complex, class I, B", - "version" : 40 + "version" : 2920 } ], "prescribingMarkdown" : { "id" : 1450380035, "html" : "

Excerpt from the oxcarbazepine (OXTELLAR XR) drug label:

\n
\n

The use of oxcarbazepine should be avoided in patients positive for HLA-B*1502 unless the benefits clearly outweigh the risks. Consideration should also be given to avoid the use of other drugs associated with SJS/TEN in HLA-B*1502 positive patients, when alternative therapies are otherwise equally available.

\n
\n", - "version" : 2 + "version" : 3 }, "relatedAlleles" : [ { @@ -155550,7 +158106,7 @@ "id" : "PA165954769", "symbol" : "HLA-B*15:02", "name" : "*15:02", - "version" : 5 + "version" : 21 } ], "relatedChemicals" : [ @@ -155558,7 +158114,7 @@ "objCls" : "Chemical", "id" : "PA450732", "name" : "oxcarbazepine", - "version" : 9 + "version" : 27 } ], "relatedGenes" : [ @@ -155567,7 +158123,7 @@ "id" : "PA35056", "symbol" : "HLA-B", "name" : "major histocompatibility complex, class I, B", - "version" : 40 + "version" : 2920 } ], "source" : "FDA", @@ -155590,10 +158146,10 @@ "textMarkdown" : { "id" : 1447981847, "html" : "

Excerpts from the oxcarbazepine (OXTELLAR XR) drug label:

\n
\n

Patients carrying the HLA-B*1502 allele may be at increased risk for SJS/TEN with oxcarbazepine treatment.

\n
\n
\n

The frequency of the HLA-B*1502 allele ranges from 2 to 12% in Han Chinese populations, is about 8% in Thai populations, and above 15% in the Philippines and in some Malaysian populations. Allele frequencies up to about 2% and 6% have been reported in Korea and India, respectively. The frequency of the HLA-B*1502 allele is negligible in people from European descent, several African populations, indigenous peoples of the Americas, Hispanic populations, and in Japanese (<1%).

\n
\n
\n

Testing for the presence of the HLA-B*1502 allele should be considered in patients with ancestry in genetically at-risk populations, prior to initiating treatment with oxcarbazepine. The use of oxcarbazepine should be avoided in patients positive for HLA-B*1502 unless the benefits clearly outweigh the risks. Consideration should also be given to avoid the use of other drugs associated with SJS/TEN in HLA-B*1502 positive patients, when alternative therapies are otherwise equally available.

\n
\n

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the oxcarbazepine drug label.

\n

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

\n", - "version" : 11 + "version" : 12 }, "userId" : "jmbarbarino", - "version" : 31 + "version" : 63 }, "recommendations" : [ { @@ -155610,14 +158166,14 @@ "objCls" : "Chemical", "id" : "PA450732", "name" : "oxcarbazepine", - "version" : 9 + "version" : 27 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166105213", "name" : "Annotation of FDA Label for oxcarbazepine and HLA-B", - "version" : 31 + "version" : 63 }, "text" : { "id" : 1452213280, @@ -155658,7 +158214,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 3, + "version" : 4, "year" : -1 } ], @@ -155702,27 +158258,27 @@ "id" : "PA25294", "symbol" : "BCHE", "name" : "butyrylcholinesterase", - "version" : 144 + "version" : 5492 }, { "objCls" : "Gene", "id" : "PA27331", "symbol" : "CYB5R3", "name" : "cytochrome b5 reductase 3", - "version" : 13 + "version" : 80 }, { "objCls" : "Gene", "id" : "PA28469", "symbol" : "G6PD", "name" : "glucose-6-phosphate dehydrogenase", - "version" : 135 + "version" : 1326 } ], "prescribingMarkdown" : { "id" : 1450824516, "html" : "

Excerpts from the Oxymetazoline and Tetracaine (KOVANAZE) FDA drug label:

\n
\n

Although all patients are at risk for methemoglobinemia, patients with glucose-6-phosphate dehydrogenase deficiency, congenital or idiopathic methemoglobinemia ... are more susceptible to developing clinical manifestations of the condition. If local anesthetics must be used in these patients, close monitoring for symptoms and signs of methemoglobinemia is recommended.

\n
\n
\n

Because of an inability to metabolize local anesthetics, those patients with pseudocholinesterase deficiency may\nbe at a greater risk of developing toxic plasma concentrations of tetracaine. Monitor patients with\npseudocholinesterase deficiency for signs of local anesthetic toxicity.

\n
\n", - "version" : 1 + "version" : 2 }, "relatedAlleles" : [], "relatedChemicals" : [ @@ -155739,28 +158295,28 @@ "id" : "PA25294", "symbol" : "BCHE", "name" : "butyrylcholinesterase", - "version" : 144 + "version" : 5492 }, { "objCls" : "Gene", "id" : "PA27331", "symbol" : "CYB5R3", "name" : "cytochrome b5 reductase 3", - "version" : 13 + "version" : 80 }, { "objCls" : "Gene", "id" : "PA28469", "symbol" : "G6PD", "name" : "glucose-6-phosphate dehydrogenase", - "version" : 135 + "version" : 1326 } ], "source" : "FDA", "summaryMarkdown" : { "id" : 1450821526, "html" : "

The FDA-approved drug label for Oxymetazoline and Tetracaine (KOVANAZE) states that patients with G6PD deficiency or congenital methemoglobinemia may be at increased risk for methemoglobinemia when treated with this drug. There is also a warning for pseudocholinesterase deficiency (BCHE) and risk for toxicity which is not listed on the FDA biomarker table.

\n", - "version" : 0 + "version" : 1 }, "terms" : [], "testing" : { @@ -155776,20 +158332,20 @@ "textMarkdown" : { "id" : 1450821527, "html" : "

Excerpts from the Oxymetazoline and Tetracaine (KOVANAZE) FDA drug label:

\n
\n

Methemoglobinemia

\n

Cases of methemoglobinemia have been reported in association with local anesthetic use. Although all patients\nare at risk for methemoglobinemia, patients with glucose-6-phosphate dehydrogenase deficiency, congenital or\nidiopathic methemoglobinemia, cardiac or pulmonary compromise, infants under 6 months of age, and\nconcurrent exposure to oxidizing agents or their metabolites are more susceptible to developing clinical\nmanifestations of the condition. If local anesthetics must be used in these patients, close monitoring for\nsymptoms and signs of methemoglobinemia is recommended.

\n
\n
\n

Pseudocholinesterase Deficiency

\n

Because of an inability to metabolize local anesthetics, those patients with pseudocholinesterase deficiency may\nbe at a greater risk of developing toxic plasma concentrations of tetracaine. Monitor patients with\npseudocholinesterase deficiency for signs of local anesthetic toxicity.

\n
\n

NOTE: While the CYB5R3 gene is not explicitly stated in the drug label variants in this gene are associated with congenital methemoglobinemia I and II OMIM 250800:

\n

NOTE: While the BCHE gene is not explicitly stated in the drug label there is a warning for pseudocholinesterase deficiency which is associated with variants in BCHE.

\n

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Kovanaze drug label.

\n

*Disclaimer: The contents of this page are the sole responsibility of PharmGKB.

\n", - "version" : 1 + "version" : 2 }, "userId" : "cfthorn", - "version" : 7 + "version" : 14 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166312394", - "name" : "Recommendation Annotation PA166312394", + "id" : "PA166315141", + "name" : "Recommendation Annotation PA166315141", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"G6PD": "Deficient with CNSHA"}, + "lookupKey" : {"G6PD": "Variable"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { @@ -155803,10 +158359,10 @@ "objCls" : "Label Annotation", "id" : "PA166184637", "name" : "Annotation of FDA Label for oxymetazoline and tetracaine and BCHE, CYB5R3, G6PD", - "version" : 7 + "version" : 14 }, "text" : { - "id" : 1452216674, + "id" : 1452245680, "html" : "

"Although all patients are at risk for methemoglobinemia, patients with glucose-6-phosphate dehydrogenase deficiency, ... are more susceptible to developing clinical manifestations of the condition. If local anesthetics must be used in these patients, close monitoring for symptoms and signs of methemoglobinemia is recommended." See label for more information.

\n", "version" : 0 }, @@ -155814,12 +158370,12 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166315141", - "name" : "Recommendation Annotation PA166315141", + "id" : "PA166312394", + "name" : "Recommendation Annotation PA166312394", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"G6PD": "Variable"}, + "lookupKey" : {"G6PD": "Deficient with CNSHA"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { @@ -155833,10 +158389,10 @@ "objCls" : "Label Annotation", "id" : "PA166184637", "name" : "Annotation of FDA Label for oxymetazoline and tetracaine and BCHE, CYB5R3, G6PD", - "version" : 7 + "version" : 14 }, "text" : { - "id" : 1452245680, + "id" : 1452216674, "html" : "

"Although all patients are at risk for methemoglobinemia, patients with glucose-6-phosphate dehydrogenase deficiency, ... are more susceptible to developing clinical manifestations of the condition. If local anesthetics must be used in these patients, close monitoring for symptoms and signs of methemoglobinemia is recommended." See label for more information.

\n", "version" : 0 }, @@ -155863,7 +158419,7 @@ "objCls" : "Label Annotation", "id" : "PA166184637", "name" : "Annotation of FDA Label for oxymetazoline and tetracaine and BCHE, CYB5R3, G6PD", - "version" : 7 + "version" : 14 }, "text" : { "id" : 1452216675, @@ -155904,7 +158460,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 5, + "version" : 6, "year" : -1 } ], @@ -155952,7 +158508,7 @@ "id" : "PA124", "symbol" : "CYP2C19", "name" : "cytochrome P450 family 2 subfamily C member 19", - "version" : 7210 + "version" : 7266 } ], "prescribingMarkdown" : { @@ -155966,7 +158522,7 @@ "objCls" : "Chemical", "id" : "PA450774", "name" : "pantoprazole", - "version" : 15 + "version" : 37 } ], "relatedGenes" : [ @@ -155975,14 +158531,14 @@ "id" : "PA124", "symbol" : "CYP2C19", "name" : "cytochrome P450 family 2 subfamily C member 19", - "version" : 7210 + "version" : 7266 } ], "source" : "FDA", "summaryMarkdown" : { "id" : 1447981779, "html" : "

The FDA-approved drug label for pantoprazole (PROTONIX) states that pediatric patients who are CYP2C19 poor metabolizers exhibited ~10-fold lower clearance of the drug as compared to extensive metabolizers, and that a dose reduction should be considered in these patients. No dosage adjustment is needed in adult CYP2C19 poor metabolizers.

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Pantoprazole is indicated for short-term treatment of erosive esophagitis associated with gastroesophageal reflux disease, maintenance of healing of erosive esophagitis, and pathological hypersecretory conditions including Zollinger-Ellison Syndrome.

\n

Excerpt from the pantoprazole (PROTONIX) label:

\n
\n

CYP2C19 displays a known genetic polymorphism due to its deficiency in some subpopulations (e.g., approximately 3% of Caucasians and African-Americans and\n17% to 23% of Asians are poor metabolizers). Although these subpopulations of pantoprazole poor metabolizers have elimination half-life values of 3.5 to 10 hours in adults, they still have minimal accumulation (23% or less) with once-daily dosing. For adult patients who are CYP2C19 poor metabolizers, no dosage adjustment is needed. Similar to adults, pediatric patients who have the poor metabolizer genotype of CYP2C19 (CYP2C19 *2/*2) exhibited greater than a 6-fold increase in AUC compared to pediatric extensive (CYP2C19 *1/*1) and intermediate (CYP2C19 *1/*x) metabolizers. Poor metabolizers exhibited approximately 10-fold lower apparent oral clearance compared to extensive metabolizers. For known pediatric poor metabolizers, a dose reduction should be considered.

\n
\n

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the pantoprazole drug label.

\n

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

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"For adult patients who are CYP2C19 poor metabolizers, no dosage adjustment is needed...For known pediatric poor metabolizers, a dose reduction should be considered." See label for more information.

\n", - "version" : 0 + "version" : 1 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", @@ -156048,21 +158604,21 @@ "objCls" : "Chemical", "id" : "PA450774", "name" : "pantoprazole", - "version" : 15 + "version" : 37 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104901", "name" : "Annotation of FDA Label for pantoprazole and CYP2C19", - "version" : 33 + "version" : 61 }, "text" : { "id" : 1452211505, "html" : "

"For adult patients who are CYP2C19 poor metabolizers, no dosage adjustment is needed...For known pediatric poor metabolizers, a dose reduction should be considered." See label for more information.

\n", - "version" : 0 + "version" : 1 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/labelAnnotation/PA166104901" @@ -156096,7 +158652,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 4, + "version" : 5, "year" : -1 } ], @@ -156152,7 +158708,7 @@ "id" : "PA28469", "symbol" : "G6PD", "name" : "glucose-6-phosphate dehydrogenase", - "version" : 135 + "version" : 1326 } ], "prescribingMarkdown" : { @@ -156166,7 +158722,7 @@ "objCls" : "Chemical", "id" : "PA165963961", "name" : "pegloticase", - "version" : 6 + "version" : 11 } ], "relatedGenes" : [ @@ -156175,7 +158731,7 @@ "id" : "PA28469", "symbol" : "G6PD", "name" : "glucose-6-phosphate dehydrogenase", - "version" : 135 + "version" : 1326 } ], "source" : "FDA", @@ -156201,34 +158757,34 @@ "version" : 12 }, "userId" : "jmbarbarino", - "version" : 32 + "version" : 52 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166312287", - "name" : "Recommendation Annotation PA166312287", + "id" : "PA166315003", + "name" : "Recommendation Annotation PA166315003", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"G6PD": "Deficient"}, + "lookupKey" : {"G6PD": "Variable"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA165963961", "name" : "pegloticase", - "version" : 6 + "version" : 11 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104900", "name" : "Annotation of FDA Label for pegloticase and G6PD", - "version" : 32 + "version" : 52 }, "text" : { - "id" : 1452216546, + "id" : 1452245542, "html" : "

"KRYSTEXXA [pegloticase] is contraindicated inpatients with G6PD deficiency." See label for more information.

\n", "version" : 0 }, @@ -156236,29 +158792,29 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166315003", - "name" : "Recommendation Annotation PA166315003", + "id" : "PA166312287", + "name" : "Recommendation Annotation PA166312287", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"G6PD": "Variable"}, + "lookupKey" : {"G6PD": "Deficient"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA165963961", "name" : "pegloticase", - "version" : 6 + "version" : 11 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104900", "name" : "Annotation of FDA Label for pegloticase and G6PD", - "version" : 32 + "version" : 52 }, "text" : { - "id" : 1452245542, + "id" : 1452216546, "html" : "

"KRYSTEXXA [pegloticase] is contraindicated inpatients with G6PD deficiency." See label for more information.

\n", "version" : 0 }, @@ -156278,14 +158834,14 @@ "objCls" : "Chemical", "id" : "PA165963961", "name" : "pegloticase", - "version" : 6 + "version" : 11 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104900", "name" : "Annotation of FDA Label for pegloticase and G6PD", - "version" : 32 + "version" : 52 }, "text" : { "id" : 1452216580, @@ -156326,7 +158882,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 4, + "version" : 5, "year" : -1 } ], @@ -156390,14 +158946,14 @@ "id" : "PA126", "symbol" : "CYP2C9", "name" : "cytochrome P450 family 2 subfamily C member 9", - "version" : 7877 + "version" : 7952 }, { "objCls" : "Gene", "id" : "PA35056", "symbol" : "HLA-B", "name" : "major histocompatibility complex, class I, B", - "version" : 40 + "version" : 2920 } ], "prescribingMarkdown" : { @@ -156411,21 +158967,21 @@ "id" : "PA165816543", "symbol" : "CYP2C9*2", "name" : "*2", - "version" : 23 + "version" : 52 }, { "objCls" : "Haplotype", "id" : "PA165816544", "symbol" : "CYP2C9*3", "name" : "*3", - "version" : 25 + "version" : 55 }, { "objCls" : "Haplotype", "id" : "PA165954769", "symbol" : "HLA-B*15:02", "name" : "*15:02", - "version" : 5 + "version" : 21 } ], "relatedChemicals" : [ @@ -156433,7 +158989,7 @@ "objCls" : "Chemical", "id" : "PA450947", "name" : "phenytoin", - "version" : 14 + "version" : 49 } ], "relatedGenes" : [ @@ -156442,21 +158998,21 @@ "id" : "PA124", "symbol" : "CYP2C19", "name" : "cytochrome P450 family 2 subfamily C member 19", - "version" : 7210 + "version" : 7266 }, { "objCls" : "Gene", "id" : "PA126", "symbol" : "CYP2C9", "name" : "cytochrome P450 family 2 subfamily C member 9", - "version" : 7877 + "version" : 7952 }, { "objCls" : "Gene", "id" : "PA35056", "symbol" : "HLA-B", "name" : "major histocompatibility complex, class I, B", - "version" : 40 + "version" : 2920 } ], "source" : "FDA", @@ -156479,428 +159035,428 @@ "textMarkdown" : { "id" : 1447981712, "html" : "

Excerpts from the phenytoin (DILANTIN) drug label:

\n
\n

Studies in patients of Chinese ancestry have found a strong association between the risk of developing SJS/TEN and the presence of HLA-B*1502, an inherited allelic variant of the HLA B gene, in patients using carbamazepine. Limited evidence suggests that HLA-B*1502 may be a risk factor for the development of SJS/TEN in patients of Asian ancestry taking other antiepileptic drugs associated with SJS/TEN, including phenytoin. In addition, retrospective, case-control, genome-wide association studies in patients of southeast Asian ancestry have also identified an increased risk of SCARs in carriers of the decreased function CYP2C9*3 variant, which has also been associated with decreased clearance of phenytoin. Consider avoiding DILANTIN as an alternative to carbamazepine in patients who are positive for HLA-B*1502 or in CYP2C9*3 carriers.

\n

The use of HLA-B*1502 or CYP2C9 genotyping has important limitations and must never substitute for appropriate clinical vigilance and patient management. The role of other possible factors in the development of, and morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring have not been studied.

\n
\n
\n

Use in Patients with Decreased CYP2C9 Function\nPatients who are intermediate or poor metabolizers of CYP2C9 substrates (e.g., *1/*3, *2/*2, *3/*3) may exhibit increased phenytoin serum concentrations compared to patients who are normal metabolizers (e.g., *1/*1). Thus, patients who are known to be intermediate or poor metabolizers may ultimately require lower doses of phenytoin to maintain similar steady-state concentrations compared to normal metabolizers. If early signs of dose-related central nervous system (CNS) toxicity develop, serum concentrations should be checked immediately.

\n
\n
\n

Metabolism...Phenytoin is primarily metabolized by the hepatic cytochrome P450 enzyme CYP2C9 and to a lesser extent by CYP2C19.

\n
\n

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the phenytoin drug label.

\n

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

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"Patients who are intermediate or poor metabolizers of CYP2C9 substrates (e.g., *1/*3, *2/*2, *3/*3) may exhibit increased phenytoin serum concentrations compared to patients who are normal metabolizers (e.g., *1/*1). Thus, patients who are known to be intermediate or poor metabolizers may ultimately require lower doses of phenytoin to maintain similar steady-state concentrations compared to normal metabolizers...Consider avoiding DILANTIN [phenytoin] as an alternative to carbamazepine in patients who are positive for HLA-B*1502 or in CYP2C9*3 carriers." See label for more information.

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"Patients who are intermediate or poor metabolizers of CYP2C9 substrates (e.g., *1/*3, *2/*2, *3/*3) may exhibit increased phenytoin serum concentrations compared to patients who are normal metabolizers (e.g., *1/*1). Thus, patients who are known to be intermediate or poor metabolizers may ultimately require lower doses of phenytoin to maintain similar steady-state concentrations compared to normal metabolizers." See label for more information.

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"Consider avoiding DILANTIN [phenytoin] as an alternative to carbamazepine in patients who are positive for HLA-B*1502 or in CYP2C9*3 carriers." See label for more information.

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"Patients who are intermediate or poor metabolizers of CYP2C9 substrates (e.g., *1/*3, *2/*2, *3/*3) may exhibit increased phenytoin serum concentrations compared to patients who are normal metabolizers (e.g., *1/*1). Thus, patients who are known to be intermediate or poor metabolizers may ultimately require lower doses of phenytoin to maintain similar steady-state concentrations compared to normal metabolizers." See label for more information.

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"Consider avoiding DILANTIN [phenytoin] as an alternative to carbamazepine in patients who are positive for HLA-B*1502 or in CYP2C9*3 carriers." See label for more information.

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"Patients who are intermediate or poor metabolizers of CYP2C9 substrates (e.g., *1/*3, *2/*2, *3/*3) may exhibit increased phenytoin serum concentrations compared to patients who are normal metabolizers (e.g., *1/*1). Thus, patients who are known to be intermediate or poor metabolizers may ultimately require lower doses of phenytoin to maintain similar steady-state concentrations compared to normal metabolizers...Consider avoiding DILANTIN [phenytoin] as an alternative to carbamazepine in patients who are positive for HLA-B*1502 or in CYP2C9*3 carriers." See label for more information.

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"Consider avoiding DILANTIN [phenytoin] as an alternative to carbamazepine in patients who are positive for HLA-B*1502 or in CYP2C9*3 carriers." See label for more information.

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"Patients who are intermediate or poor metabolizers of CYP2C9 substrates (e.g., *1/*3, *2/*2, *3/*3) may exhibit increased phenytoin serum concentrations compared to patients who are normal metabolizers (e.g., *1/*1). Thus, patients who are known to be intermediate or poor metabolizers may ultimately require lower doses of phenytoin to maintain similar steady-state concentrations compared to normal metabolizers...Consider avoiding DILANTIN [phenytoin] as an alternative to carbamazepine in patients who are positive for HLA-B*1502 or in CYP2C9*3 carriers." See label for more information.

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"Consider avoiding DILANTIN [phenytoin] as an alternative to carbamazepine in patients who are positive for HLA-B*1502 or in CYP2C9*3 carriers." See label for more information.

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"Consider avoiding DILANTIN [phenytoin] as an alternative to carbamazepine in patients who are positive for HLA-B*1502 or in CYP2C9*3 carriers." See label for more information.

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"Patients who are intermediate or poor metabolizers of CYP2C9 substrates (e.g., *1/*3, *2/*2, *3/*3) may exhibit increased phenytoin serum concentrations compared to patients who are normal metabolizers (e.g., *1/*1). Thus, patients who are known to be intermediate or poor metabolizers may ultimately require lower doses of phenytoin to maintain similar steady-state concentrations compared to normal metabolizers...Consider avoiding DILANTIN [phenytoin] as an alternative to carbamazepine in patients who are positive for HLA-B*1502 or in CYP2C9*3 carriers." See label for more information.

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"Patients who are intermediate or poor metabolizers of CYP2C9 substrates (e.g., *1/*3, *2/*2, *3/*3) may exhibit increased phenytoin serum concentrations compared to patients who are normal metabolizers (e.g., *1/*1). Thus, patients who are known to be intermediate or poor metabolizers may ultimately require lower doses of phenytoin to maintain similar steady-state concentrations compared to normal metabolizers...Consider avoiding DILANTIN [phenytoin] as an alternative to carbamazepine in patients who are positive for HLA-B*1502 or in CYP2C9*3 carriers." See label for more information.

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"Consider avoiding DILANTIN [phenytoin] as an alternative to carbamazepine in patients who are positive for HLA-B*1502 or in CYP2C9*3 carriers." See label for more information.

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"Consider avoiding DILANTIN [phenytoin] as an alternative to carbamazepine in patients who are positive for HLA-B*1502 or in CYP2C9*3 carriers." See label for more information.

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"Consider avoiding DILANTIN [phenytoin] as an alternative to carbamazepine in patients who are positive for HLA-B*1502 or in CYP2C9*3 carriers." See label for more information.

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"Patients who are intermediate or poor metabolizers of CYP2C9 substrates (e.g., *1/*3, *2/*2, *3/*3) may exhibit increased phenytoin serum concentrations compared to patients who are normal metabolizers (e.g., *1/*1). Thus, patients who are known to be intermediate or poor metabolizers may ultimately require lower doses of phenytoin to maintain similar steady-state concentrations compared to normal metabolizers...Consider avoiding DILANTIN [phenytoin] as an alternative to carbamazepine in patients who are positive for HLA-B*1502 or in CYP2C9*3 carriers." See label for more information.

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"Consider avoiding DILANTIN [phenytoin] as an alternative to carbamazepine in patients who are positive for HLA-B*1502 or in CYP2C9*3 carriers." See label for more information.

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"Consider avoiding DILANTIN [phenytoin] as an alternative to carbamazepine in patients who are positive for HLA-B*1502 or in CYP2C9*3 carriers." See label for more information.

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"Patients who are intermediate or poor metabolizers of CYP2C9 substrates (e.g., *1/*3, *2/*2, *3/*3) may exhibit increased phenytoin serum concentrations compared to patients who are normal metabolizers (e.g., *1/*1). Thus, patients who are known to be intermediate or poor metabolizers may ultimately require lower doses of phenytoin to maintain similar steady-state concentrations compared to normal metabolizers." See label for more information.

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Excerpts from the pimozide (ORAP) drug label:

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Individuals with genetic variations resulting in poor CYP2D6 metabolism (approximately 5 to 10% of the population) exhibit higher pimozide concentrations than extensive CYP2D6 metabolizers. The concentrations observed in poor CYP 2D6 metabolizers are similar to those seen with strong CYP2D6 inhibitors such as paroxetine. The time to achieve steady state pimozide concentrations is expected to be longer (approximately 2 weeks) in poor CYP2D6 metabolizers because of the prolonged half-life. Alternative dosing strategies are recommended in patients who are genetically poor CYP2D6 metabolizers.

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In children: At doses above 0.05mg/kg/day, CYP2D6 genotyping should be performed. In poor CYP2D6 metabolizers, ORAP doses should not exceed 0.05mg/kg/day, and doses should not be increased earlier than 14 days.

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In adults: At doses above 4 mg/day, CYP2D6 genotyping should be performed. In poor CYP2D6 metabolizers, ORAP doses should not exceed 4 mg/day, and doses should not be increased earlier than 14 days.

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For the complete drug label text with sections containing pharmacogenetic information highlighted, see the pimozide drug label.

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*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

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"At doses above 4 mg/day, CYP2D6 genotyping should be performed. In poor CYP2D6 metabolizers, ORAP [pimozide] doses should not exceed 4 mg/day, and doses should not be increased earlier than 14 days." See label for more information.

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"At doses above 0.05 mg/kg/day, CYP2D6 genotyping should be performed. In poor CYP2D6 metabolizers, ORAP [pimozide] doses should not exceed 0.05 mg/kg/day, and doses should not be increased earlier than 14 days." See label for more information.

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Piroxicam (FELDENE) is a nonsteroidal anti-inflammatory drug indicated for osteoarthritis and rheumatoid arthritis.

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Excerpts from the piroxicam (FELDENE) drug label:

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In vitro studies indicate...CYP2C9...as the main enzyme involved in the formation to the 5'-hydroxy-piroxicam, the major metabolite.

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Pharmacogenomics...CYP2C9 activity is reduced in individuals with genetic polymorphisms, such as the CYP2C9*2 and CYP2C9*3 polymorphisms. Limited data from two published reports showed that subjects with heterozygous CYP2C9*1/*2 (n=9), heterozygous CYP2C9*1/*3 (n=9), and homozygous CYP2C9*3/*3 (n=1) genotypes showed 1.7-, 1.7-, and 5.3-fold higher piroxicam systemic levels, respectively, than the subjects with CYP2C9*1/*1 (n=17, normal metabolizer genotype) following administration of a single oral dose. The mean elimination half-life values of piroxicam for subjects with CYP2C9*1/*3 (n=9) and CYP2C9*3/*3 (n=1) genotypes were 1.7- and 8.8-fold higher than subjects with CYP2C9*1/*1 (n=17). It is estimated that the frequency of the homozygous *3/*3 genotype is 0% to 1% in the population at large; however, frequencies as high as 5.7% have been reported in certain ethnic groups.

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Poor Metabolizers of CYP2C9 Substrates: In patients who are known or suspected to be poor CYP2C9 metabolizers based on genotype or previous history/experience with other CYP2C9 substrates (such as warfarin and phenytoin) consider dose reduction as they may have abnormally high plasma levels due to reduced metabolic clearance.

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For the complete drug label text with sections containing pharmacogenetic information highlighted, see the piroxicam drug label.

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*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

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In case of known maternal history of ototoxicity due to aminoglycoside use or a known mitochondrial DNA variant in the patient, consider alternative treatments other than aminoglycosides unless the increased risk of permanent hearing loss is outweighed by the severity of infection and lack of safe and effective alternative therapies.

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Plazomicin (ZEMDRI) is an aminoglycoside antibacterial indicated for the treatment of patients 18 years of age or older with Complicated Urinary Tract Infections (cUTI) including Pyelonephritis.

\n

Cases of ototoxicity with aminoglycosides have been observed in patients with certain variants in the mitochondrially encoded 12S rRNA gene (MT-RNR1), particularly the m.1555A>G variant. In case of known maternal history of ototoxicity due to aminoglycoside use or a known mitochondrial DNA variant in the patient, consider alternative treatments other than aminoglycosides unless the increased risk of permanent hearing loss is outweighed by the severity of infection and lack of safe and effective alternative therapies.

\n", + "version" : 1 + }, + "terms" : [], + "testing" : { + "id" : 1183672111, + "description" : "The label does not discuss genetic or other testing for gene/protein/chromosomal variants, but does contain information about changes in efficacy, dosage or toxicity due to such variants. The label may mention contraindication of the drug in a particular subset of patients but does not require or recommend gene, protein or chromosomal testing.", + "parents" : [], + "resource" : "Genetic Testing Level", + "term" : "Actionable PGx", + "termId" : "geneTestLevel:1183672111", + "valid" : true, + "version" : 2 + }, + "textMarkdown" : { + "id" : 1452252281, + "html" : "

Excerpts from the plazomicin (ZEMDRI) label:

\n
\n

Cases of ototoxicity with aminoglycosides have been observed in patients with certain variants in the mitochondrially encoded 12S rRNA gene (MT-RNR1), particularly the m.1555A>G variant. Ototoxicity occurred in some patients even when their aminoglycoside serum levels were within the recommended range. Mitochondrial DNA variants are present in less than 1% of the general US population, and the proportion of the variant carriers who may develop ototoxicity as well as the severity of ototoxicity is unknown. In case of known maternal history of ototoxicity due to aminoglycoside use or a known mitochondrial DNA variant in the patient, consider alternative treatments other than aminoglycosides unless the increased risk of permanent hearing loss is outweighed by the severity of infection and lack of safe and effective alternative therapies.

\n
\n

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the plazomicin drug label.

\n

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

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The plazomicin label states: "Cases of ototoxicity with aminoglycosides have been observed in patients with certain variants in\nthe mitochondrially encoded 12S rRNA gene (MT-RNR1), particularly the m.1555A>G variant. ... In case of known maternal history of ototoxicity due to aminoglycoside use or a known mitochondrial DNA variant in the patient, consider alternative treatments other than aminoglycosides unless the increased risk of permanent hearing loss is outweighed by the severity of infection and lack of safe and effective alternative therapies." See label for more information.

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Primaquine is indicated for the radical cure (prevention of relapse) of vivax malaria. Excerpts from the primaquine drug label:

\n
\n

Due to the risk of hemolytic anemia in patients with G6PD deficiency, G6PD testing has to be performed before using primaquine. Due to the limitations of G6PD tests, physicians need to be aware of residual risk of hemolysis and adequate medical support and follow-up to manage hemolytic risk should be available.

\n
\n
\n

Primaquine should not be prescribed for patients with severe G6PD deficiency.

\n
\n
\n

In case of mild to moderate G6PD deficiency, a decision to prescribe primaquine must be based on an assessment of the risks and benefits...

\n
\n
\n

When the G6PD status is unknown and G6PD testing is not available, a decision to prescribe primaquine must be based on an assessment of the risks and benefits...

\n
\n

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the primaquine drug label

\n

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

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"Primaquine should not be prescribed for patients with severe G6PD deficiency." See label for more information.

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"In case of mild to moderate G6PD deficiency, a decision to prescribe primaquine must be based on an assessment of the risks and benefits..." See label for more information.

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"In case of mild to moderate G6PD deficiency, a decision to prescribe primaquine must be based on an assessment of the risks and benefits..." See label for more information.

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"Primaquine should not be prescribed for patients with severe G6PD deficiency." See label for more information.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166314961", - "name" : "Recommendation Annotation PA166314961", + "id" : "PA166312223", + "name" : "Recommendation Annotation PA166312223", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"G6PD": "Variable"}, + "lookupKey" : {"G6PD": "Deficient"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451103", "name" : "primaquine", - "version" : 7 + "version" : 35 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104876", "name" : "Annotation of FDA Label for primaquine and G6PD", - "version" : 31 + "version" : 58 }, "text" : { - "id" : 1452245500, + "id" : 1452216482, "html" : "

"In case of mild to moderate G6PD deficiency, a decision to prescribe primaquine must be based on an assessment of the risks and benefits..." See label for more information.

\n", "version" : 0 }, @@ -157701,7 +160409,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 4, + "version" : 5, "year" : -1 } ], @@ -157737,7 +160445,7 @@ "id" : "PA28469", "symbol" : "G6PD", "name" : "glucose-6-phosphate dehydrogenase", - "version" : 135 + "version" : 1326 } ], "prescribingMarkdown" : { @@ -157751,7 +160459,7 @@ "objCls" : "Chemical", "id" : "PA10176", "name" : "rasburicase", - "version" : 7 + "version" : 20 } ], "relatedGenes" : [ @@ -157760,14 +160468,14 @@ "id" : "PA28469", "symbol" : "G6PD", "name" : "glucose-6-phosphate dehydrogenase", - "version" : 135 + "version" : 1326 } ], "source" : "FDA", "summaryMarkdown" : { "id" : 1447982323, "html" : "

The FDA-approved drug label for rasburicase (Elitek) states that patients at higher risk for G6PD deficiency, such as those of African or Mediterranean ancestry, should be screened prior to starting treatment, as rasburicase is contraindicated in patients with G6PD deficiency. The label also states that It is unclear whether patients with NADH cytochrome b5 reductase (CYB5R1, 2, 3, 4) deficiency are at risk for methemoglobinemia or hemolytic anemia.

\n", - "version" : 2 + "version" : 1 }, "terms" : [], "testing" : { @@ -157786,34 +160494,34 @@ "version" : 10 }, "userId" : "jmbarbarino", - "version" : 24 + "version" : 46 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166312326", - "name" : "Recommendation Annotation PA166312326", + "id" : "PA166315061", + "name" : "Recommendation Annotation PA166315061", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"G6PD": "Deficient with CNSHA"}, + "lookupKey" : {"G6PD": "Variable"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA10176", "name" : "rasburicase", - "version" : 7 + "version" : 20 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166151881", "name" : "Annotation of FDA Label for rasburicase and G6PD", - "version" : 24 + "version" : 46 }, "text" : { - "id" : 1452216585, + "id" : 1452245600, "html" : "

"Do not administer Elitek [rasburicase] to patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency...Elitek [rasburicase] is contraindicated in patients with G6PD deficiency..." See label for more information.

\n", "version" : 0 }, @@ -157821,29 +160529,29 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166315061", - "name" : "Recommendation Annotation PA166315061", + "id" : "PA166312326", + "name" : "Recommendation Annotation PA166312326", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"G6PD": "Variable"}, + "lookupKey" : {"G6PD": "Deficient with CNSHA"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA10176", "name" : "rasburicase", - "version" : 7 + "version" : 20 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166151881", "name" : "Annotation of FDA Label for rasburicase and G6PD", - "version" : 24 + "version" : 46 }, "text" : { - "id" : 1452245600, + "id" : 1452216585, "html" : "

"Do not administer Elitek [rasburicase] to patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency...Elitek [rasburicase] is contraindicated in patients with G6PD deficiency..." See label for more information.

\n", "version" : 0 }, @@ -157863,14 +160571,14 @@ "objCls" : "Chemical", "id" : "PA10176", "name" : "rasburicase", - "version" : 7 + "version" : 20 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166151881", "name" : "Annotation of FDA Label for rasburicase and G6PD", - "version" : 24 + "version" : 46 }, "text" : { "id" : 1452216586, @@ -157911,7 +160619,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 4, + "version" : 5, "year" : -1 } ], @@ -157948,7 +160656,7 @@ "id" : "PA420", "symbol" : "UGT1A1", "name" : "UDP glucuronosyltransferase 1 family, polypeptide A1", - "version" : 6110 + "version" : 6350 } ], "prescribingMarkdown" : { @@ -157962,7 +160670,7 @@ "id" : "PA166115842", "symbol" : "UGT1A1*28", "name" : "*28", - "version" : 16 + "version" : 34 } ], "relatedChemicals" : [ @@ -157970,7 +160678,7 @@ "objCls" : "Chemical", "id" : "PA166225061", "name" : "sacituzumab govitecan", - "version" : 4 + "version" : 8 } ], "relatedGenes" : [ @@ -157979,7 +160687,7 @@ "id" : "PA420", "symbol" : "UGT1A1", "name" : "UDP glucuronosyltransferase 1 family, polypeptide A1", - "version" : 6110 + "version" : 6350 } ], "source" : "FDA", @@ -158005,7 +160713,7 @@ "version" : 2 }, "userId" : "lgong", - "version" : 10 + "version" : 21 }, "recommendations" : [ { @@ -158022,18 +160730,48 @@ "objCls" : "Chemical", "id" : "PA166225061", "name" : "sacituzumab govitecan", - "version" : 4 + "version" : 8 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166225101", "name" : "Annotation of FDA Label for sacituzumab govitecan and UGT1A1", - "version" : 10 + "version" : 21 }, "text" : { "id" : 1452229480, "html" : "

"Individuals who are homozygous for the uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1)*28 allele are at increased risk for neutropenia and may be at increased risk for other adverse reactions following initiation of TRODELVY [sacituzumab govitecan] treatment...Closely monitor patients with reduced UGT1A1 activity for severe neutropenia. The appropriate dose for patients who are homozygous for UGT1A1*28 is not known and should be considered based on individual patient tolerance to treatment." See label for more information.

\n", + "version" : 1 + }, + "version" : 1 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166339782", + "name" : "Recommendation Annotation PA166339782", + "alternateDrugAvailable" : false, + "dosingInformation" : false, + "implications" : [], + "lookupKey" : {"UGT1A1": {"*80+*28": 2}}, + "otherPrescribingGuidance" : true, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA166225061", + "name" : "sacituzumab govitecan", + "version" : 8 + } + ], + "source" : { + "objCls" : "Label Annotation", + "id" : "PA166225101", + "name" : "Annotation of FDA Label for sacituzumab govitecan and UGT1A1", + "version" : 21 + }, + "text" : { + "id" : 1452486241, + "html" : "

"Individuals who are homozygous for the uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1)*28 allele are at increased risk for neutropenia and may be at increased risk for other adverse reactions following initiation of TRODELVY [sacituzumab govitecan] treatment...Closely monitor patients with reduced UGT1A1 activity for severe neutropenia. The appropriate dose for patients who are homozygous for UGT1A1*28 is not known and should be considered based on individual patient tolerance to treatment." See label for more information.

\n", "version" : 0 }, "version" : 0 @@ -158070,7 +160808,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 4, + "version" : 5, "year" : -1 } ], @@ -158114,14 +160852,14 @@ "id" : "PA85", "symbol" : "CACNA1S", "name" : "calcium voltage-gated channel subunit alpha1 S", - "version" : 19 + "version" : 59 }, { "objCls" : "Gene", "id" : "PA34896", "symbol" : "RYR1", "name" : "ryanodine receptor 1", - "version" : 131 + "version" : 7467 } ], "prescribingMarkdown" : { @@ -158135,7 +160873,7 @@ "objCls" : "Chemical", "id" : "PA451341", "name" : "sevoflurane", - "version" : 9 + "version" : 34 } ], "relatedGenes" : [ @@ -158144,21 +160882,21 @@ "id" : "PA85", "symbol" : "CACNA1S", "name" : "calcium voltage-gated channel subunit alpha1 S", - "version" : 19 + "version" : 59 }, { "objCls" : "Gene", "id" : "PA34896", "symbol" : "RYR1", "name" : "ryanodine receptor 1", - "version" : 131 + "version" : 7467 } ], "source" : "FDA", "summaryMarkdown" : { "id" : 1447982407, "html" : "

The FDA-approved drug label for sevoflurane (ULTANE) states that it should not be used in patients with known or suspected susceptibility to malignant hyperthermia. Specific variants in the RYR1 and CACNA1S genes are associated with risk of malignant hyperthermia in individuals administered potent inhalational anesthetics, including sevoflurane. The label does not mention genetic testing.

\n", - "version" : 0 + "version" : 2 }, "terms" : [], "testing" : { @@ -158177,34 +160915,34 @@ "version" : 13 }, "userId" : "jmbarbarino", - "version" : 33 + "version" : 61 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166312621", - "name" : "Recommendation Annotation PA166312621", + "id" : "PA166312601", + "name" : "Recommendation Annotation PA166312601", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"RYR1": "No Result", "CACNA1S": "Uncertain Susceptibility"}, + "lookupKey" : {"RYR1": "Uncertain Susceptibility", "CACNA1S": "No Result"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451341", "name" : "sevoflurane", - "version" : 9 + "version" : 34 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166129519", "name" : "Annotation of FDA Label for sevoflurane and CACNA1S, RYR1", - "version" : 33 + "version" : 61 }, "text" : { - "id" : 1452218680, + "id" : 1452218665, "html" : "

"CONTRAINDICATIONS: Known or suspected genetic susceptibility to malignant hyperthermia...ULTANE [sevoflurane] can induce malignant hyperthermia in patients with known or suspected susceptibility based on genetic factors or family history, including those with certain inherited ryanodine receptor (RYR1) or dihydropyridine receptor (CACNA1S) variants." See label for more information.

\n", "version" : 0 }, @@ -158212,29 +160950,29 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312601", - "name" : "Recommendation Annotation PA166312601", + "id" : "PA166312621", + "name" : "Recommendation Annotation PA166312621", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"RYR1": "Uncertain Susceptibility", "CACNA1S": "No Result"}, + "lookupKey" : {"RYR1": "No Result", "CACNA1S": "Uncertain Susceptibility"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451341", "name" : "sevoflurane", - "version" : 9 + "version" : 34 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166129519", "name" : "Annotation of FDA Label for sevoflurane and CACNA1S, RYR1", - "version" : 33 + "version" : 61 }, "text" : { - "id" : 1452218665, + "id" : 1452218680, "html" : "

"CONTRAINDICATIONS: Known or suspected genetic susceptibility to malignant hyperthermia...ULTANE [sevoflurane] can induce malignant hyperthermia in patients with known or suspected susceptibility based on genetic factors or family history, including those with certain inherited ryanodine receptor (RYR1) or dihydropyridine receptor (CACNA1S) variants." See label for more information.

\n", "version" : 0 }, @@ -158242,29 +160980,29 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166311901", - "name" : "Recommendation Annotation PA166311901", + "id" : "PA166312602", + "name" : "Recommendation Annotation PA166312602", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"RYR1": "Malignant Hyperthermia Susceptibility", "CACNA1S": "No Result"}, + "lookupKey" : {"RYR1": "Uncertain Susceptibility", "CACNA1S": "Uncertain Susceptibility"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451341", "name" : "sevoflurane", - "version" : 9 + "version" : 34 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166129519", "name" : "Annotation of FDA Label for sevoflurane and CACNA1S, RYR1", - "version" : 33 + "version" : 61 }, "text" : { - "id" : 1452216100, + "id" : 1452218666, "html" : "

"CONTRAINDICATIONS: Known or suspected genetic susceptibility to malignant hyperthermia...ULTANE [sevoflurane] can induce malignant hyperthermia in patients with known or suspected susceptibility based on genetic factors or family history, including those with certain inherited ryanodine receptor (RYR1) or dihydropyridine receptor (CACNA1S) variants." See label for more information.

\n", "version" : 0 }, @@ -158284,14 +161022,14 @@ "objCls" : "Chemical", "id" : "PA451341", "name" : "sevoflurane", - "version" : 9 + "version" : 34 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166129519", "name" : "Annotation of FDA Label for sevoflurane and CACNA1S, RYR1", - "version" : 33 + "version" : 61 }, "text" : { "id" : 1452216080, @@ -158302,29 +161040,29 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166311883", - "name" : "Recommendation Annotation PA166311883", + "id" : "PA166311882", + "name" : "Recommendation Annotation PA166311882", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"RYR1": "Uncertain Susceptibility", "CACNA1S": "Malignant Hyperthermia Susceptibility"}, + "lookupKey" : {"RYR1": "No Result", "CACNA1S": "Malignant Hyperthermia Susceptibility"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451341", "name" : "sevoflurane", - "version" : 9 + "version" : 34 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166129519", "name" : "Annotation of FDA Label for sevoflurane and CACNA1S, RYR1", - "version" : 33 + "version" : 61 }, "text" : { - "id" : 1452216082, + "id" : 1452216081, "html" : "

"CONTRAINDICATIONS: Known or suspected genetic susceptibility to malignant hyperthermia...ULTANE [sevoflurane] can induce malignant hyperthermia in patients with known or suspected susceptibility based on genetic factors or family history, including those with certain inherited ryanodine receptor (RYR1) or dihydropyridine receptor (CACNA1S) variants." See label for more information.

\n", "version" : 0 }, @@ -158332,29 +161070,29 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312602", - "name" : "Recommendation Annotation PA166312602", + "id" : "PA166311883", + "name" : "Recommendation Annotation PA166311883", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"RYR1": "Uncertain Susceptibility", "CACNA1S": "Uncertain Susceptibility"}, + "lookupKey" : {"RYR1": "Uncertain Susceptibility", "CACNA1S": "Malignant Hyperthermia Susceptibility"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451341", "name" : "sevoflurane", - "version" : 9 + "version" : 34 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166129519", "name" : "Annotation of FDA Label for sevoflurane and CACNA1S, RYR1", - "version" : 33 + "version" : 61 }, "text" : { - "id" : 1452218666, + "id" : 1452216082, "html" : "

"CONTRAINDICATIONS: Known or suspected genetic susceptibility to malignant hyperthermia...ULTANE [sevoflurane] can induce malignant hyperthermia in patients with known or suspected susceptibility based on genetic factors or family history, including those with certain inherited ryanodine receptor (RYR1) or dihydropyridine receptor (CACNA1S) variants." See label for more information.

\n", "version" : 0 }, @@ -158362,29 +161100,29 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166311902", - "name" : "Recommendation Annotation PA166311902", + "id" : "PA166311901", + "name" : "Recommendation Annotation PA166311901", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"RYR1": "Malignant Hyperthermia Susceptibility", "CACNA1S": "Uncertain Susceptibility"}, + "lookupKey" : {"RYR1": "Malignant Hyperthermia Susceptibility", "CACNA1S": "No Result"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451341", "name" : "sevoflurane", - "version" : 9 + "version" : 34 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166129519", "name" : "Annotation of FDA Label for sevoflurane and CACNA1S, RYR1", - "version" : 33 + "version" : 61 }, "text" : { - "id" : 1452216101, + "id" : 1452216100, "html" : "

"CONTRAINDICATIONS: Known or suspected genetic susceptibility to malignant hyperthermia...ULTANE [sevoflurane] can induce malignant hyperthermia in patients with known or suspected susceptibility based on genetic factors or family history, including those with certain inherited ryanodine receptor (RYR1) or dihydropyridine receptor (CACNA1S) variants." See label for more information.

\n", "version" : 0 }, @@ -158392,29 +161130,29 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166311882", - "name" : "Recommendation Annotation PA166311882", + "id" : "PA166311902", + "name" : "Recommendation Annotation PA166311902", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"RYR1": "No Result", "CACNA1S": "Malignant Hyperthermia Susceptibility"}, + "lookupKey" : {"RYR1": "Malignant Hyperthermia Susceptibility", "CACNA1S": "Uncertain Susceptibility"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451341", "name" : "sevoflurane", - "version" : 9 + "version" : 34 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166129519", "name" : "Annotation of FDA Label for sevoflurane and CACNA1S, RYR1", - "version" : 33 + "version" : 61 }, "text" : { - "id" : 1452216081, + "id" : 1452216101, "html" : "

"CONTRAINDICATIONS: Known or suspected genetic susceptibility to malignant hyperthermia...ULTANE [sevoflurane] can induce malignant hyperthermia in patients with known or suspected susceptibility based on genetic factors or family history, including those with certain inherited ryanodine receptor (RYR1) or dihydropyridine receptor (CACNA1S) variants." See label for more information.

\n", "version" : 0 }, @@ -158452,7 +161190,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 3, + "version" : 4, "year" : -1 } ], @@ -158492,7 +161230,7 @@ "date" : "2023-03-07T00:00:00-08:00", "description" : "update with new PGx information including CYP2C9*5, *6, *8, *11", "type" : "Update", - "version" : 0 + "version" : 1 }, { "id" : 1452400860, @@ -158517,13 +161255,13 @@ "id" : "PA126", "symbol" : "CYP2C9", "name" : "cytochrome P450 family 2 subfamily C member 9", - "version" : 7877 + "version" : 7952 } ], "prescribingMarkdown" : { "id" : 1450400240, "html" : "

Excerpts from the siponimod drug label:

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MAYZENT is contraindicated in patients who have:

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Recommended Dosage in Patients With CYP2C9 Genotypes *1/*1, *1/*2, or *2/*2\nMaintenance Dosage\nAfter treatment titration (see Treatment Initiation), the recommended maintenance dosage of MAYZENT is 2 mg taken orally once daily starting on Day 6. Dosage adjustment is required in patients with a CYP2C9 *1/*3 or *2/*3 genotype (see Dosage and Administration (2.3)).

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Treatment Initiation\nInitiate MAYZENT with a 5-day titration, as shown in Table 1 (see Warnings and Precautions (5.3)). A starter pack should be used for patients who will be titrated to the 2-mg maintenance dosage (see How Supplied/Storage and Handling (16.1, 16.2)).

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Recommended Dosage in Patients With CYP2C9 Genotypes *1/*3 or *2/*3 .
\nMaintenance Dosage In patients with a CYP2C9 *1/*3 or *2/*3 genotype, after treatment titration (see Treatment Initiation), the recommended maintenance dosage of MAYZENT is 1 mg taken orally once daily starting on Day 5.

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Treatment Initiation Initiate MAYZENT with a 4-day titration, as shown in Table 2 (see Warnings and Precautions (5.3) and Use in Specific Populations (8.6)). Do not use the starter pack for patients who will be titrated to the 1-mg maintenance dosage.

\n
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Excerpts from the siponimod drug label:

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Test patients for CYP2C9 variants to determine CYP2C9 genotype (see Dosage and Administration (2.2, 2.3),\nContraindications (4), and Use in Specific Populations (8.6)). An FDA-cleared or -approved test for the detection of CYP2C9 variants to direct the use of siponimod is not currently available.

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Recommended Dosage in Patients With CYP2C9 Genotypes *1/*1, *1/*2, or *2/*2\nMaintenance Dosage\nAfter treatment titration (see Treatment Initiation), the recommended maintenance dosage of MAYZENT is 2 mg taken orally once daily starting on Day 6. Dosage adjustment is required in patients with a CYP2C9 *1/*3 or *2/*3 genotype (see Dosage and Administration (2.3)).

\n
\n
\n

Treatment Initiation\nInitiate MAYZENT with a 5-day titration, as shown in Table 1 (see Warnings and Precautions (5.3)). A starter pack should be used for patients who will be titrated to the 2-mg maintenance dosage (see How Supplied/Storage and Handling (16.1, 16.2)).

\n
\n
\n

Recommended Dosage in Patients With CYP2C9 Genotypes *1/*3 or *2/*3 .
\nMaintenance Dosage In patients with a CYP2C9 *1/*3 or *2/*3 genotype, after treatment titration (see Treatment Initiation), the recommended maintenance dosage of MAYZENT is 1 mg taken orally once daily starting on Day 5.

\n
\n
\n

Treatment Initiation Initiate MAYZENT with a 4-day titration, as shown in Table 2 (see Warnings and Precautions (5.3) and Use in Specific Populations (8.6)). Do not use the starter pack for patients who will be titrated to the 1-mg maintenance dosage.

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MAYZENT is contraindicated in patients who have:

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CYP2C9 genotype:

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Before initiation of treatment with MAYZENT, test patients to determine CYP2C9 genotype.

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MAYZENT is contraindicated in patients homozygous for CYP2C9*3 (i.e., CYP2C9*3/*3 genotype) because of substantially elevated siponimod plasma levels. The *3/*3 genotype is present in approximately 0.5% of white patients and 1% of Asian patients, and is less prevalent in other racial/ethnic groups.\nMAYZENT dosage adjustment is recommended in patients with CYP2C9*1/*3 or *2/*3 genotype because of an increase in exposure to siponimod (see Dosage and Administration (2.3) and Clinical Pharmacology (12.5)). The *1/*3 or *2/*3 genotypes are present in 2% to 20% of the population depending on ancestry.

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There are other less frequently occurring polymorphisms in CYP2C9. Some polymorphisms, such as *5, *6, *8, and *11, are associated with decreased or loss of enzyme function. The impact of variants other than *2 and *3 on the pharmacokinetics of siponimod has not been evaluated. It is anticipated that variants that result in loss of CYP2C9 function (e.g., *6) will have similar effects on siponimod pharmacokinetics as the *3 variant (see Dosage and Administration (2.3) and Clinical Pharmacology (12.5)).

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12.5 Pharmacogenomics

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The CYP2C9 genotype has a significant impact on siponimod metabolism. After a single dose of 0.25 mg siponimod, AUCinf and AUClast was approximately 2-and 4-fold higher in subjects with the CYP2C9*2/*3 and CYP2C9*3/*3 genotypes, respectively, while there was only a minor increase of Cmax by 21% and 16%, respectively, compared to extensive metabolizers (CYP2C9*1/*1). Mean half-life is prolonged in CYP2C9*2/*3 and CYP2C9*3/*3 carriers (51 hours and 126 hours, respectively).

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An apparent systemic clearance (CL/F) of about 3.11 L/h was estimated in CYP2C9 extensive metabolizer (CYP2C9*1/*1 and CYP2C9*1/*2) MS patients after multiple oral administrations of siponimod. Cl/F is 2.5, 1.9, 1.6, and 0.9 L/h in subjects with the CYP2C9*2/*2, CYP2C9*1/*3, CYP2C9*2/*3, and CYP2C9*3/*3 genotypes respectively. The resultant increase in siponimod AUC was approximatively 25, 61, 91, and 285% higher in CYP2C9*2/*2, CYP2C9*1/*3, CYP2C9*2/*3, and CYP2C9*3/*3 subjects, respectively, as compared to CYP2C9*1/*1 subjects (see Dosage and Administration (2.1, 2.3) and Contraindications (4)). As the apparent clearance estimated for CYP2C9*1*2 subjects is comparable to that of CYP2C9*1/*1 subjects, similar siponimod exposure is expected for both genotypes.

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Variants other than *2 and *3 may also lead to decreased or loss of CYP2C9 function (e.g., *5, *6, *8, *11) and may have substrate-specific effects. The frequency of certain CYP2C9 variants differs based on ancestry. The *2 and *3 variants are more prevalent in patients of European or Asian ancestry, while *5, *6, *8, and *11 are more prevalent in individuals of African ancestry (see Use in Specific Populations (8.6)).

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For the complete drug label text with sections containing pharmacogenetic information highlighted, see the siponimod drug label.

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*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

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"Maintenance Dosage In patients with a CYP2C9 *1/*3 or *2/*3 genotype, after treatment titration (see Treatment Initiation), the recommended maintenance dosage of MAYZENT is 1 mg taken orally once daily starting on Day 5." See label for more information.

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The MAYZENT (siponimod) label states: "Initiate MAYZENT with a 4-day titration, as shown in Table 2... Do not use the starter pack for patients who will be titrated to the 1-mg maintenance dosage." "In patients with a CYP2C9 *1/*3 or *2/*3 genotype, after treatment titration (see Treatment Initiation), the recommended maintenance dosage of MAYZENT is 1 mg taken orally once daily starting on Day 5." See label for more information.

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"Maintenance Dosage After treatment titration (see Treatment Initiation), the recommended maintenance dosage of MAYZENT is 2 mg taken orally once daily starting on Day 6." See label for more information.

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The MAYZENT (siponimod) label states: "Initiate MAYZENT with a 4-day titration, as shown in Table 2... Do not use the starter pack for patients who will be titrated to the 1-mg maintenance dosage." "In patients with a CYP2C9 *1/*3 or *2/*3 genotype, after treatment titration (see Treatment Initiation), the recommended maintenance dosage of MAYZENT is 1 mg taken orally once daily starting on Day 5." See label for more information.

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The MAYZENT (siponimod) label states: "MAYZENT is contraindicated in patients who have [a] CYP2C9*3/*3 genotype." See label for more information.

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"Maintenance Dosage After treatment titration (see Treatment Initiation), the recommended maintenance dosage of MAYZENT is 2 mg taken orally once daily starting on Day 6." See label for more information.

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The MAYZENT (siponimod) label states: "Recommended Dosage in Patients With CYP2C9 Genotypes *1/*1, *1/*2, or *2/*2" "Initiate MAYZENT with a 5-day titration, as shown in Table 1... A starter pack should be used for patients who will be titrated to the 2-mg maintenance dosage" "After treatment titration (see Treatment Initiation), the recommended maintenance dosage of MAYZENT is 2 mg taken orally once daily starting on Day 6." See label for more information.

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"Because patients with G6PD deficiency are at increased risk of a hemolytic crisis with sodium nitrite administration, alternative therapeutic approaches should be considered in these patients." See label for more information.

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"Because patients with G6PD deficiency are at increased risk of a hemolytic crisis with sodium nitrite administration, alternative therapeutic approaches should be considered in these patients." See label for more information.

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In case of known maternal history of ototoxicity due to aminoglycoside use or a known mitochondrial DNA variant in the patient, consider alternative treatments other than aminoglycosides unless the increased risk of permanent hearing loss is outweighed by the severity of infection and lack of safe and effective alternative therapies.

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Streptomycin is a bactericidal aminoglycoside antibiotic derived from Streptomyces griseus.

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Cases of ototoxicity with aminoglycosides have been observed in patients with certain variants in the mitochondrially encoded 12S rRNA gene (MT-RNR1), particularly the m.1555A>G variant. In case of known maternal history of ototoxicity due to aminoglycoside use or a known mitochondrial DNA variant in the patient, consider alternative treatments other than aminoglycosides unless the increased risk of permanent hearing loss is outweighed by the severity of infection and lack of safe and effective alternative therapies.

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Excerpts from the streptomycin label:

\n
\n

Cases of ototoxicity with aminoglycosides have been observed in patients with certain variants in the mitochondrially encoded 12S rRNA gene ( MT-RNR1), particularly the\nm.1555A>G variant. Ototoxicity occurred in some patients even when their aminoglycoside serum levels were within the recommended range. Mitochondrial DNA variants are present in less than 1% of the general US population, and the proportion of the variant carriers who may develop ototoxicity as well as the severity of ototoxicity is unknown. In case of known maternal history of ototoxicity due to aminoglycoside use or a known mitochondrial DNA variant in the patient, consider alternative treatments other than aminoglycosides unless the increased risk of permanent hearing loss is outweighed by the severity of infection and lack of safe and effective alternative therapies.

\n
\n

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the streptomycin drug label.

\n

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

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The streptomycin label states: "Cases of ototoxicity with aminoglycosides have been observed in patients with certain variants in the mitochondrially encoded 12S rRNA gene (MT-RNR1), particularly the m.1555A>G variant. ... In case of known maternal history of ototoxicity due to aminoglycoside use or a known mitochondrial DNA variant in the patient, consider alternative treatments other than aminoglycosides unless the increased risk of permanent hearing loss is outweighed by the severity of infection and lack of safe and effective alternative therapies." See label for more information.

\n", + "version" : 2 + }, + "version" : 2 + } + ], + "url" : "https://www.pharmgkb.org/labelAnnotation/PA166316361" + }, { "citations" : [ { @@ -159027,7 +161918,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 4, + "version" : 5, "year" : -1 } ], @@ -159071,21 +161962,21 @@ "id" : "PA25294", "symbol" : "BCHE", "name" : "butyrylcholinesterase", - "version" : 144 + "version" : 5492 }, { "objCls" : "Gene", "id" : "PA85", "symbol" : "CACNA1S", "name" : "calcium voltage-gated channel subunit alpha1 S", - "version" : 19 + "version" : 59 }, { "objCls" : "Gene", "id" : "PA34896", "symbol" : "RYR1", "name" : "ryanodine receptor 1", - "version" : 131 + "version" : 7467 } ], "prescribingMarkdown" : { @@ -159099,7 +161990,7 @@ "objCls" : "Chemical", "id" : "PA451522", "name" : "succinylcholine", - "version" : 7 + "version" : 26 } ], "relatedGenes" : [ @@ -159108,28 +161999,28 @@ "id" : "PA25294", "symbol" : "BCHE", "name" : "butyrylcholinesterase", - "version" : 144 + "version" : 5492 }, { "objCls" : "Gene", "id" : "PA85", "symbol" : "CACNA1S", "name" : "calcium voltage-gated channel subunit alpha1 S", - "version" : 19 + "version" : 59 }, { "objCls" : "Gene", "id" : "PA34896", "symbol" : "RYR1", "name" : "ryanodine receptor 1", - "version" : 131 + "version" : 7467 } ], "source" : "FDA", "summaryMarkdown" : { "id" : 1447982091, "html" : "

Succinylcholine (QUELICIN) is rapid acting, depolarizing skeletal muscle relaxant indicated as an adjunct to general anesthesia. The label warns that individuals who are carriers of the atypical variant of the plasma cholinesterase gene (BCHE) are at risk of prolonged apnea if administered succinylcholine. The label also notes the risk for malignant hyperthermia.

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Specific variants in the RYR1 and CACNA1S genes are associated with risk of malignant hyperthermia in individuals administered succinylcholine.

\n

Excerpts from the succinylcholine chloride (QUELICIN) drug label:

\n
\n

Succinylcholine is contraindicated in persons with personal or familial history of malignant hyperthermia, skeletal muscle myopathies, and known hypersensitivity to the drug.

\n
\n
\n

WARNINGS...Succinylcholine is metabolized by plasma cholinesterase and should be used with caution, if at all, in patients known to be or suspected of being homozygous for the atypical plasma cholinesterase gene.

\n
\n
\n

Patients homozygous for atypical plasma cholinesterase gene (1 in 2500 patients) are extremely sensitive to the neuromuscular blocking effect of succinylcholine. In these patients, a 5- to 10-mg test dose of succinylcholine may be administered to evaluate sensitivity to succinylcholine, or neuromuscular blockade may be produced by the cautious administration of a 1-mg/mL solution of succinylcholine by slow IV infusion. Apnea or prolonged muscle paralysis should be treated with controlled respiration.

\n
\n
\n

The risk of developing malignant hyperthermia increases with the concomitant administration of succinylcholine and volatile anesthetic agents. Anectine can induce malignant hyperthermia in patients with known or suspected susceptibility based on genetic factors or family history, including those with certain inherited ryanodine receptor (RYR1) or dihydropyridine receptor (CACNA1S) variants.

\n
\n
\n

Pharmacogenomics: RYR1 and CACNA1S are polymorphic genes, and multiple pathogenic variants have been associated with malignant hyperthermia susceptibility (MHS) in patients receiving succinylcholine, including Anectine. Case reports as well as ex-vivo studies have identified multiple variants in RYR1 and CACNA1S associated with MHS. Variant pathogenicity should be assessed based on prior clinical experience, functional studies, prevalence information, or other evidence.

\n
\n

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the succinylcholine drug label.

\n

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

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"ANECTINE [succinylcholine] is contraindicated in patients with...[k]nown or suspected genetic susceptibility to malignant hyperthermia...Anectine [succinylcholine] can induce malignant hyperthermia in patients with known or suspected susceptibility based on genetic factors or family history, including those with certain inherited ryanodine receptor (RYR1) or dihydropyridine receptor (CACNA1S) variants...Succinylcholine is metabolized by plasma cholinesterase and should be used with caution, if at all, in patients known to be or suspected of being homozygous for the atypical plasma cholinesterase gene [BCHE] ." See label for more information.

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"ANECTINE [succinylcholine] is contraindicated in patients with...[k]nown or suspected genetic susceptibility to malignant hyperthermia...Anectine [succinylcholine] can induce malignant hyperthermia in patients with known or suspected susceptibility based on genetic factors or family history, including those with certain inherited ryanodine receptor (RYR1) or dihydropyridine receptor (CACNA1S) variants...Succinylcholine is metabolized by plasma cholinesterase and should be used with caution, if at all, in patients known to be or suspected of being homozygous for the atypical plasma cholinesterase gene [BCHE] ." See label for more information.

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"ANECTINE [succinylcholine] is contraindicated in patients with...[k]nown or suspected genetic susceptibility to malignant hyperthermia...Anectine [succinylcholine] can induce malignant hyperthermia in patients with known or suspected susceptibility based on genetic factors or family history, including those with certain inherited ryanodine receptor (RYR1) or dihydropyridine receptor (CACNA1S) variants...Succinylcholine is metabolized by plasma cholinesterase and should be used with caution, if at all, in patients known to be or suspected of being homozygous for the atypical plasma cholinesterase gene [BCHE] ." See label for more information.

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"ANECTINE [succinylcholine] is contraindicated in patients with...[k]nown or suspected genetic susceptibility to malignant hyperthermia...Anectine [succinylcholine] can induce malignant hyperthermia in patients with known or suspected susceptibility based on genetic factors or family history, including those with certain inherited ryanodine receptor (RYR1) or dihydropyridine receptor (CACNA1S) variants." See label for more information.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166311926", - "name" : "Recommendation Annotation PA166311926", + "id" : "PA166311924", + "name" : "Recommendation Annotation PA166311924", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"RYR1": "Malignant Hyperthermia Susceptibility", "CACNA1S": "Uncertain Susceptibility"}, + "lookupKey" : {"RYR1": "Uncertain Susceptibility", "CACNA1S": "Malignant Hyperthermia Susceptibility"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451522", "name" : "succinylcholine", - "version" : 7 + "version" : 26 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166122970", "name" : "Annotation of FDA Label for succinylcholine and BCHE, CACNA1S, RYR1", - "version" : 41 + "version" : 91 }, "text" : { - "id" : 1452216125, + "id" : 1452216123, "html" : "

"ANECTINE [succinylcholine] is contraindicated in patients with...[k]nown or suspected genetic susceptibility to malignant hyperthermia...Anectine [succinylcholine] can induce malignant hyperthermia in patients with known or suspected susceptibility based on genetic factors or family history, including those with certain inherited ryanodine receptor (RYR1) or dihydropyridine receptor (CACNA1S) variants." See label for more information.

\n", "version" : 0 }, @@ -159333,59 +162224,59 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312605", - "name" : "Recommendation Annotation PA166312605", + "id" : "PA166311925", + "name" : "Recommendation Annotation PA166311925", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"RYR1": "Uncertain Susceptibility", "CACNA1S": "No Result"}, - "otherPrescribingGuidance" : true, + "lookupKey" : {"RYR1": "Malignant Hyperthermia Susceptibility", "CACNA1S": "No Result"}, + "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451522", "name" : "succinylcholine", - "version" : 7 + "version" : 26 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166122970", "name" : "Annotation of FDA Label for succinylcholine and BCHE, CACNA1S, RYR1", - "version" : 41 + "version" : 91 }, "text" : { - "id" : 1452218673, - "html" : "

"ANECTINE [succinylcholine] is contraindicated in patients with...[k]nown or suspected genetic susceptibility to malignant hyperthermia...Anectine [succinylcholine] can induce malignant hyperthermia in patients with known or suspected susceptibility based on genetic factors or family history, including those with certain inherited ryanodine receptor (RYR1) or dihydropyridine receptor (CACNA1S) variants...Succinylcholine is metabolized by plasma cholinesterase and should be used with caution, if at all, in patients known to be or suspected of being homozygous for the atypical plasma cholinesterase gene [BCHE] ." See label for more information.

\n", + "id" : 1452216124, + "html" : "

"ANECTINE [succinylcholine] is contraindicated in patients with...[k]nown or suspected genetic susceptibility to malignant hyperthermia...Anectine [succinylcholine] can induce malignant hyperthermia in patients with known or suspected susceptibility based on genetic factors or family history, including those with certain inherited ryanodine receptor (RYR1) or dihydropyridine receptor (CACNA1S) variants." See label for more information.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166311924", - "name" : "Recommendation Annotation PA166311924", + "id" : "PA166311926", + "name" : "Recommendation Annotation PA166311926", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"RYR1": "Uncertain Susceptibility", "CACNA1S": "Malignant Hyperthermia Susceptibility"}, + "lookupKey" : {"RYR1": "Malignant Hyperthermia Susceptibility", "CACNA1S": "Uncertain Susceptibility"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451522", "name" : "succinylcholine", - "version" : 7 + "version" : 26 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166122970", "name" : "Annotation of FDA Label for succinylcholine and BCHE, CACNA1S, RYR1", - "version" : 41 + "version" : 91 }, "text" : { - "id" : 1452216123, + "id" : 1452216125, "html" : "

"ANECTINE [succinylcholine] is contraindicated in patients with...[k]nown or suspected genetic susceptibility to malignant hyperthermia...Anectine [succinylcholine] can induce malignant hyperthermia in patients with known or suspected susceptibility based on genetic factors or family history, including those with certain inherited ryanodine receptor (RYR1) or dihydropyridine receptor (CACNA1S) variants." See label for more information.

\n", "version" : 0 }, @@ -159423,7 +162314,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 4, + "version" : 5, "year" : -1 } ], @@ -159479,7 +162370,7 @@ "id" : "PA28469", "symbol" : "G6PD", "name" : "glucose-6-phosphate dehydrogenase", - "version" : 135 + "version" : 1326 } ], "prescribingMarkdown" : { @@ -159493,7 +162384,7 @@ "objCls" : "Chemical", "id" : "PA451547", "name" : "sulfasalazine", - "version" : 10 + "version" : 37 } ], "relatedGenes" : [ @@ -159502,21 +162393,21 @@ "id" : "PA28469", "symbol" : "G6PD", "name" : "glucose-6-phosphate dehydrogenase", - "version" : 135 + "version" : 1326 }, { "objCls" : "Gene", "id" : "PA18", "symbol" : "NAT2", "name" : "N-acetyltransferase 2", - "version" : 148 + "version" : 7191 } ], "source" : "FDA", "summaryMarkdown" : { "id" : 1447981759, "html" : "

Sulfasalazine (Azulfidine) is used to treat and prolong remission for ulcerative colitis. The label warns that people with G6PD are susceptible to hemolytic anemia on this drug. The label also notes that acetylator status may affect metabolism of the drug and risk for adverse events; acetylation status of an individual can be determined by examining genetic variants in the NAT2 gene. However, the label never mentions any specific gene with regard to inactivator or acetylator status.

\n", - "version" : 1 + "version" : 2 }, "terms" : [], "testing" : { @@ -159535,34 +162426,34 @@ "version" : 14 }, "userId" : "jmbarbarino", - "version" : 34 + "version" : 52 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166312421", - "name" : "Recommendation Annotation PA166312421", + "id" : "PA166315121", + "name" : "Recommendation Annotation PA166315121", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"G6PD": "Deficient"}, + "lookupKey" : {"G6PD": "Variable"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451547", "name" : "sulfasalazine", - "version" : 10 + "version" : 37 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104892", "name" : "Annotation of FDA Label for sulfasalazine and G6PD, NAT2", - "version" : 34 + "version" : 52 }, "text" : { - "id" : 1452216720, + "id" : 1452245660, "html" : "

"Patients with glucose-6 phosphate dehydrogenase deficiency should be observed closely for signs of hemolytic anemia. This reaction is frequently dose related. If toxic or hypersensitivity reactions occur, the drug should be discontinued immediately." See label for more information.

\n", "version" : 0 }, @@ -159582,14 +162473,14 @@ "objCls" : "Chemical", "id" : "PA451547", "name" : "sulfasalazine", - "version" : 10 + "version" : 37 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104892", "name" : "Annotation of FDA Label for sulfasalazine and G6PD, NAT2", - "version" : 34 + "version" : 52 }, "text" : { "id" : 1452216666, @@ -159600,29 +162491,29 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166315121", - "name" : "Recommendation Annotation PA166315121", + "id" : "PA166312421", + "name" : "Recommendation Annotation PA166312421", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"G6PD": "Variable"}, + "lookupKey" : {"G6PD": "Deficient"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451547", "name" : "sulfasalazine", - "version" : 10 + "version" : 37 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104892", "name" : "Annotation of FDA Label for sulfasalazine and G6PD, NAT2", - "version" : 34 + "version" : 52 }, "text" : { - "id" : 1452245660, + "id" : 1452216720, "html" : "

"Patients with glucose-6 phosphate dehydrogenase deficiency should be observed closely for signs of hemolytic anemia. This reaction is frequently dose related. If toxic or hypersensitivity reactions occur, the drug should be discontinued immediately." See label for more information.

\n", "version" : 0 }, @@ -159660,7 +162551,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 3, + "version" : 4, "year" : -1 } ], @@ -159689,7 +162580,7 @@ "id" : "PA28469", "symbol" : "G6PD", "name" : "glucose-6-phosphate dehydrogenase", - "version" : 135 + "version" : 1326 } ], "prescribingMarkdown" : { @@ -159703,7 +162594,7 @@ "objCls" : "Chemical", "id" : "PA166115580", "name" : "tafenoquine", - "version" : 6 + "version" : 8 } ], "relatedGenes" : [ @@ -159712,7 +162603,7 @@ "id" : "PA28469", "symbol" : "G6PD", "name" : "glucose-6-phosphate dehydrogenase", - "version" : 135 + "version" : 1326 } ], "source" : "FDA", @@ -159735,10 +162626,10 @@ "textMarkdown" : { "id" : 1450400319, "html" : "

Excerpts from the tafenoquine (ARAKODA) drug label:

\n
\n

All patients must be tested for glucose-6-phosphate dehydrogenase (G6PD) deficiency prior to\nprescribing ARAKODA.

\n
\n
\n

ARAKODA is contraindicated in:

\n\n
\n
\n

Hemolytic Anemia\nDue to the risk of hemolytic anemia in patients with G6PD deficiency, G6PD testing must be\nperformed before prescribing ARAKODA [see Contraindications (4)]. Due to the limitations\nwith G6PD tests, physicians need to be aware of residual risk of hemolysis and adequate medical\nsupport and follow-up to manage hemolytic risk should be available. Treatment with\nARAKODA is contraindicated in patients with G6PD deficiency or unknown G6PD status [see\nContraindications (4)]. In clinical trials, declines in hemoglobin levels were reported in some\nG6PD-normal patients [see Adverse Reactions (6.1)]. Monitor patients for clinical signs or\nsymptoms of hemolysis [see Warnings and Precautions (5.6)]. Advise patients to discontinue\nARAKODA and seek medical attention if signs of hemolysis occur.

\n
\n
\n

G6PD Deficiency in Pregnancy and Lactation .
\nPotential Harm to the Fetus\nThe use of ARAKODA during pregnancy may cause hemolytic anemia in a G6PD-deficient\nfetus. Even if a pregnant woman has normal levels of G6PD, the fetus could be G6PD deficient.\nAdvise females of reproductive potential that treatment with ARAKODA during pregnancy is\nnot recommended and to avoid pregnancy or use effective contraception during treatment and for\n3 months after the last dose of ARAKODA. If a pregnancy is detected during ARAKODA use,\ndiscontinue ARAKODA as soon as possible and switch to an alternative prophylactic drug for\nmalaria during pregnancy [see Use in Specific Populations (8.1 and 8.3)].
\nPotential Harm to the Breastfeeding Infant\nA G6PD-deficient infant may be at risk for hemolytic anemia from exposure to ARAKODA\nthrough breast milk. Infant G6PD status should be checked before breastfeeding begins.\nARAKODA is contraindicated in breastfeeding women when the infant is found to be G6PD\ndeficient or the G6PD status of the infant is unknown [see Contraindications (4)]. Advise the\nwoman with a G6PD-deficient infant or if the G6PD status of the infant is unknown not to\nbreastfeed during treatment with ARAKODA and for 3 months after the final dose [see Use in\nSpecific Populations (8.2)].

\n
\n

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the tafenoquine drug label.

\n

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

\n", - "version" : 0 + "version" : 1 }, "userId" : "rachel", - "version" : 11 + "version" : 18 }, "recommendations" : [ { @@ -159755,14 +162646,14 @@ "objCls" : "Chemical", "id" : "PA166115580", "name" : "tafenoquine", - "version" : 6 + "version" : 8 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166182739", "name" : "Annotation of FDA Label for tafenoquine and G6PD", - "version" : 11 + "version" : 18 }, "text" : { "id" : 1452245620, @@ -159785,14 +162676,14 @@ "objCls" : "Chemical", "id" : "PA166115580", "name" : "tafenoquine", - "version" : 6 + "version" : 8 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166182739", "name" : "Annotation of FDA Label for tafenoquine and G6PD", - "version" : 11 + "version" : 18 }, "text" : { "id" : 1452216552, @@ -159815,14 +162706,14 @@ "objCls" : "Chemical", "id" : "PA166115580", "name" : "tafenoquine", - "version" : 6 + "version" : 8 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166182739", "name" : "Annotation of FDA Label for tafenoquine and G6PD", - "version" : 11 + "version" : 18 }, "text" : { "id" : 1452216553, @@ -159863,7 +162754,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 5, + "version" : 6, "year" : -1 } ], @@ -159892,7 +162783,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "prescribingMarkdown" : { @@ -159906,7 +162797,7 @@ "objCls" : "Chemical", "id" : "PA451583", "name" : "tamsulosin", - "version" : 8 + "version" : 33 } ], "relatedGenes" : [ @@ -159915,7 +162806,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "FDA", @@ -159938,10 +162829,10 @@ "textMarkdown" : { "id" : 1448265297, "html" : "

Excerpts from the tamsulosin (FLOMAX) drug label:

\n
\n

Tamsulosin is extensively metabolized, mainly by CYP3A4 and CYP2D6.

\n
\n
\n

FLOMAX capsules should be used with caution...in patients known to be CYP2D6 poor metabolizers particularly at a dose higher than 0.4 mg (e.g., 0.8 mg).

\n
\n
\n

The effects of paroxetine (a strong inhibitor of CYP2D6) at 20 mg once daily for 9 days on the pharmacokinetics of a single FLOMAX capsule 0.4 mg dose was investigated in 24 healthy volunteers (age range 23 to 47 years). Concomitant treatment with paroxetine resulted in an increase in the Cmax and AUC of tamsulosin by a factor of 1.3 and 1.6, respectively...A similar increase in exposure is expected in CYP2D6 poor metabolizers (PM) as compared to extensive metabolizers (EM). A fraction of the population (about 7% of Caucasians and 2% of African Americans) are CYP2D6 PMs. Since CYP2D6 PMs cannot be readily identified and the potential for significant increase in tamsulosin exposure exists when FLOMAX 0.4 mg is co-administered with strong CYP3A4 inhibitors in CYP2D6 PMs, FLOMAX 0.4 mg capsules should not be used in combination with strong inhibitors of CYP3A4 (e.g., ketoconazole).

\n
\n

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the tamsulosin drug label.

\n

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

\n", - "version" : 7 + "version" : 10 }, "userId" : "jmbarbarino", - "version" : 26 + "version" : 45 }, "recommendations" : [ { @@ -159958,14 +162849,14 @@ "objCls" : "Chemical", "id" : "PA451583", "name" : "tamsulosin", - "version" : 8 + "version" : 33 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166160672", "name" : "Annotation of FDA Label for tamsulosin and CYP2D6", - "version" : 26 + "version" : 45 }, "text" : { "id" : 1452216520, @@ -160006,7 +162897,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 4, + "version" : 5, "year" : -1 } ], @@ -160042,13 +162933,13 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "prescribingMarkdown" : { "id" : 1450383072, "html" : "

Excerpts from the tetrabenazine drug label:

\n
\n

The maximum daily dose in PMs is 50 mg with a maximum single dose of 25 mg.

\n
\n
\n

The maximum daily dose in EMs and intermediate metabolizers (IMs) 100 mg with a maximum single dose of 37.5 mg.

\n
\n", - "version" : 2 + "version" : 3 }, "relatedAlleles" : [], "relatedChemicals" : [ @@ -160056,7 +162947,7 @@ "objCls" : "Chemical", "id" : "PA140222719", "name" : "tetrabenazine", - "version" : 8 + "version" : 28 } ], "relatedGenes" : [ @@ -160065,7 +162956,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "FDA", @@ -160088,191 +162979,191 @@ "textMarkdown" : { "id" : 1447981627, "html" : "

Tetrabenazine is used to treat Huntington's Disease chorea.

\n

Excerpts from the tetrabenazine drug label:

\n
\n

Patients requiring doses above 50 mg per day should be genotyped for the drug metabolizing enzyme CYP2D6 to determine if the patient is a poor metabolizer (PM) or an extensive metabolizer (EM).

\n

The maximum daily dose in PMs is 50 mg with a maximum single dose of 25 mg.

\n

The maximum daily dose in EMs and intermediate metabolizers (IMs) 100 mg with a maximum single dose of 37.5 mg.

\n
\n
\n

Before patients are given a daily dose of greater than 50 mg, they should be tested for the CYP2D6 gene to determine whether they are poor metabolizers (PMs) or extensive or intermediate metabolizers (EMs or IMs). When a dose of tetrabenazine is given to PMs, exposure will be substantially higher (about 3-fold for a-HTBZ and 9-fold for b-HTBZ) than it would be in EMs. The dosage should therefore be adjusted according to a patient's CYP2D6 metabolizer status by limiting the dose to 50 mg in patients who are CYP2D6 poor metabolizers.

\n
\n

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the tetrabenazine drug label.

\n

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

\n", - "version" : 11 + "version" : 14 }, "userId" : "jmbarbarino", - "version" : 28 + "version" : 47 }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166309041", - "name" : "Recommendation Annotation PA166309041", + "id" : "PA166309061", + "name" : "Recommendation Annotation PA166309061", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"CYP2D6": "0.0"}, + "lookupKey" : {"CYP2D6": "0.25"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA140222719", "name" : "tetrabenazine", - "version" : 8 + "version" : 28 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104829", "name" : "Annotation of FDA Label for tetrabenazine and CYP2D6", - "version" : 28 + "version" : 47 }, "text" : { - "id" : 1452198060, - "html" : "

"In [CYP2D6] PMs, the initial dose and titration is similar to EMs except that the recommended maximum single dose is 25 mg, and the recommended daily dose should not exceed a maximum of 50 mg." See label for more information

\n", - "version" : 0 + "id" : 1452198080, + "html" : "

"Genotyped patients who are identified as extensive (EMs) or intermediate metabolizers (IMs) of\nCYP2D6, who need doses of XENAZINE [tetrabenazine] above 50 mg per day, should be titrated up slowly at\nweekly intervals by 12.5 mg daily, to allow the identification of a tolerated dose that reduces\nchorea. Doses above 50 mg per day should be given in a three times a day regimen. The\nmaximum recommended daily dose is 100 mg and the maximum recommended single dose is\n37.5 mg. If adverse reactions such as akathisia, parkinsonism, depression, insomnia, anxiety or\nsedation occur, titration should be stopped and the dose should be reduced. If the adverse\nreaction does not resolve, consideration should be given to withdrawing XENAZINE [tetrabenazine] treatment\nor initiating other specific treatment." See label for more information

\n", + "version" : 2 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166309043", - "name" : "Recommendation Annotation PA166309043", + "id" : "PA166309048", + "name" : "Recommendation Annotation PA166309048", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"CYP2D6": "0.75"}, + "lookupKey" : {"CYP2D6": "2.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA140222719", "name" : "tetrabenazine", - "version" : 8 + "version" : 28 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104829", "name" : "Annotation of FDA Label for tetrabenazine and CYP2D6", - "version" : 28 + "version" : 47 }, "text" : { - "id" : 1452198062, + "id" : 1452198067, "html" : "

"Genotyped patients who are identified as extensive (EMs) or intermediate metabolizers (IMs) of\nCYP2D6, who need doses of XENAZINE [tetrabenazine] above 50 mg per day, should be titrated up slowly at\nweekly intervals by 12.5 mg daily, to allow the identification of a tolerated dose that reduces\nchorea. Doses above 50 mg per day should be given in a three times a day regimen. The\nmaximum recommended daily dose is 100 mg and the maximum recommended single dose is\n37.5 mg. If adverse reactions such as akathisia, parkinsonism, depression, insomnia, anxiety or\nsedation occur, titration should be stopped and the dose should be reduced. If the adverse\nreaction does not resolve, consideration should be given to withdrawing XENAZINE [tetrabenazine] treatment\nor initiating other specific treatment." See label for more information

\n", - "version" : 0 + "version" : 1 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166309045", - "name" : "Recommendation Annotation PA166309045", + "id" : "PA166309041", + "name" : "Recommendation Annotation PA166309041", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"CYP2D6": "1.25"}, + "lookupKey" : {"CYP2D6": "0.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA140222719", "name" : "tetrabenazine", - "version" : 8 + "version" : 28 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104829", "name" : "Annotation of FDA Label for tetrabenazine and CYP2D6", - "version" : 28 + "version" : 47 }, "text" : { - "id" : 1452198064, - "html" : "

"Genotyped patients who are identified as extensive (EMs) or intermediate metabolizers (IMs) of\nCYP2D6, who need doses of XENAZINE [tetrabenazine] above 50 mg per day, should be titrated up slowly at\nweekly intervals by 12.5 mg daily, to allow the identification of a tolerated dose that reduces\nchorea. Doses above 50 mg per day should be given in a three times a day regimen. The\nmaximum recommended daily dose is 100 mg and the maximum recommended single dose is\n37.5 mg. If adverse reactions such as akathisia, parkinsonism, depression, insomnia, anxiety or\nsedation occur, titration should be stopped and the dose should be reduced. If the adverse\nreaction does not resolve, consideration should be given to withdrawing XENAZINE [tetrabenazine] treatment\nor initiating other specific treatment." See label for more information

\n", - "version" : 0 + "id" : 1452198060, + "html" : "

"In [CYP2D6] PMs, the initial dose and titration is similar to EMs except that the recommended maximum single dose is 25 mg, and the recommended daily dose should not exceed a maximum of 50 mg." See label for more information

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"Genotyped patients who are identified as extensive (EMs) or intermediate metabolizers (IMs) of\nCYP2D6, who need doses of XENAZINE [tetrabenazine] above 50 mg per day, should be titrated up slowly at\nweekly intervals by 12.5 mg daily, to allow the identification of a tolerated dose that reduces\nchorea. Doses above 50 mg per day should be given in a three times a day regimen. The\nmaximum recommended daily dose is 100 mg and the maximum recommended single dose is\n37.5 mg. If adverse reactions such as akathisia, parkinsonism, depression, insomnia, anxiety or\nsedation occur, titration should be stopped and the dose should be reduced. If the adverse\nreaction does not resolve, consideration should be given to withdrawing XENAZINE [tetrabenazine] treatment\nor initiating other specific treatment." See label for more information

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"Genotyped patients who are identified as extensive (EMs) or intermediate metabolizers (IMs) of\nCYP2D6, who need doses of XENAZINE [tetrabenazine] above 50 mg per day, should be titrated up slowly at\nweekly intervals by 12.5 mg daily, to allow the identification of a tolerated dose that reduces\nchorea. Doses above 50 mg per day should be given in a three times a day regimen. The\nmaximum recommended daily dose is 100 mg and the maximum recommended single dose is\n37.5 mg. If adverse reactions such as akathisia, parkinsonism, depression, insomnia, anxiety or\nsedation occur, titration should be stopped and the dose should be reduced. If the adverse\nreaction does not resolve, consideration should be given to withdrawing XENAZINE [tetrabenazine] treatment\nor initiating other specific treatment." See label for more information

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"Genotyped patients who are identified as extensive (EMs) or intermediate metabolizers (IMs) of\nCYP2D6, who need doses of XENAZINE [tetrabenazine] above 50 mg per day, should be titrated up slowly at\nweekly intervals by 12.5 mg daily, to allow the identification of a tolerated dose that reduces\nchorea. Doses above 50 mg per day should be given in a three times a day regimen. The\nmaximum recommended daily dose is 100 mg and the maximum recommended single dose is\n37.5 mg. If adverse reactions such as akathisia, parkinsonism, depression, insomnia, anxiety or\nsedation occur, titration should be stopped and the dose should be reduced. If the adverse\nreaction does not resolve, consideration should be given to withdrawing XENAZINE [tetrabenazine] treatment\nor initiating other specific treatment." See label for more information

\n", - "version" : 0 + "version" : 2 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", @@ -160288,21 +163179,21 @@ "objCls" : "Chemical", "id" : "PA140222719", "name" : "tetrabenazine", - "version" : 8 + "version" : 28 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104829", "name" : "Annotation of FDA Label for tetrabenazine and CYP2D6", - "version" : 28 + "version" : 47 }, "text" : { "id" : 1452198063, "html" : "

"Genotyped patients who are identified as extensive (EMs) or intermediate metabolizers (IMs) of\nCYP2D6, who need doses of XENAZINE [tetrabenazine] above 50 mg per day, should be titrated up slowly at\nweekly intervals by 12.5 mg daily, to allow the identification of a tolerated dose that reduces\nchorea. Doses above 50 mg per day should be given in a three times a day regimen. The\nmaximum recommended daily dose is 100 mg and the maximum recommended single dose is\n37.5 mg. If adverse reactions such as akathisia, parkinsonism, depression, insomnia, anxiety or\nsedation occur, titration should be stopped and the dose should be reduced. If the adverse\nreaction does not resolve, consideration should be given to withdrawing XENAZINE [tetrabenazine] treatment\nor initiating other specific treatment." See label for more information

\n", - "version" : 0 + "version" : 2 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", @@ -160318,81 +163209,81 @@ "objCls" : "Chemical", "id" : "PA140222719", "name" : "tetrabenazine", - "version" : 8 + "version" : 28 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104829", "name" : "Annotation of FDA Label for tetrabenazine and CYP2D6", - "version" : 28 + "version" : 47 }, "text" : { "id" : 1452198065, "html" : "

"Genotyped patients who are identified as extensive (EMs) or intermediate metabolizers (IMs) of\nCYP2D6, who need doses of XENAZINE [tetrabenazine] above 50 mg per day, should be titrated up slowly at\nweekly intervals by 12.5 mg daily, to allow the identification of a tolerated dose that reduces\nchorea. Doses above 50 mg per day should be given in a three times a day regimen. The\nmaximum recommended daily dose is 100 mg and the maximum recommended single dose is\n37.5 mg. If adverse reactions such as akathisia, parkinsonism, depression, insomnia, anxiety or\nsedation occur, titration should be stopped and the dose should be reduced. If the adverse\nreaction does not resolve, consideration should be given to withdrawing XENAZINE [tetrabenazine] treatment\nor initiating other specific treatment." See label for more information

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"Genotyped patients who are identified as extensive (EMs) or intermediate metabolizers (IMs) of\nCYP2D6, who need doses of XENAZINE [tetrabenazine] above 50 mg per day, should be titrated up slowly at\nweekly intervals by 12.5 mg daily, to allow the identification of a tolerated dose that reduces\nchorea. Doses above 50 mg per day should be given in a three times a day regimen. The\nmaximum recommended daily dose is 100 mg and the maximum recommended single dose is\n37.5 mg. If adverse reactions such as akathisia, parkinsonism, depression, insomnia, anxiety or\nsedation occur, titration should be stopped and the dose should be reduced. If the adverse\nreaction does not resolve, consideration should be given to withdrawing XENAZINE [tetrabenazine] treatment\nor initiating other specific treatment." See label for more information

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"Genotyped patients who are identified as extensive (EMs) or intermediate metabolizers (IMs) of\nCYP2D6, who need doses of XENAZINE [tetrabenazine] above 50 mg per day, should be titrated up slowly at\nweekly intervals by 12.5 mg daily, to allow the identification of a tolerated dose that reduces\nchorea. Doses above 50 mg per day should be given in a three times a day regimen. The\nmaximum recommended daily dose is 100 mg and the maximum recommended single dose is\n37.5 mg. If adverse reactions such as akathisia, parkinsonism, depression, insomnia, anxiety or\nsedation occur, titration should be stopped and the dose should be reduced. If the adverse\nreaction does not resolve, consideration should be given to withdrawing XENAZINE [tetrabenazine] treatment\nor initiating other specific treatment." See label for more information

\n", - "version" : 0 + "version" : 1 }, - "version" : 0 + "version" : 2 } ], "url" : "https://www.pharmgkb.org/labelAnnotation/PA166104829" @@ -160426,7 +163317,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 4, + "version" : 5, "year" : -1 } ], @@ -160462,14 +163353,14 @@ "id" : "PA134963132", "symbol" : "NUDT15", "name" : "nudix hydrolase 15", - "version" : 11 + "version" : 39 }, { "objCls" : "Gene", "id" : "PA356", "symbol" : "TPMT", "name" : "thiopurine S-methyltransferase", - "version" : 7545 + "version" : 7628 } ], "prescribingMarkdown" : { @@ -160483,7 +163374,7 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "relatedGenes" : [ @@ -160492,21 +163383,21 @@ "id" : "PA134963132", "symbol" : "NUDT15", "name" : "nudix hydrolase 15", - "version" : 11 + "version" : 39 }, { "objCls" : "Gene", "id" : "PA356", "symbol" : "TPMT", "name" : "thiopurine S-methyltransferase", - "version" : 7545 + "version" : 7628 } ], "source" : "FDA", "summaryMarkdown" : { "id" : 1447981646, "html" : "

The FDA-approved drug label for thioguanine (TABLOID) says to consider testing for TPMT and NUDT15 deficiency in patients who experience severe bone marrow toxicities or repeated episodes of myelosuppression. It also says to reduce initial dosage in patients known to have homozygous TPMT or NUDT15 deficiency.

\n", - "version" : 2 + "version" : 4 }, "terms" : [], "testing" : { @@ -160522,98 +163413,68 @@ "textMarkdown" : { "id" : 1447981645, "html" : "

Thioguanine (TABLOID) is indicated for the treatment of acute nonlymphocytic leukemias. Excerpts from the thioguanine (TABLOID) drug label:

\n
\n

Consider testing for TPMT and NUDT15 deficiency in patients who experience severe bone marrow toxicities or repeated episodes of myelosuppression.

\n
\n
\n

Patients with homozygous deficiency of either TPMT or NUDT15 enzyme typically require 10% or less of the standard thioguanine dosage. Reduce initial dosage in patients who are known to have homozygous TPMT or NUDT15 deficiency. Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended thioguanine doses, but some require dose reduction based on toxicities. Patients who are heterozygous for both TPMT and NUDT15 may require more substantial dosage reductions. Reduce the dosage based on tolerability.

\n
\n

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the thioguanine drug label.

\n

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

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"Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended thioguanine doses, but some require dose reduction based on toxicities...Reduce the dosage based on tolerability." See label for more information.

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"Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended thioguanine doses, but some require dose reduction based on toxicities. Patients who are heterozygous for both TPMT and NUDT15 may require more substantial dosage reductions. Reduce the dosage based on tolerability." See label for more information.

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"Patients with homozygous deficiency of either TPMT or NUDT15 enzyme typically require 10% or less of the standard thioguanine dosage. Reduce initial dosage in patients who are known to have homozygous TPMT or NUDT15 deficiency." See label for more information.

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"Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended thioguanine doses, but some require dose reduction based on toxicities...Reduce the dosage based on tolerability." See label for more information.

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"Patients with homozygous deficiency of either TPMT or NUDT15 enzyme typically require 10% or less of the standard thioguanine dosage. Reduce initial dosage in patients who are known to have homozygous TPMT or NUDT15 deficiency." See label for more information.

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"Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended thioguanine doses, but some require dose reduction based on toxicities...Reduce the dosage based on tolerability." See label for more information.

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"Patients with homozygous deficiency of either TPMT or NUDT15 enzyme typically require 10% or less of the standard thioguanine dosage. Reduce initial dosage in patients who are known to have homozygous TPMT or NUDT15 deficiency." See label for more information.

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"Patients with homozygous deficiency of either TPMT or NUDT15 enzyme typically require 10% or less of the standard thioguanine dosage. Reduce initial dosage in patients who are known to have homozygous TPMT or NUDT15 deficiency." See label for more information.

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"Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended thioguanine doses, but some require dose reduction based on toxicities...Reduce the dosage based on tolerability." See label for more information.

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"Patients with homozygous deficiency of either TPMT or NUDT15 enzyme typically require 10% or less of the standard thioguanine dosage. Reduce initial dosage in patients who are known to have homozygous TPMT or NUDT15 deficiency." See label for more information.

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"Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended thioguanine doses, but some require dose reduction based on toxicities. Patients who are heterozygous for both TPMT and NUDT15 may require more substantial dosage reductions. Reduce the dosage based on tolerability." See label for more information.

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"Patients with homozygous deficiency of either TPMT or NUDT15 enzyme typically require 10% or less of the standard thioguanine dosage. Reduce initial dosage in patients who are known to have homozygous TPMT or NUDT15 deficiency." See label for more information.

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"Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended thioguanine doses, but some require dose reduction based on toxicities...Reduce the dosage based on tolerability." See label for more information.

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"Patients with homozygous deficiency of either TPMT or NUDT15 enzyme typically require 10% or less of the standard thioguanine dosage. Reduce initial dosage in patients who are known to have homozygous TPMT or NUDT15 deficiency." See label for more information.

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"Patients with homozygous deficiency of either TPMT or NUDT15 enzyme typically require 10% or less of the standard thioguanine dosage. Reduce initial dosage in patients who are known to have homozygous TPMT or NUDT15 deficiency." See label for more information.

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"Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended thioguanine doses, but some require dose reduction based on toxicities...Reduce the dosage based on tolerability." See label for more information.

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"Patients with homozygous deficiency of either TPMT or NUDT15 enzyme typically require 10% or less of the standard thioguanine dosage. Reduce initial dosage in patients who are known to have homozygous TPMT or NUDT15 deficiency." See label for more information.

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"Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended thioguanine doses, but some require dose reduction based on toxicities...Reduce the dosage based on tolerability." See label for more information.

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"Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended thioguanine doses, but some require dose reduction based on toxicities. Patients who are heterozygous for both TPMT and NUDT15 may require more substantial dosage reductions. Reduce the dosage based on tolerability." See label for more information.

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"Patients with homozygous deficiency of either TPMT or NUDT15 enzyme typically require 10% or less of the standard thioguanine dosage. Reduce initial dosage in patients who are known to have homozygous TPMT or NUDT15 deficiency." See label for more information.

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"Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended thioguanine doses, but some require dose reduction based on toxicities. Patients who are heterozygous for both TPMT and NUDT15 may require more substantial dosage reductions. Reduce the dosage based on tolerability." See label for more information.

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"Patients with homozygous deficiency of either TPMT or NUDT15 enzyme typically require 10% or less of the standard thioguanine dosage. Reduce initial dosage in patients who are known to have homozygous TPMT or NUDT15 deficiency." See label for more information.

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"Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended thioguanine doses, but some require dose reduction based on toxicities. Patients who are heterozygous for both TPMT and NUDT15 may require more substantial dosage reductions. Reduce the dosage based on tolerability." See label for more information.

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"Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended thioguanine doses, but some require dose reduction based on toxicities...Reduce the dosage based on tolerability." See label for more information.

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"Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended thioguanine doses, but some require dose reduction based on toxicities. Patients who are heterozygous for both TPMT and NUDT15 may require more substantial dosage reductions. Reduce the dosage based on tolerability." See label for more information.

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"Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended thioguanine doses, but some require dose reduction based on toxicities. Patients who are heterozygous for both TPMT and NUDT15 may require more substantial dosage reductions. Reduce the dosage based on tolerability." See label for more information.

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"Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended thioguanine doses, but some require dose reduction based on toxicities...Reduce the dosage based on tolerability." See label for more information.

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"Patients with homozygous deficiency of either TPMT or NUDT15 enzyme typically require 10% or less of the standard thioguanine dosage. Reduce initial dosage in patients who are known to have homozygous TPMT or NUDT15 deficiency." See label for more information.

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"Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended thioguanine doses, but some require dose reduction based on toxicities...Reduce the dosage based on tolerability." See label for more information.

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"Patients with homozygous deficiency of either TPMT or NUDT15 enzyme typically require 10% or less of the standard thioguanine dosage. Reduce initial dosage in patients who are known to have homozygous TPMT or NUDT15 deficiency." See label for more information.

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"Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended thioguanine doses, but some require dose reduction based on toxicities...Reduce the dosage based on tolerability." See label for more information.

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"Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended thioguanine doses, but some require dose reduction based on toxicities...Reduce the dosage based on tolerability." See label for more information.

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"Patients with homozygous deficiency of either TPMT or NUDT15 enzyme typically require 10% or less of the standard thioguanine dosage. Reduce initial dosage in patients who are known to have homozygous TPMT or NUDT15 deficiency." See label for more information.

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"Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended thioguanine doses, but some require dose reduction based on toxicities...Reduce the dosage based on tolerability." See label for more information.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312144", - "name" : "Recommendation Annotation PA166312144", + "id" : "PA166312142", + "name" : "Recommendation Annotation PA166312142", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "Possible Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "Possible Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104838", "name" : "Annotation of FDA Label for thioguanine and NUDT15, TPMT", - "version" : 30 + "version" : 52 }, "text" : { - "id" : 1452216383, + "id" : 1452216381, "html" : "

"Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended thioguanine doses, but some require dose reduction based on toxicities...Reduce the dosage based on tolerability." See label for more information.

\n", "version" : 0 }, @@ -161220,59 +164081,59 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312133", - "name" : "Recommendation Annotation PA166312133", + "id" : "PA166312143", + "name" : "Recommendation Annotation PA166312143", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104838", "name" : "Annotation of FDA Label for thioguanine and NUDT15, TPMT", - "version" : 30 + "version" : 52 }, "text" : { - "id" : 1452216372, - "html" : "

"Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended thioguanine doses, but some require dose reduction based on toxicities. Patients who are heterozygous for both TPMT and NUDT15 may require more substantial dosage reductions. Reduce the dosage based on tolerability." See label for more information.

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"Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended thioguanine doses, but some require dose reduction based on toxicities...Reduce the dosage based on tolerability." See label for more information.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312140", - "name" : "Recommendation Annotation PA166312140", + "id" : "PA166312144", + "name" : "Recommendation Annotation PA166312144", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Indeterminate"}, + "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "Possible Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104838", "name" : "Annotation of FDA Label for thioguanine and NUDT15, TPMT", - "version" : 30 + "version" : 52 }, "text" : { - "id" : 1452216379, + "id" : 1452216383, "html" : "

"Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended thioguanine doses, but some require dose reduction based on toxicities...Reduce the dosage based on tolerability." See label for more information.

\n", "version" : 0 }, @@ -161280,60 +164141,90 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312127", - "name" : "Recommendation Annotation PA166312127", + "id" : "PA166312145", + "name" : "Recommendation Annotation PA166312145", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Indeterminate"}, + "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104838", "name" : "Annotation of FDA Label for thioguanine and NUDT15, TPMT", - "version" : 30 + "version" : 52 }, "text" : { - "id" : 1452216366, - "html" : "

"Patients with homozygous deficiency of either TPMT or NUDT15 enzyme typically require 10% or less of the standard thioguanine dosage. Reduce initial dosage in patients who are known to have homozygous TPMT or NUDT15 deficiency." See label for more information.

\n", + "id" : 1452216384, + "html" : "

"Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended thioguanine doses, but some require dose reduction based on toxicities...Reduce the dosage based on tolerability." See label for more information.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312129", - "name" : "Recommendation Annotation PA166312129", + "id" : "PA166312146", + "name" : "Recommendation Annotation PA166312146", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "No Result"}, + "lookupKey" : {"TPMT": "No Result", "NUDT15": "Possible Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104838", "name" : "Annotation of FDA Label for thioguanine and NUDT15, TPMT", - "version" : 30 + "version" : 52 }, "text" : { - "id" : 1452216368, - "html" : "

"Patients with homozygous deficiency of either TPMT or NUDT15 enzyme typically require 10% or less of the standard thioguanine dosage. Reduce initial dosage in patients who are known to have homozygous TPMT or NUDT15 deficiency." See label for more information.

\n", + "id" : 1452216385, + "html" : "

"Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended thioguanine doses, but some require dose reduction based on toxicities...Reduce the dosage based on tolerability." See label for more information.

\n", + "version" : 0 + }, + "version" : 0 + }, + { + "objCls" : "Recommendation Annotation", + "id" : "PA166312147", + "name" : "Recommendation Annotation PA166312147", + "alternateDrugAvailable" : false, + "dosingInformation" : true, + "implications" : [], + "lookupKey" : {"TPMT": "No Result", "NUDT15": "Intermediate Metabolizer"}, + "otherPrescribingGuidance" : false, + "relatedChemicals" : [ + { + "objCls" : "Chemical", + "id" : "PA451663", + "name" : "thioguanine", + "version" : 41 + } + ], + "source" : { + "objCls" : "Label Annotation", + "id" : "PA166104838", + "name" : "Annotation of FDA Label for thioguanine and NUDT15, TPMT", + "version" : 52 + }, + "text" : { + "id" : 1452216386, + "html" : "

"Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended thioguanine doses, but some require dose reduction based on toxicities...Reduce the dosage based on tolerability." See label for more information.

\n", "version" : 0 }, "version" : 0 @@ -161370,7 +164261,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 4, + "version" : 5, "year" : -1 } ], @@ -161406,7 +164297,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "prescribingMarkdown" : { @@ -161420,7 +164311,7 @@ "objCls" : "Chemical", "id" : "PA451666", "name" : "thioridazine", - "version" : 12 + "version" : 30 } ], "relatedGenes" : [ @@ -161429,7 +164320,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "FDA", @@ -161452,12 +164343,42 @@ "textMarkdown" : { "id" : 1447981577, "html" : "

Excerpts from the thioridazine drug label:

\n
\n

Therefore, thioridazine is contraindicated with these drugs as well as in patients, comprising about 7% of the normal population, who are known to have a genetic defect leading to reduced levels of activity of P450 2D6.

\n
\n
\n

Certain circumstances may increase the risk of Torsades de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval, including 1) bradycardia, 2) hypokalemia, 3) concomitant use of other drugs that prolong the QTc interval, 4) presence of congenital prolongation of the QT interval, and 5) for thioridazine in particular, its use in patients with reduced activity of P450 2D6 or its coadministration with drugs that may inhibit P450 2D6 or by some other mechanism interfere with the clearance of thioridazine.

\n
\n

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the thioridazine drug label.

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*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

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"...thioridazine is contraindicated...in patients, comprising about 7% of the normal population, who are known to have a genetic defect leading to reduced levels of activity of P450 2D6." See label for more information.

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"...thioridazine is contraindicated...in patients, comprising about 7% of the normal population, who are known to have a genetic defect leading to reduced levels of activity of P450 2D6." See label for more information.

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In case of known maternal history of ototoxicity due to aminoglycoside use or a known mitochondrial DNA variant in the patient, consider alternative treatments other than aminoglycosides unless the increased risk of permanent hearing loss is outweighed by the severity of infection and lack of safe and effective alternative therapies.

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Tobramycin (BETHKIS) is an inhaled aminoglycoside antibacterial indicated for the management of cystic fibrosis patients with Pseudomonas aeruginosa.

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Cases of ototoxicity with aminoglycosides have been observed in patients with certain variants in the mitochondrially encoded 12S rRNA gene (MT-RNR1), particularly the m.1555A>G variant. In case of known maternal history of ototoxicity due to aminoglycoside use or a known mitochondrial DNA variant in the patient, consider alternative treatments other than aminoglycosides unless the increased risk of permanent hearing loss is outweighed by the severity of infection and lack of safe and effective alternative therapies.

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Excerpt from the tobramycin (BETHKIS) label:

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Cases of ototoxicity with aminoglycosides have been observed in patients with certain variants in the mitochondrially encoded 12S rRNA gene (MT-RNR1), particularly the m.1555A>G variant. Ototoxicity occurred in some patients even when their aminoglycoside serum levels were within the recommended range. Mitochondrial DNA variants are present in less than 1% of the general US population, and the proportion of the variant carriers who may develop ototoxicity as well as the severity of ototoxicity is unknown. In case of known maternal history of ototoxicity due to aminoglycoside use or a known mitochondrial DNA variant in the patient, consider alternative treatments other than aminoglycosides unless the increased risk of permanent hearing loss is outweighed by the severity of infection and lack of safe and effective alternative therapies.

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For the complete drug label text with sections containing pharmacogenetic information highlighted, see the tobramycin drug label.

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*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

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"...thioridazine is contraindicated...in patients, comprising about 7% of the normal population, who are known to have a genetic defect leading to reduced levels of activity of P450 2D6." See label for more information.

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The tobramycin label states: "Cases of ototoxicity with aminoglycosides have been observed in patients with certain variants in the mitochondrially encoded 12S rRNA gene (MT-RNR1), particularly the m.1555A>G variant. ... In case of known maternal history of ototoxicity due to aminoglycoside use or a known mitochondrial DNA variant in the patient, consider alternative treatments other than aminoglycosides unless the increased risk of permanent hearing loss is outweighed by the severity of infection and lack of safe and effective alternative therapies." See label for more information.

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Excerpt from the tolazamide drug label:

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Treatment of patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency with sulfonylurea\nagents can lead to hemolytic anemia. Because tolazamide belongs to the class of sulfonylurea agents,\ncaution should be used in patients with G6PD deficiency and a non-sulfonylurea alternative should be\nconsidered. In post-marketing reports, hemolytic anemia has also been reported in patients who did not\nhave known G6PD deficiency.

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For the complete drug label text with sections containing pharmacogenetic information highlighted, see the tolazamide drug label.

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*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

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"Because tolazamide belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD deficiency and a non-sulfonylurea alternative should be considered." See label for more information.

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"Because tolazamide belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD deficiency and a non-sulfonylurea alternative should be considered." See label for more information.

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Excerpt from the tolbutamide drug label:

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Treatment of patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency with sulfonylurea agents can lead to hemolytic anemia. Because tolbutamide belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD deficiency and a non-sulfonylurea alternative should be considered. In post-marketing reports, hemolytic anemia has also been reported in patients who did not have known G6PD deficiency.

\n
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For the complete drug label text with sections containing pharmacogenetic information highlighted, see the tolbutamide drug label.

\n

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

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"Because tolbutamide belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD deficiency and a non-sulfonylurea alternative should be considered." See label for more information.

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"Because tolbutamide belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD deficiency and a non-sulfonylurea alternative should be considered." See label for more information.

\n", "version" : 0 }, @@ -162002,29 +165045,29 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166315102", - "name" : "Recommendation Annotation PA166315102", + "id" : "PA166312382", + "name" : "Recommendation Annotation PA166312382", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"G6PD": "Variable"}, + "lookupKey" : {"G6PD": "Deficient"}, "otherPrescribingGuidance" : true, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451718", "name" : "tolbutamide", - "version" : 10 + "version" : 36 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166182787", "name" : "Annotation of FDA Label for tolbutamide and G6PD", - "version" : 10 + "version" : 18 }, "text" : { - "id" : 1452245641, + "id" : 1452216662, "html" : "

"Because tolbutamide belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD deficiency and a non-sulfonylurea alternative should be considered." See label for more information.

\n", "version" : 0 }, @@ -162062,7 +165105,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 4, + "version" : 5, "year" : -1 } ], @@ -162104,7 +165147,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "prescribingMarkdown" : { @@ -162118,7 +165161,7 @@ "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "relatedGenes" : [ @@ -162127,14 +165170,14 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "FDA", "summaryMarkdown" : { "id" : 1447981548, "html" : "

The FDA-approved label for tramadol (ULTRAM) states that individuals who are CYP2D6 ultra-rapid metabolizers convert tramadol into its active metabolite more rapidly than other people, and that even at labeled dosage regimens they may have life-threatening or fatal respiratory depression; these individuals should not use tramadol.

\n", - "version" : 2 + "version" : 6 }, "terms" : [], "testing" : { @@ -162150,341 +165193,341 @@ "textMarkdown" : { "id" : 1447981547, "html" : "

On April 20th 2017, the FDA released a safety announcement stating that they are restricting the use of codeine and tramadol in children, and recommending against the use of codeine and tramadol in breastfeeding mothers due to possible harm to their infants. Please refer to the link above for full details on the safety announcement.

\n

Excerpts from the tramadol (ULTRAM) drug label:

\n
\n

ULTRA-RAPID METABOLISM OF TRAMADOL AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN. Life-threatening respiratory depression and death have occurred in children who received tramadol. Some of the reported cases following tonsillectomy and/or adenoidectomy; in at least one case, the child had evidence of being an ultra-rapid metabolizer of tramadol due to CYP2D6 polymorphism.

\n
\n
\n

Approximately 7% of the population has reduced activity of the CYPD2D6 isoenzyme...Based on a population PK analysis...concentrations of tramadol were approximately 20% higher in "poor metabolizers" versus "extensive metabolizers"...

\n
\n
\n

Tramadol is subject to the same polymorphic metabolism as codeine, with ultra-rapid metabolizers of CYP2D6 substrates being potentially exposed to life-threatening levels of the active metabolite O-desmethyltramadol (M1). At least one death was reported in a nursing infant who was exposed to high levels of morphine in breast milk because the mother was an ultra-rapid metabolizer of codeine.

\n
\n
\n

Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype...These individuals convert tramadol into its active metabolite, O-desmethyltramadol (M1), more rapidly and completely than other people. This rapid conversion results in higher than expected serum M1 levels. Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may have life-threatening or fatal respiratory depression...Therefore, individuals who are ultra-rapid metabolizers should not use ULTRAM.

\n
\n

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the tramadol drug label.

\n

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

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"... individuals who are ultra-rapid metabolizers should not use ULTRAM [tramadol]." See label for more information.

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"... individuals who are ultra-rapid metabolizers should not use ULTRAM [tramadol]." See label for more information.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166309422", - "name" : "Recommendation Annotation PA166309422", + "id" : "PA166309426", + "name" : "Recommendation Annotation PA166309426", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "3.0"}, + "lookupKey" : {"CYP2D6": "≥4.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104799", "name" : "Annotation of FDA Label for tramadol and CYP2D6", - "version" : 35 + "version" : 70 }, "text" : { - "id" : 1452203841, + "id" : 1452203845, "html" : "

"... individuals who are ultra-rapid metabolizers should not use ULTRAM [tramadol]." See label for more information.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166309424", - "name" : "Recommendation Annotation PA166309424", + "id" : "PA166309427", + "name" : "Recommendation Annotation PA166309427", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "≥3.25"}, + "lookupKey" : {"CYP2D6": "≥6.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104799", "name" : "Annotation of FDA Label for tramadol and CYP2D6", - "version" : 35 + "version" : 70 }, "text" : { - "id" : 1452203843, + "id" : 1452203846, "html" : "

"... individuals who are ultra-rapid metabolizers should not use ULTRAM [tramadol]." See label for more information.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166309426", - "name" : "Recommendation Annotation PA166309426", + "id" : "PA166309421", + "name" : "Recommendation Annotation PA166309421", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "≥4.0"}, + "lookupKey" : {"CYP2D6": "2.5"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104799", "name" : "Annotation of FDA Label for tramadol and CYP2D6", - "version" : 35 + "version" : 70 }, "text" : { - "id" : 1452203845, + "id" : 1452203840, "html" : "

"... individuals who are ultra-rapid metabolizers should not use ULTRAM [tramadol]." See label for more information.

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166309441", - "name" : "Recommendation Annotation PA166309441", + "id" : "PA166309425", + "name" : "Recommendation Annotation PA166309425", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "2.75"}, + "lookupKey" : {"CYP2D6": "≥3.5"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104799", "name" : "Annotation of FDA Label for tramadol and CYP2D6", - "version" : 35 + "version" : 70 }, "text" : { - "id" : 1452203860, + "id" : 1452203844, "html" : "

"... individuals who are ultra-rapid metabolizers should not use ULTRAM [tramadol]." See label for more information.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166309443", - "name" : "Recommendation Annotation PA166309443", + "id" : "PA166309442", + "name" : "Recommendation Annotation PA166309442", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "≥3.75"}, + "lookupKey" : {"CYP2D6": "≥3.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104799", "name" : "Annotation of FDA Label for tramadol and CYP2D6", - "version" : 35 + "version" : 70 }, "text" : { - "id" : 1452203862, + "id" : 1452203861, "html" : "

"... individuals who are ultra-rapid metabolizers should not use ULTRAM [tramadol]." See label for more information.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166309421", - "name" : "Recommendation Annotation PA166309421", + "id" : "PA166309423", + "name" : "Recommendation Annotation PA166309423", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "2.5"}, + "lookupKey" : {"CYP2D6": "4.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104799", "name" : "Annotation of FDA Label for tramadol and CYP2D6", - "version" : 35 + "version" : 70 }, "text" : { - "id" : 1452203840, + "id" : 1452203842, "html" : "

"... individuals who are ultra-rapid metabolizers should not use ULTRAM [tramadol]." See label for more information.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166309423", - "name" : "Recommendation Annotation PA166309423", + "id" : "PA166309422", + "name" : "Recommendation Annotation PA166309422", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "4.0"}, + "lookupKey" : {"CYP2D6": "3.0"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104799", "name" : "Annotation of FDA Label for tramadol and CYP2D6", - "version" : 35 + "version" : 70 }, "text" : { - "id" : 1452203842, + "id" : 1452203841, "html" : "

"... individuals who are ultra-rapid metabolizers should not use ULTRAM [tramadol]." See label for more information.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166309425", - "name" : "Recommendation Annotation PA166309425", + "id" : "PA166309441", + "name" : "Recommendation Annotation PA166309441", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "≥3.5"}, + "lookupKey" : {"CYP2D6": "2.75"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104799", "name" : "Annotation of FDA Label for tramadol and CYP2D6", - "version" : 35 + "version" : 70 }, "text" : { - "id" : 1452203844, + "id" : 1452203860, "html" : "

"... individuals who are ultra-rapid metabolizers should not use ULTRAM [tramadol]." See label for more information.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166309427", - "name" : "Recommendation Annotation PA166309427", + "id" : "PA166309424", + "name" : "Recommendation Annotation PA166309424", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "≥6.0"}, + "lookupKey" : {"CYP2D6": "≥3.25"}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104799", "name" : "Annotation of FDA Label for tramadol and CYP2D6", - "version" : 35 + "version" : 70 }, "text" : { - "id" : 1452203846, + "id" : 1452203843, "html" : "

"... individuals who are ultra-rapid metabolizers should not use ULTRAM [tramadol]." See label for more information.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/labelAnnotation/PA166104799" @@ -162518,7 +165561,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 4, + "version" : 5, "year" : -1 } ], @@ -162555,7 +165598,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "prescribingMarkdown" : { @@ -162569,7 +165612,7 @@ "objCls" : "Chemical", "id" : "PA166170051", "name" : "valbenazine", - "version" : 4 + "version" : 6 } ], "relatedGenes" : [ @@ -162578,7 +165621,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "FDA", @@ -162601,10 +165644,10 @@ "textMarkdown" : { "id" : 1448993493, "html" : "

Excerpts from the valbenazine (INGREZZA) drug label:

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\n

Dosage Recommendations for Known CYP2D6 Poor Metabolizers:

\n
\n
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The recommended dosage for known CYP2D6 poor metabolizers is INGREZZA 40 mg once daily.

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CYP2D6 Poor Metabolizers: Dosage reduction of INGREZZA is recommended for known CYP2D6 poor metabolizers. Increased exposure (Cmax and AUC) to valbenazine’s active metabolite is anticipated in CYP2D6 poor metabolizers. Increased exposure of active metabolite may increase the risk of exposure-related adverse reactions.

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For the complete drug label text with sections containing pharmacogenetic information highlighted, see the valbenazine drug label.

\n

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

\n", - "version" : 2 + "version" : 3 }, "userId" : "jmbarbarino", - "version" : 18 + "version" : 33 }, "recommendations" : [ { @@ -162621,21 +165664,21 @@ "objCls" : "Chemical", "id" : "PA166170051", "name" : "valbenazine", - "version" : 4 + "version" : 6 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166170052", "name" : "Annotation of FDA Label for valbenazine and CYP2D6", - "version" : 18 + "version" : 33 }, "text" : { "id" : 1452216551, "html" : "

"The recommended dosage for known CYP2D6 poor metabolizers is INGREZZA [valbenazine] 40 mg once daily." See label for more information

\n", - "version" : 0 + "version" : 1 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/labelAnnotation/PA166170052" @@ -162669,7 +165712,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 4, + "version" : 5, "year" : -1 } ], @@ -162712,7 +165755,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "prescribingMarkdown" : { @@ -162726,7 +165769,7 @@ "objCls" : "Chemical", "id" : "PA166122595", "name" : "vortioxetine", - "version" : 5 + "version" : 10 } ], "relatedGenes" : [ @@ -162735,14 +165778,14 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "source" : "FDA", "summaryMarkdown" : { "id" : 1447982109, "html" : "

Vortioxetine (TRINTELLIX) is indicated as a treatment for major depressive disorder. The FDA-approved drug label for vortioxetine notes that the maximum recommended dose in patients who are known CYP2D6 poor metabolizers is 10 mg/day.

\n", - "version" : 1 + "version" : 2 }, "terms" : [], "testing" : { @@ -162761,7 +165804,7 @@ "version" : 12 }, "userId" : "jmbarbarino", - "version" : 35 + "version" : 67 }, "recommendations" : [ { @@ -162778,21 +165821,21 @@ "objCls" : "Chemical", "id" : "PA166122595", "name" : "vortioxetine", - "version" : 5 + "version" : 10 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166122607", "name" : "Annotation of FDA Label for vortioxetine and CYP2D6", - "version" : 35 + "version" : 67 }, "text" : { "id" : 1452203900, "html" : "

"The maximum recommended dose of TRINTELLIX [vortioxetine] is 10 mg/day in known CYP2D6 poor metabolizers." See label for more information.

\n", "version" : 0 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/labelAnnotation/PA166122607" @@ -162826,7 +165869,7 @@ {"id":1452267780,"resource":"PharmGKB Tags","term":"Has PGx","termId":"pgkbTags:1452267780"} ], "type" : "Drug Label", - "version" : 4, + "version" : 5, "year" : -1 } ], @@ -162883,14 +165926,14 @@ "id" : "PA126", "symbol" : "CYP2C9", "name" : "cytochrome P450 family 2 subfamily C member 9", - "version" : 7877 + "version" : 7952 }, { "objCls" : "Gene", "id" : "PA133787052", "symbol" : "VKORC1", "name" : "vitamin K epoxide reductase complex subunit 1", - "version" : 16 + "version" : 52 } ], "prescribingMarkdown" : { @@ -162904,28 +165947,28 @@ "id" : "PA165816542", "symbol" : "CYP2C9*1", "name" : "*1", - "version" : 23 + "version" : 51 }, { "objCls" : "Haplotype", "id" : "PA165816543", "symbol" : "CYP2C9*2", "name" : "*2", - "version" : 23 + "version" : 52 }, { "objCls" : "Haplotype", "id" : "PA165816544", "symbol" : "CYP2C9*3", "name" : "*3", - "version" : 25 + "version" : 55 }, { "objCls" : "Variant", "id" : "PA166155091", "symbol" : "rs9923231", "name" : "rs9923231", - "version" : 5 + "version" : 10 } ], "relatedChemicals" : [ @@ -162933,7 +165976,7 @@ "objCls" : "Chemical", "id" : "PA451906", "name" : "warfarin", - "version" : 17 + "version" : 70 } ], "relatedGenes" : [ @@ -162942,35 +165985,35 @@ "id" : "PA126", "symbol" : "CYP2C9", "name" : "cytochrome P450 family 2 subfamily C member 9", - "version" : 7877 + "version" : 7952 }, { "objCls" : "Gene", "id" : "PA33799", "symbol" : "PROC", "name" : "protein C, inactivator of coagulation factors Va and VIIIa", - "version" : 34 + "version" : 157 }, { "objCls" : "Gene", "id" : "PA33809", "symbol" : "PROS1", "name" : "protein S", - "version" : 28 + "version" : 127 }, { "objCls" : "Gene", "id" : "PA133787052", "symbol" : "VKORC1", "name" : "vitamin K epoxide reductase complex subunit 1", - "version" : 16 + "version" : 52 } ], "source" : "FDA", "summaryMarkdown" : { "id" : 1447981534, "html" : "

Warfarin (COUMADIN) is an anticoagulant used as a prophylaxis and to treat venous thrombosis, pulmonary embolism, thromboembolic complications from atrial fibrillation and cardiac valve replacement, and to reduce the recurrence of myocardial infarction. Pharmacogenomics-related dosing information for CYP2C9 and VKORC1 variants is provided within the label. The drug label notes that deficiency in protein C (PROC) or protein S (PROS1) have been associated with tissue necrosis following warfarin administration.

\n", - "version" : 2 + "version" : 5 }, "terms" : [], "testing" : { @@ -162986,68 +166029,68 @@ "textMarkdown" : { "id" : 1447981533, "html" : "

The VKORC1:G-1639A polymorphism is associated with lower dose requirements for warfarin in Caucasian and Asian patients. Increased bleeding risk and lower initial warfarin dose requirements have been associated with the CYP2C9*2 and CYP2C9*3 alleles. Approximately 30% of the variance in warfarin dose could be attributed to genetic variation in VKORC1, and about 40% of dose variance could be explained taking into consideration both VKORC1 and CYP2C9 genetic polymorphisms. Accounting for genetic variation in both VKORC1 and CYP2C9, age, height, body weight, interacting drugs, and indication for warfarin therapy explained about 55% of the variability in warfarin dose.

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Excerpts from the warfarin (COUMADIN) drug label:

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Table 1 displays three ranges of expected maintenance COUMADIN doses observed in subgroups of patients having different combinations of CYP2C9 and VKORC1 gene variants...If the patient’s CYP2C9 and/or VKORC1 genotype are known, consider these ranges in choosing the initial dose. Patients with CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3 may require more prolonged time (>2 to 4 weeks) to achieve maximum INR effect for a given dosage regimen than patients without these CYP variants.

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Known or suspected deficiency in protein C mediated anticoagulant response: Hereditary or acquired deficiencies of protein C or its cofactor, protein S, have been associated with tissue necrosis following warfarin administration.

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For the complete drug label text with sections containing pharmacogenetic information highlighted, see the warfarin drug label. Pharmacogenomics-related dosing information is found in Table 5 on page 27.

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*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

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Table 1 in the drug label provides ranges of expected maintenance daily doses of warfarin (COUMADIN) based on CYP2C9*2, CYP2C9*3 and VKORC1−1639G>A (rs9923231) genotypes. For CYP2C9*2/*3, VKORC1 AA (rs9923231 TT), the range of expected maintenance daily dose is 0.5-2 mg.

\n", + "id" : 1452337687, + "html" : "

Table 1 in the drug label provides ranges of expected maintenance daily doses of warfarin (COUMADIN) based on CYP2C9*2, CYP2C9*3 and VKORC1−1639G>A (rs9923231) genotypes. For CYP2C9*3/*3, VKORC1 AA (rs9923231 TT), the range of expected maintenance daily dose is 0.5-2 mg.

\n", "version" : 0 }, "version" : 0 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166324243", - "name" : "Recommendation Annotation PA166324243", + "id" : "PA166324229", + "name" : "Recommendation Annotation PA166324229", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"CYP2C9": {"*1": 2}, "VKORC1": {"rs9923231 variant (T)": 1, "rs9923231 reference (C)": 1}}, + "lookupKey" : {"CYP2C9": {"*3": 2}, "VKORC1": {"rs9923231 reference (C)": 2}}, "otherPrescribingGuidance" : false, "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA451906", "name" : "warfarin", - "version" : 17 + "version" : 70 } ], "source" : { "objCls" : "Label Annotation", "id" : "PA166104776", "name" : "Annotation of FDA Label for warfarin and CYP2C9, PROC, PROS1, VKORC1", - "version" : 35 + "version" : 61 }, "text" : { - "id" : 1452337702, - "html" : "

Table 1 in the drug label provides ranges of expected maintenance daily doses of warfarin (COUMADIN) based on CYP2C9*2, CYP2C9*3 and VKORC1−1639G>A (rs9923231) genotypes. For CYP2C9*1/*1, VKORC1 AG (rs9923231TC), the range of expected maintenance daily dose is 5-7 mg.

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Table 1 in the drug label provides ranges of expected maintenance daily doses of warfarin (COUMADIN) based on CYP2C9*2, CYP2C9*3 and VKORC1−1639G>A (rs9923231) genotypes. For CYP2C9*3/*3, VKORC1 GG (rs9923231CC), the range of expected maintenance daily dose is 0.5-2 mg.

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Table 1 in the drug label provides ranges of expected maintenance daily doses of warfarin (COUMADIN) based on CYP2C9*2, CYP2C9*3 and VKORC1−1639G>A (rs9923231) genotypes. For CYP2C9*1/*1, VKORC1 GG (rs9923231CC), the range of expected maintenance daily dose is 5-7 mg.

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Table 1 in the drug label provides ranges of expected maintenance daily doses of warfarin (COUMADIN) based on CYP2C9*2, CYP2C9*3 and VKORC1−1639G>A (rs9923231) genotypes. For CYP2C9*2/*2, VKORC1 GG (rs9923231CC), the range of expected maintenance daily dose is 3-4 mg.

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Table 1 in the drug label provides ranges of expected maintenance daily doses of warfarin (COUMADIN) based on CYP2C9*2, CYP2C9*3 and VKORC1−1639G>A (rs9923231) genotypes. For CYP2C9*2/*3, VKORC1 GG (rs9923231CC), the range of expected maintenance daily dose is 3-4 mg.

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Table 1 in the drug label provides ranges of expected maintenance daily doses of warfarin (COUMADIN) based on CYP2C9*2, CYP2C9*3 and VKORC1−1639G>A (rs9923231) genotypes. For CYP2C9*2/*3, VKORC1 AA (rs9923231 TT), the range of expected maintenance daily dose is 0.5-2 mg.

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Table 1 in the drug label provides ranges of expected maintenance daily doses of warfarin (COUMADIN) based on CYP2C9*2, CYP2C9*3 and VKORC1−1639G>A (rs9923231) genotypes. For CYP2C9*1/*3, VKORC1 AA (rs9923231 TT), the range of expected maintenance daily dose is 0.5-2 mg.

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Table 1 in the drug label provides ranges of expected maintenance daily doses of warfarin (COUMADIN) based on CYP2C9*2, CYP2C9*3 and VKORC1−1639G>A (rs9923231) genotypes. For CYP2C9*2/*3, VKORC1 AG (rs9923231 TC), the range of expected maintenance daily dose is 0.5-2 mg.

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Table 1 in the drug label provides ranges of expected maintenance daily doses of warfarin (COUMADIN) based on CYP2C9*2, CYP2C9*3 and VKORC1−1639G>A (rs9923231) genotypes. For CYP2C9*3/*3, VKORC1 AA (rs9923231 TT), the range of expected maintenance daily dose is 0.5-2 mg.

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Table 1 in the drug label provides ranges of expected maintenance daily doses of warfarin (COUMADIN) based on CYP2C9*2, CYP2C9*3 and VKORC1−1639G>A (rs9923231) genotypes. For CYP2C9*2/*3, VKORC1 GG (rs9923231CC), the range of expected maintenance daily dose is 3-4 mg.

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Table 1 in the drug label provides ranges of expected maintenance daily doses of warfarin (COUMADIN) based on CYP2C9*2, CYP2C9*3 and VKORC1−1639G>A (rs9923231) genotypes. For CYP2C9*2/*3, VKORC1 AG (rs9923231 TC), the range of expected maintenance daily dose is 0.5-2 mg.

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Table 1 in the drug label provides ranges of expected maintenance daily doses of warfarin (COUMADIN) based on CYP2C9*2, CYP2C9*3 and VKORC1−1639G>A (rs9923231) genotypes. For CYP2C9*1/*1, VKORC1 AA (rs9923231 TT), the range of expected maintenance daily dose is 3-4 mg.

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Table 1 in the drug label provides ranges of expected maintenance daily doses of warfarin (COUMADIN) based on CYP2C9*2, CYP2C9*3 and VKORC1−1639G>A (rs9923231) genotypes. For CYP2C9*1/*2, VKORC1 AG (rs9923231TC), the range of expected maintenance daily dose is 3-4 mg.

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Table 1 in the drug label provides ranges of expected maintenance daily doses of warfarin (COUMADIN) based on CYP2C9*2, CYP2C9*3 and VKORC1−1639G>A (rs9923231) genotypes. For CYP2C9*1/*1, VKORC1 GG (rs9923231CC), the range of expected maintenance daily dose is 5-7 mg.

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Table 1 in the drug label provides ranges of expected maintenance daily doses of warfarin (COUMADIN) based on CYP2C9*2, CYP2C9*3 and VKORC1−1639G>A (rs9923231) genotypes. For CYP2C9*1/*3, VKORC1 GG (rs9923231CC), the range of expected maintenance daily dose is 3-4 mg.

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Table 1 in the drug label provides ranges of expected maintenance daily doses of warfarin (COUMADIN) based on CYP2C9*2, CYP2C9*3 and VKORC1−1639G>A (rs9923231) genotypes. For CYP2C9*2/*3, VKORC1 AG (rs9923231 TC), the range of expected maintenance daily dose is 0.5-2 mg.

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Table 1 in the drug label provides ranges of expected maintenance daily doses of warfarin (COUMADIN) based on CYP2C9*2, CYP2C9*3 and VKORC1−1639G>A (rs9923231) genotypes. For CYP2C9*2/*3, VKORC1 AG (rs9923231 TC), the range of expected maintenance daily dose is 0.5-2 mg.

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Table 1 in the drug label provides ranges of expected maintenance daily doses of warfarin (COUMADIN) based on CYP2C9*2, CYP2C9*3 and VKORC1−1639G>A (rs9923231) genotypes. For CYP2C9*2/*2, VKORC1 AA (rs9923231 TT), the range of expected maintenance daily dose is 0.5-2 mg.

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Table 1 in the drug label provides ranges of expected maintenance daily doses of warfarin (COUMADIN) based on CYP2C9*2, CYP2C9*3 and VKORC1−1639G>A (rs9923231) genotypes. For CYP2C9*2/*2, VKORC1 GG (rs9923231CC), the range of expected maintenance daily dose is 3-4 mg.

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Table 1 in the drug label provides ranges of expected maintenance daily doses of warfarin (COUMADIN) based on CYP2C9*2, CYP2C9*3 and VKORC1−1639G>A (rs9923231) genotypes. For CYP2C9*1/*1, VKORC1 AG (rs9923231TC), the range of expected maintenance daily dose is 5-7 mg.

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Table 1 in the drug label provides ranges of expected maintenance daily doses of warfarin (COUMADIN) based on CYP2C9*2, CYP2C9*3 and VKORC1−1639G>A (rs9923231) genotypes. For CYP2C9*2/*2, VKORC1 AA (rs9923231 TT), the range of expected maintenance daily dose is 0.5-2 mg.

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Table 1 in the drug label provides ranges of expected maintenance daily doses of warfarin (COUMADIN) based on CYP2C9*2, CYP2C9*3 and VKORC1−1639G>A (rs9923231) genotypes. For CYP2C9*1/*3, VKORC1 AA (rs9923231 TT), the range of expected maintenance daily dose is 0.5-2 mg.

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Table 1 in the drug label provides ranges of expected maintenance daily doses of warfarin (COUMADIN) based on CYP2C9*2, CYP2C9*3 and VKORC1−1639G>A (rs9923231) genotypes. For CYP2C9*1/*2, VKORC1 GG (rs9923231CC), the range of expected maintenance daily dose is 5-7 mg.

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Table 1 in the drug label provides ranges of expected maintenance daily doses of warfarin (COUMADIN) based on CYP2C9*2, CYP2C9*3 and VKORC1−1639G>A (rs9923231) genotypes. For CYP2C9*1/*3, VKORC1 AG (rs9923231 TC), the range of expected maintenance daily dose is 3-4 mg.

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Table 1 in the drug label provides ranges of expected maintenance daily doses of warfarin (COUMADIN) based on CYP2C9*2, CYP2C9*3 and VKORC1−1639G>A (rs9923231) genotypes. For CYP2C9*1/*1, VKORC1 AA (rs9923231 TT), the range of expected maintenance daily dose is 3-4 mg.

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Table 1 in the drug label provides ranges of expected maintenance daily doses of warfarin (COUMADIN) based on CYP2C9*2, CYP2C9*3 and VKORC1−1639G>A (rs9923231) genotypes. For CYP2C9*1/*3, VKORC1 GG (rs9923231CC), the range of expected maintenance daily dose is 3-4 mg.

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Table 1 in the drug label provides ranges of expected maintenance daily doses of warfarin (COUMADIN) based on CYP2C9*2, CYP2C9*3 and VKORC1−1639G>A (rs9923231) genotypes. For CYP2C9*3/*3, VKORC1 GG (rs9923231CC), the range of expected maintenance daily dose is 0.5-2 mg.

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Table 1 in the drug label provides ranges of expected maintenance daily doses of warfarin (COUMADIN) based on CYP2C9*2, CYP2C9*3 and VKORC1−1639G>A (rs9923231) genotypes. For CYP2C9*1/*2, VKORC1 AA (rs9923231\nTT), the range of expected maintenance daily dose is 3-4 mg.

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Table 1 in the drug label provides ranges of expected maintenance daily doses of warfarin (COUMADIN) based on CYP2C9*2, CYP2C9*3 and VKORC1−1639G>A (rs9923231) genotypes. For CYP2C9*1/*2, VKORC1 AA (rs9923231\nTT), the range of expected maintenance daily dose is 3-4 mg.

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Table 1 in the drug label provides ranges of expected maintenance daily doses of warfarin (COUMADIN) based on CYP2C9*2, CYP2C9*3 and VKORC1−1639G>A (rs9923231) genotypes. For CYP2C9*1/*2, VKORC1 AG (rs9923231TC), the range of expected maintenance daily dose is 3-4 mg.

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Table 1 in the drug label provides ranges of expected maintenance daily doses of warfarin (COUMADIN) based on CYP2C9*2, CYP2C9*3 and VKORC1−1639G>A (rs9923231) genotypes. For CYP2C9*1/*3, VKORC1 AG (rs9923231 TC), the range of expected maintenance daily dose is 3-4 mg.

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Table 1 in the drug label provides ranges of expected maintenance daily doses of warfarin (COUMADIN) based on CYP2C9*2, CYP2C9*3 and VKORC1−1639G>A (rs9923231) genotypes. For CYP2C9*1/*2, VKORC1 GG (rs9923231CC), the range of expected maintenance daily dose is 5-7 mg.

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"May alter systemic concentrations."

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"May alter systemic concentrations."

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"May alter systemic concentrations."

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"May alter systemic concentrations."

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"May alter systemic concentrations."

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"May alter systemic concentrations"

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"May alter systemic concentrations."

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"May alter systemic concentrations."

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"May alter systemic concentrations."

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"May alter systemic concentrations."

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"May alter systemic concentrations."

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"May alter systemic concentrations."

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"May alter systemic concentrations."

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"May alter systemic concentrations."

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"May alter systemic concentrations."

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"May alter systemic concentrations."

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"May alter systemic concentrations."

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"May alter systemic concentrations."

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\n", "version" : 0 }, @@ -167010,12 +170053,12 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166315858", - "name" : "Recommendation Annotation PA166315858", + "id" : "PA166315849", + "name" : "Recommendation Annotation PA166315849", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "2.75"}, + "lookupKey" : {"CYP2D6": "≥6.0"}, "otherPrescribingGuidance" : true, "population" : "Affected subgroup: CYP2D6 ultrarapid or poor metabolizers", "relatedChemicals" : [ @@ -167023,17 +170066,17 @@ "objCls" : "Chemical", "id" : "PA449394", "name" : "donepezil", - "version" : 6 + "version" : 27 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329638", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Demonstrate a Potential Impact on Pharmacokinetic Properties Only]: Donepezil - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452246837, + "id" : 1452246828, "html" : "

"Alters systemic concentrations."

\n", "version" : 0 }, @@ -167041,12 +170084,12 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166315856", - "name" : "Recommendation Annotation PA166315856", + "id" : "PA166315850", + "name" : "Recommendation Annotation PA166315850", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "4.0"}, + "lookupKey" : {"CYP2D6": "≥5.0"}, "otherPrescribingGuidance" : true, "population" : "Affected subgroup: CYP2D6 ultrarapid or poor metabolizers", "relatedChemicals" : [ @@ -167054,17 +170097,17 @@ "objCls" : "Chemical", "id" : "PA449394", "name" : "donepezil", - "version" : 6 + "version" : 27 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329638", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Demonstrate a Potential Impact on Pharmacokinetic Properties Only]: Donepezil - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452246835, + "id" : 1452246829, "html" : "

"Alters systemic concentrations."

\n", "version" : 0 }, @@ -167072,12 +170115,12 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166315854", - "name" : "Recommendation Annotation PA166315854", + "id" : "PA166315851", + "name" : "Recommendation Annotation PA166315851", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "≥3.25"}, + "lookupKey" : {"CYP2D6": "≥4.0"}, "otherPrescribingGuidance" : true, "population" : "Affected subgroup: CYP2D6 ultrarapid or poor metabolizers", "relatedChemicals" : [ @@ -167085,17 +170128,17 @@ "objCls" : "Chemical", "id" : "PA449394", "name" : "donepezil", - "version" : 6 + "version" : 27 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329638", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Demonstrate a Potential Impact on Pharmacokinetic Properties Only]: Donepezil - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452246833, + "id" : 1452246830, "html" : "

"Alters systemic concentrations."

\n", "version" : 0 }, @@ -167103,12 +170146,12 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166315851", - "name" : "Recommendation Annotation PA166315851", + "id" : "PA166315852", + "name" : "Recommendation Annotation PA166315852", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "≥4.0"}, + "lookupKey" : {"CYP2D6": "≥3.75"}, "otherPrescribingGuidance" : true, "population" : "Affected subgroup: CYP2D6 ultrarapid or poor metabolizers", "relatedChemicals" : [ @@ -167116,17 +170159,17 @@ "objCls" : "Chemical", "id" : "PA449394", "name" : "donepezil", - "version" : 6 + "version" : 27 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329638", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Demonstrate a Potential Impact on Pharmacokinetic Properties Only]: Donepezil - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452246830, + "id" : 1452246831, "html" : "

"Alters systemic concentrations."

\n", "version" : 0 }, @@ -167134,12 +170177,12 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166315848", - "name" : "Recommendation Annotation PA166315848", + "id" : "PA166315853", + "name" : "Recommendation Annotation PA166315853", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "0.0"}, + "lookupKey" : {"CYP2D6": "≥3.5"}, "otherPrescribingGuidance" : true, "population" : "Affected subgroup: CYP2D6 ultrarapid or poor metabolizers", "relatedChemicals" : [ @@ -167147,17 +170190,17 @@ "objCls" : "Chemical", "id" : "PA449394", "name" : "donepezil", - "version" : 6 + "version" : 27 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329638", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Demonstrate a Potential Impact on Pharmacokinetic Properties Only]: Donepezil - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452246827, + "id" : 1452246832, "html" : "

"Alters systemic concentrations."

\n", "version" : 0 }, @@ -167165,12 +170208,12 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166315859", - "name" : "Recommendation Annotation PA166315859", + "id" : "PA166315854", + "name" : "Recommendation Annotation PA166315854", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "2.5"}, + "lookupKey" : {"CYP2D6": "≥3.25"}, "otherPrescribingGuidance" : true, "population" : "Affected subgroup: CYP2D6 ultrarapid or poor metabolizers", "relatedChemicals" : [ @@ -167178,17 +170221,17 @@ "objCls" : "Chemical", "id" : "PA449394", "name" : "donepezil", - "version" : 6 + "version" : 27 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329638", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Demonstrate a Potential Impact on Pharmacokinetic Properties Only]: Donepezil - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452246838, + "id" : 1452246833, "html" : "

"Alters systemic concentrations."

\n", "version" : 0 }, @@ -167196,12 +170239,12 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166315857", - "name" : "Recommendation Annotation PA166315857", + "id" : "PA166315855", + "name" : "Recommendation Annotation PA166315855", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "3.0"}, + "lookupKey" : {"CYP2D6": "≥3.0"}, "otherPrescribingGuidance" : true, "population" : "Affected subgroup: CYP2D6 ultrarapid or poor metabolizers", "relatedChemicals" : [ @@ -167209,17 +170252,17 @@ "objCls" : "Chemical", "id" : "PA449394", "name" : "donepezil", - "version" : 6 + "version" : 27 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329638", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Demonstrate a Potential Impact on Pharmacokinetic Properties Only]: Donepezil - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452246836, + "id" : 1452246834, "html" : "

"Alters systemic concentrations."

\n", "version" : 0 }, @@ -167227,12 +170270,12 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166315853", - "name" : "Recommendation Annotation PA166315853", + "id" : "PA166315856", + "name" : "Recommendation Annotation PA166315856", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "≥3.5"}, + "lookupKey" : {"CYP2D6": "4.0"}, "otherPrescribingGuidance" : true, "population" : "Affected subgroup: CYP2D6 ultrarapid or poor metabolizers", "relatedChemicals" : [ @@ -167240,17 +170283,17 @@ "objCls" : "Chemical", "id" : "PA449394", "name" : "donepezil", - "version" : 6 + "version" : 27 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329638", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Demonstrate a Potential Impact on Pharmacokinetic Properties Only]: Donepezil - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452246832, + "id" : 1452246835, "html" : "

"Alters systemic concentrations."

\n", "version" : 0 }, @@ -167258,12 +170301,12 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166315855", - "name" : "Recommendation Annotation PA166315855", + "id" : "PA166315857", + "name" : "Recommendation Annotation PA166315857", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "≥3.0"}, + "lookupKey" : {"CYP2D6": "3.0"}, "otherPrescribingGuidance" : true, "population" : "Affected subgroup: CYP2D6 ultrarapid or poor metabolizers", "relatedChemicals" : [ @@ -167271,17 +170314,17 @@ "objCls" : "Chemical", "id" : "PA449394", "name" : "donepezil", - "version" : 6 + "version" : 27 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329638", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Demonstrate a Potential Impact on Pharmacokinetic Properties Only]: Donepezil - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452246834, + "id" : 1452246836, "html" : "

"Alters systemic concentrations."

\n", "version" : 0 }, @@ -167289,12 +170332,12 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166315852", - "name" : "Recommendation Annotation PA166315852", + "id" : "PA166315858", + "name" : "Recommendation Annotation PA166315858", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "≥3.75"}, + "lookupKey" : {"CYP2D6": "2.75"}, "otherPrescribingGuidance" : true, "population" : "Affected subgroup: CYP2D6 ultrarapid or poor metabolizers", "relatedChemicals" : [ @@ -167302,17 +170345,17 @@ "objCls" : "Chemical", "id" : "PA449394", "name" : "donepezil", - "version" : 6 + "version" : 27 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329638", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Demonstrate a Potential Impact on Pharmacokinetic Properties Only]: Donepezil - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452246831, + "id" : 1452246837, "html" : "

"Alters systemic concentrations."

\n", "version" : 0 }, @@ -167320,12 +170363,12 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166315850", - "name" : "Recommendation Annotation PA166315850", + "id" : "PA166315859", + "name" : "Recommendation Annotation PA166315859", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "≥5.0"}, + "lookupKey" : {"CYP2D6": "2.5"}, "otherPrescribingGuidance" : true, "population" : "Affected subgroup: CYP2D6 ultrarapid or poor metabolizers", "relatedChemicals" : [ @@ -167333,17 +170376,17 @@ "objCls" : "Chemical", "id" : "PA449394", "name" : "donepezil", - "version" : 6 + "version" : 27 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329638", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Demonstrate a Potential Impact on Pharmacokinetic Properties Only]: Donepezil - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452246829, + "id" : 1452246838, "html" : "

"Alters systemic concentrations."

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"Results in higher systemic concentrations."

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"Results in higher systemic concentrations."

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"Results in higher systemic concentrations."

\n", "version" : 0 }, @@ -167527,12 +170570,12 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166315861", - "name" : "Recommendation Annotation PA166315861", + "id" : "PA166315863", + "name" : "Recommendation Annotation PA166315863", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : true, "population" : "Affected subgroup: CYP2C19 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -167540,17 +170583,17 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329639", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Demonstrate a Potential Impact on Pharmacokinetic Properties Only]: Doxepin - CYP2C19", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452246840, + "id" : 1452246842, "html" : "

"Results in higher systemic concentrations."

\n", "version" : 0 }, @@ -167563,7 +170606,7 @@ "citations" : [ { "id" : 15155142, - "title" : "Table of Pharmacogenetic Associations", + "title" : "FDA Table of Pharmacogenetic Associations", "_sameAs" : "https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations", "authors" : [], "crossReferences" : [ @@ -167586,7 +170629,7 @@ "pgkbPublication" : false, "terms" : [], "type" : "Literature", - "version" : 0, + "version" : 2, "year" : -1 } ], @@ -167601,11 +170644,11 @@ "dosingInformation" : false, "history" : [], "literature" : [ - {"id":15155142,"title":"Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} + {"id":15155142,"title":"FDA Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} ], "originalDrugText" : "Doxepin", "originalGeneText" : "CYP2D6", - "otherPrescribingGuidance" : false, + "otherPrescribingGuidance" : true, "pediatric" : false, "relatedAlleles" : [], "relatedChemicals" : [ @@ -167613,7 +170656,7 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "relatedGenes" : [ @@ -167622,7 +170665,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "removed" : false, @@ -167635,18 +170678,18 @@ }, "terms" : [], "userId" : "pharmgkb", - "version" : 0, + "version" : 2, "versionDate" : "10/26/2022" }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166315638", - "name" : "Recommendation Annotation PA166315638", + "id" : "PA166315647", + "name" : "Recommendation Annotation PA166315647", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "0.25"}, + "lookupKey" : {"CYP2D6": "≥3.25"}, "otherPrescribingGuidance" : true, "population" : "Affected subgroup: CYP2D6 ultrarapid, intermediate, or poor metabolizers", "relatedChemicals" : [ @@ -167654,17 +170697,17 @@ "objCls" : "Chemical", "id" : "PA449409", "name" : "doxepin", - "version" : 9 + "version" : 38 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329640", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Demonstrate a Potential Impact on Pharmacokinetic Properties Only]: Doxepin - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452246557, + "id" : 1452246586, "html" : "

"May alter systemic concentrations."

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"May alter systemic concentrations."

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"May alter systemic concentrations."

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"May alter systemic concentrations."

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"May alter systemic concentrations."

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"May alter systemic concentrations."

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"May alter systemic concentrations."

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"May alter systemic concentrations."

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"May alter systemic concentrations."

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"May alter systemic concentrations."

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"May alter systemic concentrations."

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"May alter systemic concentrations."

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"Results in higher adverse reaction risk (severe skin reactions)."

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"May result in higher adverse reaction risk. Use with caution."

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"Results in lower systemic active metabolite concentrations and may result in reduced efficacy."

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"Results in higher systemic concentrations and higher adverse reaction risk (QT prolongation)."

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"Results in higher systemic concentrations and may have higher adverse reaction risk (heart failure). Dosage is based on individual response. The dose titration and monitoring schedule accounts for differences due to CYP2C19 genetic variation, so adjustments based on CYP2C19 genotype are not necessary. Refer to FDA labeling for specific dosing recommendations and monitoring."

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"Results in higher systemic concentrations and may have higher adverse reaction risk (heart failure). Dosage is based on individual response. The dose titration and monitoring schedule accounts for differences due to CYP2C19 genetic variation, so adjustments based on CYP2C19 genotype are not necessary. Refer to FDA labeling for specific dosing recommendations and monitoring."

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"Results in higher systemic concentrations and may have higher adverse reaction risk (heart failure). Dosage is based on individual response. The dose titration and monitoring schedule accounts for differences due to CYP2C19 genetic variation, so adjustments based on CYP2C19 genotype are not necessary. Refer to FDA labeling for specific dosing recommendations and monitoring."

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"Results in higher systemic concentrations and may have higher adverse reaction risk (heart failure). Dosage is based on individual response. The dose titration and monitoring schedule accounts for differences due to CYP2C19 genetic variation, so adjustments based on CYP2C19 genotype are not necessary. Refer to FDA labeling for specific dosing recommendations and monitoring."

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"Results in higher adverse reaction risk (hyperbilirubinemia)."

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"Results in higher adverse reaction risk (severe skin reactions). Patients positive for HLA-B*15:02 may be at increased risk of severe skin reactions with other drugs that are associated with a risk of Stevens Johnson Syndrome/Toxic Epidermal necrolysis (SJS/TEN). Genotyping is not a substitute for clinical vigilance."

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"Results in higher systemic concentrations and may result in higher adverse reaction risk. Dosage adjustment is recommended. Refer to FDA labeling for specific dosing recommendations."

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"Results in higher systemic concentrations and may result in higher adverse reaction risk. Dosage adjustment is recommended. Refer to FDA labeling for specific dosing recommendations."

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"Results in higher systemic concentrations and higher adverse reaction risk. Dosage adjustment is recommended. Refer to FDA labeling for specific dosing recommendations."

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"Results in higher systemic concentrations. Dosage adjustment is recommended. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 } ], "url" : "https://www.pharmgkb.org/fdaPgxAssociations#PA166329547" @@ -175990,7 +179073,7 @@ "citations" : [ { "id" : 15155142, - "title" : "Table of Pharmacogenetic Associations", + "title" : "FDA Table of Pharmacogenetic Associations", "_sameAs" : "https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations", "authors" : [], "crossReferences" : [ @@ -176013,7 +179096,7 @@ "pgkbPublication" : false, "terms" : [], "type" : "Literature", - "version" : 0, + "version" : 2, "year" : -1 } ], @@ -176025,10 +179108,10 @@ "alternateDrugAvailable" : false, "cancerGenome" : false, "crossReferences" : [], - "dosingInformation" : false, + "dosingInformation" : true, "history" : [], "literature" : [ - {"id":15155142,"title":"Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} + {"id":15155142,"title":"FDA Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} ], "originalDrugText" : "Atomoxetine", "originalGeneText" : "CYP2D6", @@ -176040,7 +179123,7 @@ "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "relatedGenes" : [ @@ -176049,7 +179132,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "removed" : false, @@ -176062,7 +179145,7 @@ }, "terms" : [], "userId" : "pharmgkb", - "version" : 0, + "version" : 2, "versionDate" : "10/26/2022" }, "recommendations" : [ @@ -176081,21 +179164,21 @@ "objCls" : "Chemical", "id" : "PA134688071", "name" : "atomoxetine", - "version" : 6 + "version" : 33 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329548", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Atomoxetine - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { "id" : 1452216400, "html" : "

"Results in higher systemic concentrations and higher adverse reaction risk. Adjust titration interval and increase dosage if tolerated. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 3 } ], "url" : "https://www.pharmgkb.org/fdaPgxAssociations#PA166329548" @@ -176104,7 +179187,7 @@ "citations" : [ { "id" : 15155142, - "title" : "Table of Pharmacogenetic Associations", + "title" : "FDA Table of Pharmacogenetic Associations", "_sameAs" : "https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations", "authors" : [], "crossReferences" : [ @@ -176127,7 +179210,7 @@ "pgkbPublication" : false, "terms" : [], "type" : "Literature", - "version" : 0, + "version" : 2, "year" : -1 } ], @@ -176136,13 +179219,13 @@ "id" : "PA166329549", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Azathioprine - TPMT and/or NUDT15", "affectedSubgroup" : "intermediate or poor metabolizers", - "alternateDrugAvailable" : false, + "alternateDrugAvailable" : true, "cancerGenome" : false, "crossReferences" : [], - "dosingInformation" : false, + "dosingInformation" : true, "history" : [], "literature" : [ - {"id":15155142,"title":"Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} + {"id":15155142,"title":"FDA Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} ], "originalDrugText" : "Azathioprine", "originalGeneText" : "TPMT and/or NUDT15", @@ -176154,7 +179237,7 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "relatedGenes" : [ @@ -176163,14 +179246,14 @@ "id" : "PA134963132", "symbol" : "NUDT15", "name" : "nudix hydrolase 15", - "version" : 11 + "version" : 39 }, { "objCls" : "Gene", "id" : "PA356", "symbol" : "TPMT", "name" : "thiopurine S-methyltransferase", - "version" : 7545 + "version" : 7628 } ], "removed" : false, @@ -176183,18 +179266,18 @@ }, "terms" : [], "userId" : "pharmgkb", - "version" : 0, + "version" : 2, "versionDate" : "10/26/2022" }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166310894", - "name" : "Recommendation Annotation PA166310894", + "id" : "PA166310883", + "name" : "Recommendation Annotation PA166310883", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Possible Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -176202,30 +179285,30 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329549", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Azathioprine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452213333, + "id" : 1452213322, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Consider alternative therapy in poor metabolizers. Dosage reduction is recommended in intermediate metabolizers for NUDT15 or TPMT. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166310891", - "name" : "Recommendation Annotation PA166310891", - "alternateDrugAvailable" : false, - "dosingInformation" : true, + "id" : "PA166310884", + "name" : "Recommendation Annotation PA166310884", + "alternateDrugAvailable" : true, + "dosingInformation" : false, "implications" : [], - "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Indeterminate"}, + "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -176233,30 +179316,30 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329549", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Azathioprine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452213330, + "id" : 1452213323, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Consider alternative therapy in poor metabolizers. Dosage reduction is recommended in intermediate metabolizers for NUDT15 or TPMT. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166310922", - "name" : "Recommendation Annotation PA166310922", - "alternateDrugAvailable" : false, - "dosingInformation" : true, + "id" : "PA166310862", + "name" : "Recommendation Annotation PA166310862", + "alternateDrugAvailable" : true, + "dosingInformation" : false, "implications" : [], - "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Indeterminate"}, + "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -176264,30 +179347,30 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329549", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Azathioprine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452213361, + "id" : 1452213301, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Consider alternative therapy in poor metabolizers. Dosage reduction is recommended in intermediate metabolizers for NUDT15 or TPMT. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166310895", - "name" : "Recommendation Annotation PA166310895", + "id" : "PA166310886", + "name" : "Recommendation Annotation PA166310886", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Possible Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -176295,30 +179378,30 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329549", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Azathioprine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452213334, + "id" : 1452213325, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Consider alternative therapy in poor metabolizers. Dosage reduction is recommended in intermediate metabolizers for NUDT15 or TPMT. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166310900", - "name" : "Recommendation Annotation PA166310900", - "alternateDrugAvailable" : false, - "dosingInformation" : true, + "id" : "PA166310881", + "name" : "Recommendation Annotation PA166310881", + "alternateDrugAvailable" : true, + "dosingInformation" : false, "implications" : [], - "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Normal Metabolizer"}, + "lookupKey" : {"TPMT": "No Result", "NUDT15": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -176326,30 +179409,30 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329549", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Azathioprine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452213339, + "id" : 1452213320, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Consider alternative therapy in poor metabolizers. Dosage reduction is recommended in intermediate metabolizers for NUDT15 or TPMT. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166310882", - "name" : "Recommendation Annotation PA166310882", - "alternateDrugAvailable" : true, - "dosingInformation" : false, + "id" : "PA166310887", + "name" : "Recommendation Annotation PA166310887", + "alternateDrugAvailable" : false, + "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "No Result"}, + "lookupKey" : {"TPMT": "No Result", "NUDT15": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -176357,30 +179440,30 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329549", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Azathioprine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452213321, + "id" : 1452213326, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Consider alternative therapy in poor metabolizers. Dosage reduction is recommended in intermediate metabolizers for NUDT15 or TPMT. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166310897", - "name" : "Recommendation Annotation PA166310897", - "alternateDrugAvailable" : false, - "dosingInformation" : true, + "id" : "PA166310863", + "name" : "Recommendation Annotation PA166310863", + "alternateDrugAvailable" : true, + "dosingInformation" : false, "implications" : [], - "lookupKey" : {"TPMT": "No Result", "NUDT15": "Possible Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -176388,30 +179471,30 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329549", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Azathioprine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452213336, + "id" : 1452213302, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Consider alternative therapy in poor metabolizers. Dosage reduction is recommended in intermediate metabolizers for NUDT15 or TPMT. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166310884", - "name" : "Recommendation Annotation PA166310884", - "alternateDrugAvailable" : true, - "dosingInformation" : false, + "id" : "PA166310889", + "name" : "Recommendation Annotation PA166310889", + "alternateDrugAvailable" : false, + "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Indeterminate"}, + "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -176419,30 +179502,30 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329549", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Azathioprine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452213323, + "id" : 1452213328, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Consider alternative therapy in poor metabolizers. Dosage reduction is recommended in intermediate metabolizers for NUDT15 or TPMT. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166310887", - "name" : "Recommendation Annotation PA166310887", + "id" : "PA166310890", + "name" : "Recommendation Annotation PA166310890", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "No Result", "NUDT15": "Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "No Result"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -176450,30 +179533,30 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329549", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Azathioprine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452213326, + "id" : 1452213329, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Consider alternative therapy in poor metabolizers. Dosage reduction is recommended in intermediate metabolizers for NUDT15 or TPMT. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166310863", - "name" : "Recommendation Annotation PA166310863", - "alternateDrugAvailable" : true, - "dosingInformation" : false, + "id" : "PA166310885", + "name" : "Recommendation Annotation PA166310885", + "alternateDrugAvailable" : false, + "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Poor Metabolizer"}, + "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -176481,30 +179564,30 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329549", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Azathioprine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452213302, + "id" : 1452213324, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Consider alternative therapy in poor metabolizers. Dosage reduction is recommended in intermediate metabolizers for NUDT15 or TPMT. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166310898", - "name" : "Recommendation Annotation PA166310898", + "id" : "PA166310891", + "name" : "Recommendation Annotation PA166310891", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Possible Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -176512,30 +179595,30 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329549", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Azathioprine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452213337, + "id" : 1452213330, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Consider alternative therapy in poor metabolizers. Dosage reduction is recommended in intermediate metabolizers for NUDT15 or TPMT. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166310889", - "name" : "Recommendation Annotation PA166310889", - "alternateDrugAvailable" : false, - "dosingInformation" : true, + "id" : "PA166310864", + "name" : "Recommendation Annotation PA166310864", + "alternateDrugAvailable" : true, + "dosingInformation" : false, "implications" : [], - "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Normal Metabolizer"}, + "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -176543,30 +179626,30 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329549", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Azathioprine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452213328, + "id" : 1452213303, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Consider alternative therapy in poor metabolizers. Dosage reduction is recommended in intermediate metabolizers for NUDT15 or TPMT. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166310865", - "name" : "Recommendation Annotation PA166310865", - "alternateDrugAvailable" : true, - "dosingInformation" : false, + "id" : "PA166310888", + "name" : "Recommendation Annotation PA166310888", + "alternateDrugAvailable" : false, + "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Normal Metabolizer"}, + "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -176574,30 +179657,30 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329549", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Azathioprine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452213304, + "id" : 1452213327, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Consider alternative therapy in poor metabolizers. Dosage reduction is recommended in intermediate metabolizers for NUDT15 or TPMT. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166310890", - "name" : "Recommendation Annotation PA166310890", + "id" : "PA166310921", + "name" : "Recommendation Annotation PA166310921", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "No Result"}, + "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -176605,30 +179688,30 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329549", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Azathioprine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452213329, + "id" : 1452213360, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Consider alternative therapy in poor metabolizers. Dosage reduction is recommended in intermediate metabolizers for NUDT15 or TPMT. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166310892", - "name" : "Recommendation Annotation PA166310892", - "alternateDrugAvailable" : true, - "dosingInformation" : false, + "id" : "PA166310922", + "name" : "Recommendation Annotation PA166310922", + "alternateDrugAvailable" : false, + "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Poor Metabolizer"}, + "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -176636,30 +179719,30 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329549", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Azathioprine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452213331, + "id" : 1452213361, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Consider alternative therapy in poor metabolizers. Dosage reduction is recommended in intermediate metabolizers for NUDT15 or TPMT. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166310921", - "name" : "Recommendation Annotation PA166310921", + "id" : "PA166310895", + "name" : "Recommendation Annotation PA166310895", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Possible Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -176667,30 +179750,30 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329549", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Azathioprine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452213360, + "id" : 1452213334, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Consider alternative therapy in poor metabolizers. Dosage reduction is recommended in intermediate metabolizers for NUDT15 or TPMT. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166310883", - "name" : "Recommendation Annotation PA166310883", - "alternateDrugAvailable" : true, - "dosingInformation" : false, + "id" : "PA166310900", + "name" : "Recommendation Annotation PA166310900", + "alternateDrugAvailable" : false, + "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -176698,30 +179781,30 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329549", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Azathioprine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452213322, + "id" : 1452213339, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Consider alternative therapy in poor metabolizers. Dosage reduction is recommended in intermediate metabolizers for NUDT15 or TPMT. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166310881", - "name" : "Recommendation Annotation PA166310881", - "alternateDrugAvailable" : true, - "dosingInformation" : false, + "id" : "PA166310901", + "name" : "Recommendation Annotation PA166310901", + "alternateDrugAvailable" : false, + "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "No Result", "NUDT15": "Poor Metabolizer"}, + "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "No Result"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -176729,30 +179812,30 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329549", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Azathioprine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452213320, + "id" : 1452213340, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Consider alternative therapy in poor metabolizers. Dosage reduction is recommended in intermediate metabolizers for NUDT15 or TPMT. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166310901", - "name" : "Recommendation Annotation PA166310901", + "id" : "PA166310896", + "name" : "Recommendation Annotation PA166310896", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "No Result"}, + "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "Possible Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -176760,30 +179843,30 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329549", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Azathioprine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452213340, + "id" : 1452213335, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Consider alternative therapy in poor metabolizers. Dosage reduction is recommended in intermediate metabolizers for NUDT15 or TPMT. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166310885", - "name" : "Recommendation Annotation PA166310885", + "id" : "PA166310897", + "name" : "Recommendation Annotation PA166310897", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "No Result", "NUDT15": "Possible Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -176791,30 +179874,30 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329549", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Azathioprine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452213324, + "id" : 1452213336, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Consider alternative therapy in poor metabolizers. Dosage reduction is recommended in intermediate metabolizers for NUDT15 or TPMT. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166310861", - "name" : "Recommendation Annotation PA166310861", - "alternateDrugAvailable" : true, - "dosingInformation" : false, + "id" : "PA166310898", + "name" : "Recommendation Annotation PA166310898", + "alternateDrugAvailable" : false, + "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Poor Metabolizer"}, + "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Possible Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -176822,30 +179905,30 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329549", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Azathioprine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452213300, + "id" : 1452213337, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Consider alternative therapy in poor metabolizers. Dosage reduction is recommended in intermediate metabolizers for NUDT15 or TPMT. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166310896", - "name" : "Recommendation Annotation PA166310896", + "id" : "PA166310899", + "name" : "Recommendation Annotation PA166310899", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "Possible Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "Possible Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -176853,30 +179936,30 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329549", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Azathioprine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452213335, + "id" : 1452213338, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Consider alternative therapy in poor metabolizers. Dosage reduction is recommended in intermediate metabolizers for NUDT15 or TPMT. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166310899", - "name" : "Recommendation Annotation PA166310899", - "alternateDrugAvailable" : false, - "dosingInformation" : true, + "id" : "PA166310892", + "name" : "Recommendation Annotation PA166310892", + "alternateDrugAvailable" : true, + "dosingInformation" : false, "implications" : [], - "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "Possible Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -176884,30 +179967,30 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329549", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Azathioprine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452213338, + "id" : 1452213331, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Consider alternative therapy in poor metabolizers. Dosage reduction is recommended in intermediate metabolizers for NUDT15 or TPMT. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166310886", - "name" : "Recommendation Annotation PA166310886", - "alternateDrugAvailable" : false, - "dosingInformation" : true, + "id" : "PA166310894", + "name" : "Recommendation Annotation PA166310894", + "alternateDrugAvailable" : true, + "dosingInformation" : false, "implications" : [], - "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Possible Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -176915,30 +179998,30 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329549", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Azathioprine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452213325, + "id" : 1452213333, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Consider alternative therapy in poor metabolizers. Dosage reduction is recommended in intermediate metabolizers for NUDT15 or TPMT. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166310862", - "name" : "Recommendation Annotation PA166310862", + "id" : "PA166310861", + "name" : "Recommendation Annotation PA166310861", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "Poor Metabolizer"}, + "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -176946,30 +180029,30 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329549", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Azathioprine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452213301, + "id" : 1452213300, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Consider alternative therapy in poor metabolizers. Dosage reduction is recommended in intermediate metabolizers for NUDT15 or TPMT. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166310888", - "name" : "Recommendation Annotation PA166310888", - "alternateDrugAvailable" : false, - "dosingInformation" : true, + "id" : "PA166310865", + "name" : "Recommendation Annotation PA166310865", + "alternateDrugAvailable" : true, + "dosingInformation" : false, "implications" : [], - "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -176977,30 +180060,30 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329549", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Azathioprine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452213327, + "id" : 1452213304, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Consider alternative therapy in poor metabolizers. Dosage reduction is recommended in intermediate metabolizers for NUDT15 or TPMT. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166310864", - "name" : "Recommendation Annotation PA166310864", + "id" : "PA166310882", + "name" : "Recommendation Annotation PA166310882", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "Poor Metabolizer"}, + "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "No Result"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -177008,21 +180091,21 @@ "objCls" : "Chemical", "id" : "PA448515", "name" : "azathioprine", - "version" : 26 + "version" : 57 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329549", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Azathioprine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452213303, + "id" : 1452213321, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Consider alternative therapy in poor metabolizers. Dosage reduction is recommended in intermediate metabolizers for NUDT15 or TPMT. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 } ], "url" : "https://www.pharmgkb.org/fdaPgxAssociations#PA166329549" @@ -177031,7 +180114,7 @@ "citations" : [ { "id" : 15155142, - "title" : "Table of Pharmacogenetic Associations", + "title" : "FDA Table of Pharmacogenetic Associations", "_sameAs" : "https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations", "authors" : [], "crossReferences" : [ @@ -177054,7 +180137,7 @@ "pgkbPublication" : false, "terms" : [], "type" : "Literature", - "version" : 0, + "version" : 2, "year" : -1 } ], @@ -177066,10 +180149,10 @@ "alternateDrugAvailable" : false, "cancerGenome" : false, "crossReferences" : [], - "dosingInformation" : false, + "dosingInformation" : true, "history" : [], "literature" : [ - {"id":15155142,"title":"Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} + {"id":15155142,"title":"FDA Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} ], "originalDrugText" : "Belinostat", "originalGeneText" : "UGT1A1", @@ -177081,7 +180164,7 @@ "objCls" : "Chemical", "id" : "PA165971474", "name" : "belinostat", - "version" : 5 + "version" : 12 } ], "relatedGenes" : [ @@ -177090,7 +180173,7 @@ "id" : "PA420", "symbol" : "UGT1A1", "name" : "UDP glucuronosyltransferase 1 family, polypeptide A1", - "version" : 6110 + "version" : 6350 } ], "removed" : false, @@ -177103,7 +180186,7 @@ }, "terms" : [], "userId" : "pharmgkb", - "version" : 0, + "version" : 2, "versionDate" : "10/26/2022" }, "recommendations" : [ @@ -177122,21 +180205,21 @@ "objCls" : "Chemical", "id" : "PA165971474", "name" : "belinostat", - "version" : 5 + "version" : 12 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329550", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Belinostat - UGT1A1", - "version" : 0 + "version" : 2 }, "text" : { "id" : 1452211680, "html" : "

"May result in higher systemic concentrations and higher adverse reaction risk. Reduce starting dose to 750 mg/m2 in poor metabolizers."

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"Results in higher systemic concentrations and may result in higher adverse reaction risk (anemia, hypoxia). Monitor patients who are poor metabolizers for both genes for adverse reactions."

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"Results in higher systemic concentrations and may result in higher adverse reaction risk (anemia, hypoxia). Monitor patients who are poor metabolizers for both genes for adverse reactions."

\n", - "version" : 0 + "version" : 2 }, - "version" : 0 + "version" : 5 } ], "url" : "https://www.pharmgkb.org/fdaPgxAssociations#PA166329551" @@ -177297,7 +180380,7 @@ "citations" : [ { "id" : 15155142, - "title" : "Table of Pharmacogenetic Associations", + "title" : "FDA Table of Pharmacogenetic Associations", "_sameAs" : "https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations", "authors" : [], "crossReferences" : [ @@ -177320,7 +180403,7 @@ "pgkbPublication" : false, "terms" : [], "type" : "Literature", - "version" : 0, + "version" : 2, "year" : -1 } ], @@ -177332,10 +180415,10 @@ "alternateDrugAvailable" : false, "cancerGenome" : false, "crossReferences" : [], - "dosingInformation" : false, + "dosingInformation" : true, "history" : [], "literature" : [ - {"id":15155142,"title":"Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} + {"id":15155142,"title":"FDA Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} ], "originalDrugText" : "Brexpiprazole", "originalGeneText" : "CYP2D6", @@ -177347,7 +180430,7 @@ "objCls" : "Chemical", "id" : "PA166160053", "name" : "brexpiprazole", - "version" : 5 + "version" : 8 } ], "relatedGenes" : [ @@ -177356,7 +180439,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "removed" : false, @@ -177369,7 +180452,7 @@ }, "terms" : [], "userId" : "pharmgkb", - "version" : 0, + "version" : 2, "versionDate" : "10/26/2022" }, "recommendations" : [ @@ -177388,21 +180471,21 @@ "objCls" : "Chemical", "id" : "PA166160053", "name" : "brexpiprazole", - "version" : 5 + "version" : 8 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329552", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Brexpiprazole - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { "id" : 1452216484, "html" : "

"Results in higher systemic concentrations. Dosage adjustment is recommended. Refer to FDA labeling for specific dosing recommendations."

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"Results in higher systemic concentrations and higher adverse reaction risk. Consider dosage reductions in poor metabolizers."

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"Results in higher systemic concentrations and higher adverse reaction risk. Consider dosage reductions in poor metabolizers."

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"Results in higher systemic concentrations and higher adverse reaction risk. Consider dosage reductions in poor metabolizers."

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"Results in higher systemic concentrations and higher adverse reaction risk. Consider dosage reductions in poor metabolizers."

\n", - "version" : 0 + "version" : 1 }, - "version" : 1 + "version" : 4 } ], "url" : "https://www.pharmgkb.org/fdaPgxAssociations#PA166329553" @@ -177618,7 +180701,7 @@ "citations" : [ { "id" : 15155142, - "title" : "Table of Pharmacogenetic Associations", + "title" : "FDA Table of Pharmacogenetic Associations", "_sameAs" : "https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations", "authors" : [], "crossReferences" : [ @@ -177641,7 +180724,7 @@ "pgkbPublication" : false, "terms" : [], "type" : "Literature", - "version" : 0, + "version" : 2, "year" : -1 } ], @@ -177650,17 +180733,17 @@ "id" : "PA166329554", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Capecitabine - DPYD", "affectedSubgroup" : "intermediate or poor metabolizers", - "alternateDrugAvailable" : false, + "alternateDrugAvailable" : true, "cancerGenome" : false, "crossReferences" : [], "dosingInformation" : false, "history" : [], "literature" : [ - {"id":15155142,"title":"Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} + {"id":15155142,"title":"FDA Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} ], "originalDrugText" : "Capecitabine", "originalGeneText" : "DPYD", - "otherPrescribingGuidance" : false, + "otherPrescribingGuidance" : true, "pediatric" : false, "relatedAlleles" : [], "relatedChemicals" : [ @@ -177668,7 +180751,7 @@ "objCls" : "Chemical", "id" : "PA448771", "name" : "capecitabine", - "version" : 21 + "version" : 60 } ], "relatedGenes" : [ @@ -177677,7 +180760,7 @@ "id" : "PA145", "symbol" : "DPYD", "name" : "dihydropyrimidine dehydrogenase", - "version" : 6907 + "version" : 6956 } ], "removed" : false, @@ -177690,18 +180773,18 @@ }, "terms" : [], "userId" : "pharmgkb", - "version" : 0, + "version" : 2, "versionDate" : "10/26/2022" }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166310722", - "name" : "Recommendation Annotation PA166310722", + "id" : "PA166310723", + "name" : "Recommendation Annotation PA166310723", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"DPYD": "1.0"}, + "lookupKey" : {"DPYD": "1.5"}, "otherPrescribingGuidance" : true, "population" : "Affected subgroup: DPYD intermediate or poor metabolizers", "relatedChemicals" : [ @@ -177709,52 +180792,52 @@ "objCls" : "Chemical", "id" : "PA448771", "name" : "capecitabine", - "version" : 21 + "version" : 60 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329554", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Capecitabine - DPYD", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452213161, + "id" : 1452213162, "html" : "

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"Results in higher adverse reaction risk (severe, life-threatening, or fatal toxicities). No dosage has proven safe in poor metabolizers, and insufficient data are available to recommend a dosage in intermediate metabolizers. Withhold or discontinue in the presence of early-onset or unusually severe toxicity."

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"Results in higher adverse reaction risk (severe, life-threatening, or fatal toxicities). No dosage has proven safe in poor metabolizers, and insufficient data are available to recommend a dosage in intermediate metabolizers. Withhold or discontinue in the presence of early-onset or unusually severe toxicity."

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"Results in higher adverse reaction risk (severe, life-threatening, or fatal toxicities). No dosage has proven safe in poor metabolizers, and insufficient data are available to recommend a dosage in intermediate metabolizers. Withhold or discontinue in the presence of early-onset or unusually severe toxicity."

\n", "version" : 0 }, - "version" : 0 + "version" : 3 } ], "url" : "https://www.pharmgkb.org/fdaPgxAssociations#PA166329554" @@ -177825,7 +180908,7 @@ "citations" : [ { "id" : 15155142, - "title" : "Table of Pharmacogenetic Associations", + "title" : "FDA Table of Pharmacogenetic Associations", "_sameAs" : "https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations", "authors" : [], "crossReferences" : [ @@ -177848,7 +180931,7 @@ "pgkbPublication" : false, "terms" : [], "type" : "Literature", - "version" : 0, + "version" : 2, "year" : -1 } ], @@ -177857,25 +180940,33 @@ "id" : "PA166329555", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Carbamazepine - HLA-B", "affectedSubgroup" : "*15:02 allele positive", - "alternateDrugAvailable" : false, + "alternateDrugAvailable" : true, "cancerGenome" : false, "crossReferences" : [], "dosingInformation" : false, "history" : [], "literature" : [ - {"id":15155142,"title":"Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} + {"id":15155142,"title":"FDA Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} ], "originalDrugText" : "Carbamazepine", "originalGeneText" : "HLA-B", "otherPrescribingGuidance" : false, "pediatric" : false, - "relatedAlleles" : [], + "relatedAlleles" : [ + { + "objCls" : "Haplotype", + "id" : "PA165954769", + "symbol" : "HLA-B*15:02", + "name" : "*15:02", + "version" : 21 + } + ], "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA448785", "name" : "carbamazepine", - "version" : 14 + "version" : 47 } ], "relatedGenes" : [ @@ -177884,7 +180975,7 @@ "id" : "PA35056", "symbol" : "HLA-B", "name" : "major histocompatibility complex, class I, B", - "version" : 40 + "version" : 2920 } ], "removed" : false, @@ -177897,7 +180988,7 @@ }, "terms" : [], "userId" : "pharmgkb", - "version" : 0, + "version" : 4, "versionDate" : "10/26/2022" }, "recommendations" : [ @@ -177916,21 +181007,21 @@ "objCls" : "Chemical", "id" : "PA448785", "name" : "carbamazepine", - "version" : 14 + "version" : 47 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329555", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Carbamazepine - HLA-B", - "version" : 0 + "version" : 4 }, "text" : { "id" : 1452213240, "html" : "

"Results in higher adverse reaction risk (severe skin reactions). Avoid use unless potential benefits outweigh risks and consider risks of alternative therapies. Patients positive for HLA-B*15:02 may be at increased risk of severe skin reactions with other drugs that are associated with a risk of Stevens Johnson Syndrome/Toxic Epidermal necrolysis (SJS/TEN). Genotyping is not a substitute for clinical vigilance."

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"Results in higher systemic concentrations. Reduce starting dose to half of the lowest recommended dose in poor metabolizers. Consider alternative therapy in poor metabolizers with juvenile rheumatoid arthritis."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312641", - "name" : "Recommendation Annotation PA166312641", + "id" : "PA166311941", + "name" : "Recommendation Annotation PA166311941", "alternateDrugAvailable" : true, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"CYP2C9": {"*1": 1, "*3": 1}}, + "lookupKey" : {"CYP2C9": "0.5"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: CYP2C9 poor metabolizers or *3 carriers", "relatedChemicals" : [ @@ -178061,21 +181152,21 @@ "objCls" : "Chemical", "id" : "PA448871", "name" : "celecoxib", - "version" : 22 + "version" : 43 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329556", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Celecoxib - CYP2C9", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452218940, + "id" : 1452216140, "html" : "

"Results in higher systemic concentrations. Reduce starting dose to half of the lowest recommended dose in poor metabolizers. Consider alternative therapy in poor metabolizers with juvenile rheumatoid arthritis."

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", @@ -178092,21 +181183,21 @@ "objCls" : "Chemical", "id" : "PA448871", "name" : "celecoxib", - "version" : 22 + "version" : 43 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329556", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Celecoxib - CYP2C9", - "version" : 0 + "version" : 2 }, "text" : { "id" : 1452216126, "html" : "

"Results in higher systemic concentrations. Reduce starting dose to half of the lowest recommended dose in poor metabolizers. Consider alternative therapy in poor metabolizers with juvenile rheumatoid arthritis."

\n", "version" : 0 }, - "version" : 0 + "version" : 3 } ], "url" : "https://www.pharmgkb.org/fdaPgxAssociations#PA166329556" @@ -178115,7 +181206,7 @@ "citations" : [ { "id" : 15155142, - "title" : "Table of Pharmacogenetic Associations", + "title" : "FDA Table of Pharmacogenetic Associations", "_sameAs" : "https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations", "authors" : [], "crossReferences" : [ @@ -178138,7 +181229,7 @@ "pgkbPublication" : false, "terms" : [], "type" : "Literature", - "version" : 0, + "version" : 2, "year" : -1 } ], @@ -178150,10 +181241,10 @@ "alternateDrugAvailable" : false, "cancerGenome" : false, "crossReferences" : [], - "dosingInformation" : false, + "dosingInformation" : true, "history" : [], "literature" : [ - {"id":15155142,"title":"Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} + {"id":15155142,"title":"FDA Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} ], "originalDrugText" : "Citalopram", "originalGeneText" : "CYP2C19", @@ -178165,7 +181256,7 @@ "objCls" : "Chemical", "id" : "PA449015", "name" : "citalopram", - "version" : 21 + "version" : 49 } ], "relatedGenes" : [ @@ -178174,7 +181265,7 @@ "id" : "PA124", "symbol" : "CYP2C19", "name" : "cytochrome P450 family 2 subfamily C member 19", - "version" : 7210 + "version" : 7266 } ], "removed" : false, @@ -178187,18 +181278,18 @@ }, "terms" : [], "userId" : "pharmgkb", - "version" : 0, + "version" : 2, "versionDate" : "10/26/2022" }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166309901", - "name" : "Recommendation Annotation PA166309901", + "id" : "PA166309921", + "name" : "Recommendation Annotation PA166309921", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: CYP2C19 poor metabolizers", "relatedChemicals" : [ @@ -178206,30 +181297,30 @@ "objCls" : "Chemical", "id" : "PA449015", "name" : "citalopram", - "version" : 21 + "version" : 49 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329557", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Citalopram - CYP2C19", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452208400, + "id" : 1452208420, "html" : "

"Results in higher systemic concentrations and adverse reaction risk (QT prolongation). The maximum recommended dose is 20 mg."

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"Results in higher systemic concentrations and adverse reaction risk (QT prolongation). The maximum recommended dose is 20 mg."

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"Results in higher systemic active metabolite concentrations. Poor metabolism results in higher adverse reaction risk. Dosage adjustment is recommended. Refer to FDA labeling for specific dosing recommendations."

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"Results in higher systemic active metabolite concentrations. Poor metabolism results in higher adverse reaction risk. Dosage adjustment is recommended. Refer to FDA labeling for specific dosing recommendations."

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"Results in higher systemic active metabolite concentrations. Poor metabolism results in higher adverse reaction risk. Dosage adjustment is recommended. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", @@ -178444,21 +181535,21 @@ "objCls" : "Chemical", "id" : "PA10888", "name" : "clobazam", - "version" : 11 + "version" : 27 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329558", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Clobazam - CYP2C19", - "version" : 0 + "version" : 2 }, "text" : { "id" : 1452198000, "html" : "

"Results in higher systemic active metabolite concentrations. Poor metabolism results in higher adverse reaction risk. Dosage adjustment is recommended. Refer to FDA labeling for specific dosing recommendations."

\n", - "version" : 0 + "version" : 1 }, - "version" : 0 + "version" : 5 } ], "url" : "https://www.pharmgkb.org/fdaPgxAssociations#PA166329558" @@ -178467,7 +181558,7 @@ "citations" : [ { "id" : 15155142, - "title" : "Table of Pharmacogenetic Associations", + "title" : "FDA Table of Pharmacogenetic Associations", "_sameAs" : "https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations", "authors" : [], "crossReferences" : [ @@ -178490,7 +181581,7 @@ "pgkbPublication" : false, "terms" : [], "type" : "Literature", - "version" : 0, + "version" : 2, "year" : -1 } ], @@ -178499,13 +181590,13 @@ "id" : "PA166329559", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Clopidogrel - CYP2C19", "affectedSubgroup" : "intermediate or poor metabolizers", - "alternateDrugAvailable" : false, + "alternateDrugAvailable" : true, "cancerGenome" : false, "crossReferences" : [], "dosingInformation" : false, "history" : [], "literature" : [ - {"id":15155142,"title":"Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} + {"id":15155142,"title":"FDA Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} ], "originalDrugText" : "Clopidogrel", "originalGeneText" : "CYP2C19", @@ -178517,7 +181608,7 @@ "objCls" : "Chemical", "id" : "PA449053", "name" : "clopidogrel", - "version" : 20 + "version" : 58 } ], "relatedGenes" : [ @@ -178526,7 +181617,7 @@ "id" : "PA124", "symbol" : "CYP2C19", "name" : "cytochrome P450 family 2 subfamily C member 19", - "version" : 7210 + "version" : 7266 } ], "removed" : false, @@ -178539,18 +181630,18 @@ }, "terms" : [], "userId" : "pharmgkb", - "version" : 0, + "version" : 2, "versionDate" : "10/26/2022" }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166310303", - "name" : "Recommendation Annotation PA166310303", + "id" : "PA166310302", + "name" : "Recommendation Annotation PA166310302", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: CYP2C19 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -178558,30 +181649,30 @@ "objCls" : "Chemical", "id" : "PA449053", "name" : "clopidogrel", - "version" : 20 + "version" : 58 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329559", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Clopidogrel - CYP2C19", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452211483, + "id" : 1452211482, "html" : "

"Results in lower systemic active metabolite concentrations, lower antiplatelet response, and may result in higher cardiovascular risk. Consider use of another platelet P2Y12 inhibitor."

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166307922", - "name" : "Recommendation Annotation PA166307922", + "id" : "PA166307921", + "name" : "Recommendation Annotation PA166307921", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2C19": "Intermediate Metabolizer"}, + "lookupKey" : {"CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: CYP2C19 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -178589,30 +181680,30 @@ "objCls" : "Chemical", "id" : "PA449053", "name" : "clopidogrel", - "version" : 20 + "version" : 58 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329559", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Clopidogrel - CYP2C19", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452189341, + "id" : 1452189340, "html" : "

"Results in lower systemic active metabolite concentrations, lower antiplatelet response, and may result in higher cardiovascular risk. Consider use of another platelet P2Y12 inhibitor."

\n", - "version" : 0 + "version" : 1 }, - "version" : 0 + "version" : 5 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166307921", - "name" : "Recommendation Annotation PA166307921", + "id" : "PA166310303", + "name" : "Recommendation Annotation PA166310303", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2C19": "Likely Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: CYP2C19 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -178620,30 +181711,30 @@ "objCls" : "Chemical", "id" : "PA449053", "name" : "clopidogrel", - "version" : 20 + "version" : 58 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329559", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Clopidogrel - CYP2C19", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452189340, + "id" : 1452211483, "html" : "

"Results in lower systemic active metabolite concentrations, lower antiplatelet response, and may result in higher cardiovascular risk. Consider use of another platelet P2Y12 inhibitor."

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166310302", - "name" : "Recommendation Annotation PA166310302", + "id" : "PA166307922", + "name" : "Recommendation Annotation PA166307922", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2C19": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: CYP2C19 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -178651,21 +181742,21 @@ "objCls" : "Chemical", "id" : "PA449053", "name" : "clopidogrel", - "version" : 20 + "version" : 58 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329559", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Clopidogrel - CYP2C19", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452211482, + "id" : 1452189341, "html" : "

"Results in lower systemic active metabolite concentrations, lower antiplatelet response, and may result in higher cardiovascular risk. Consider use of another platelet P2Y12 inhibitor."

\n", - "version" : 0 + "version" : 1 }, - "version" : 0 + "version" : 5 } ], "url" : "https://www.pharmgkb.org/fdaPgxAssociations#PA166329559" @@ -178674,7 +181765,7 @@ "citations" : [ { "id" : 15155142, - "title" : "Table of Pharmacogenetic Associations", + "title" : "FDA Table of Pharmacogenetic Associations", "_sameAs" : "https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations", "authors" : [], "crossReferences" : [ @@ -178697,7 +181788,7 @@ "pgkbPublication" : false, "terms" : [], "type" : "Literature", - "version" : 0, + "version" : 2, "year" : -1 } ], @@ -178709,10 +181800,10 @@ "alternateDrugAvailable" : false, "cancerGenome" : false, "crossReferences" : [], - "dosingInformation" : false, + "dosingInformation" : true, "history" : [], "literature" : [ - {"id":15155142,"title":"Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} + {"id":15155142,"title":"FDA Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} ], "originalDrugText" : "Clozapine", "originalGeneText" : "CYP2D6", @@ -178724,7 +181815,7 @@ "objCls" : "Chemical", "id" : "PA449061", "name" : "clozapine", - "version" : 9 + "version" : 46 } ], "relatedGenes" : [ @@ -178733,7 +181824,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "removed" : false, @@ -178746,7 +181837,7 @@ }, "terms" : [], "userId" : "pharmgkb", - "version" : 0, + "version" : 2, "versionDate" : "10/26/2022" }, "recommendations" : [ @@ -178765,21 +181856,21 @@ "objCls" : "Chemical", "id" : "PA449061", "name" : "clozapine", - "version" : 9 + "version" : 46 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329560", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Clozapine - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { "id" : 1452214441, "html" : "

"Results in higher systemic concentrations. Dosage reductions may be necessary."

\n", "version" : 0 }, - "version" : 0 + "version" : 3 } ], "url" : "https://www.pharmgkb.org/fdaPgxAssociations#PA166329560" @@ -178788,7 +181879,7 @@ "citations" : [ { "id" : 15155142, - "title" : "Table of Pharmacogenetic Associations", + "title" : "FDA Table of Pharmacogenetic Associations", "_sameAs" : "https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations", "authors" : [], "crossReferences" : [ @@ -178811,7 +181902,7 @@ "pgkbPublication" : false, "terms" : [], "type" : "Literature", - "version" : 0, + "version" : 2, "year" : -1 } ], @@ -178820,13 +181911,13 @@ "id" : "PA166329561", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Codeine - CYP2D6", "affectedSubgroup" : "ultrarapid metabolizers", - "alternateDrugAvailable" : false, + "alternateDrugAvailable" : true, "cancerGenome" : false, "crossReferences" : [], "dosingInformation" : false, "history" : [], "literature" : [ - {"id":15155142,"title":"Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} + {"id":15155142,"title":"FDA Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} ], "originalDrugText" : "Codeine", "originalGeneText" : "CYP2D6", @@ -178838,7 +181929,7 @@ "objCls" : "Chemical", "id" : "PA449088", "name" : "codeine", - "version" : 14 + "version" : 48 } ], "relatedGenes" : [ @@ -178847,7 +181938,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "removed" : false, @@ -178860,7 +181951,7 @@ }, "terms" : [], "userId" : "pharmgkb", - "version" : 0, + "version" : 2, "versionDate" : "10/26/2022" }, "recommendations" : [ @@ -178879,30 +181970,30 @@ "objCls" : "Chemical", "id" : "PA449088", "name" : "codeine", - "version" : 14 + "version" : 48 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329561", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Codeine - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { "id" : 1452221522, "html" : "

"Results in higher systemic active metabolite concentrations and higher adverse reaction risk (life-threatening respiratory depression and death). Codeine is contraindicated in children under 12 years of age."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166313021", - "name" : "Recommendation Annotation PA166313021", + "id" : "PA166313022", + "name" : "Recommendation Annotation PA166313022", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "4.0"}, + "lookupKey" : {"CYP2D6": "≥3.0"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: CYP2D6 Ultrarapid metabolizers", "relatedChemicals" : [ @@ -178910,30 +182001,30 @@ "objCls" : "Chemical", "id" : "PA449088", "name" : "codeine", - "version" : 14 + "version" : 48 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329561", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Codeine - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452221520, + "id" : 1452221521, "html" : "

"Results in higher systemic active metabolite concentrations and higher adverse reaction risk (life-threatening respiratory depression and death). Codeine is contraindicated in children under 12 years of age."

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166313003", - "name" : "Recommendation Annotation PA166313003", + "id" : "PA166313021", + "name" : "Recommendation Annotation PA166313021", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "2.75"}, + "lookupKey" : {"CYP2D6": "4.0"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: CYP2D6 Ultrarapid metabolizers", "relatedChemicals" : [ @@ -178941,30 +182032,30 @@ "objCls" : "Chemical", "id" : "PA449088", "name" : "codeine", - "version" : 14 + "version" : 48 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329561", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Codeine - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452221502, + "id" : 1452221520, "html" : "

"Results in higher systemic active metabolite concentrations and higher adverse reaction risk (life-threatening respiratory depression and death). Codeine is contraindicated in children under 12 years of age."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166313029", - "name" : "Recommendation Annotation PA166313029", + "id" : "PA166313004", + "name" : "Recommendation Annotation PA166313004", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "≥6.0"}, + "lookupKey" : {"CYP2D6": "3.0"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: CYP2D6 Ultrarapid metabolizers", "relatedChemicals" : [ @@ -178972,30 +182063,30 @@ "objCls" : "Chemical", "id" : "PA449088", "name" : "codeine", - "version" : 14 + "version" : 48 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329561", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Codeine - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452221528, + "id" : 1452221503, "html" : "

"Results in higher systemic active metabolite concentrations and higher adverse reaction risk (life-threatening respiratory depression and death). Codeine is contraindicated in children under 12 years of age."

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"Results in higher systemic active metabolite concentrations and higher adverse reaction risk (life-threatening respiratory depression and death). Codeine is contraindicated in children under 12 years of age."

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"Results in higher systemic active metabolite concentrations and higher adverse reaction risk (life-threatening respiratory depression and death). Codeine is contraindicated in children under 12 years of age."

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"Results in higher systemic active metabolite concentrations and higher adverse reaction risk (life-threatening respiratory depression and death). Codeine is contraindicated in children under 12 years of age."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166313022", - "name" : "Recommendation Annotation PA166313022", + "id" : "PA166313028", + "name" : "Recommendation Annotation PA166313028", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "≥3.0"}, + "lookupKey" : {"CYP2D6": "≥5.0"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: CYP2D6 Ultrarapid metabolizers", "relatedChemicals" : [ @@ -179096,30 +182187,30 @@ "objCls" : "Chemical", "id" : "PA449088", "name" : "codeine", - "version" : 14 + "version" : 48 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329561", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Codeine - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452221521, + "id" : 1452221527, "html" : "

"Results in higher systemic active metabolite concentrations and higher adverse reaction risk (life-threatening respiratory depression and death). Codeine is contraindicated in children under 12 years of age."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166313028", - "name" : "Recommendation Annotation PA166313028", + "id" : "PA166313027", + "name" : "Recommendation Annotation PA166313027", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "≥5.0"}, + "lookupKey" : {"CYP2D6": "≥4.0"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: CYP2D6 Ultrarapid metabolizers", "relatedChemicals" : [ @@ -179127,30 +182218,30 @@ "objCls" : "Chemical", "id" : "PA449088", "name" : "codeine", - "version" : 14 + "version" : 48 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329561", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Codeine - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452221527, + "id" : 1452221526, "html" : "

"Results in higher systemic active metabolite concentrations and higher adverse reaction risk (life-threatening respiratory depression and death). Codeine is contraindicated in children under 12 years of age."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166313004", - "name" : "Recommendation Annotation PA166313004", + "id" : "PA166313025", + "name" : "Recommendation Annotation PA166313025", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "3.0"}, + "lookupKey" : {"CYP2D6": "≥3.75"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: CYP2D6 Ultrarapid metabolizers", "relatedChemicals" : [ @@ -179158,30 +182249,30 @@ "objCls" : "Chemical", "id" : "PA449088", "name" : "codeine", - "version" : 14 + "version" : 48 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329561", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Codeine - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452221503, + "id" : 1452221524, "html" : "

"Results in higher systemic active metabolite concentrations and higher adverse reaction risk (life-threatening respiratory depression and death). Codeine is contraindicated in children under 12 years of age."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166313002", - "name" : "Recommendation Annotation PA166313002", + "id" : "PA166313024", + "name" : "Recommendation Annotation PA166313024", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "2.5"}, + "lookupKey" : {"CYP2D6": "≥3.5"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: CYP2D6 Ultrarapid metabolizers", "relatedChemicals" : [ @@ -179189,21 +182280,21 @@ "objCls" : "Chemical", "id" : "PA449088", "name" : "codeine", - "version" : 14 + "version" : 48 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329561", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Codeine - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452221501, + "id" : 1452221523, "html" : "

"Results in higher systemic active metabolite concentrations and higher adverse reaction risk (life-threatening respiratory depression and death). Codeine is contraindicated in children under 12 years of age."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 } ], "url" : "https://www.pharmgkb.org/fdaPgxAssociations#PA166329561" @@ -179212,7 +182303,7 @@ "citations" : [ { "id" : 15155142, - "title" : "Table of Pharmacogenetic Associations", + "title" : "FDA Table of Pharmacogenetic Associations", "_sameAs" : "https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations", "authors" : [], "crossReferences" : [ @@ -179235,7 +182326,7 @@ "pgkbPublication" : false, "terms" : [], "type" : "Literature", - "version" : 0, + "version" : 2, "year" : -1 } ], @@ -179247,10 +182338,10 @@ "alternateDrugAvailable" : false, "cancerGenome" : false, "crossReferences" : [], - "dosingInformation" : false, + "dosingInformation" : true, "history" : [], "literature" : [ - {"id":15155142,"title":"Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} + {"id":15155142,"title":"FDA Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} ], "originalDrugText" : "Deutetrabenazine", "originalGeneText" : "CYP2D6", @@ -179262,7 +182353,7 @@ "objCls" : "Chemical", "id" : "PA166169881", "name" : "deutetrabenazine", - "version" : 7 + "version" : 13 } ], "relatedGenes" : [ @@ -179271,7 +182362,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "removed" : false, @@ -179284,7 +182375,7 @@ }, "terms" : [], "userId" : "pharmgkb", - "version" : 0, + "version" : 2, "versionDate" : "10/26/2022" }, "recommendations" : [ @@ -179303,21 +182394,21 @@ "objCls" : "Chemical", "id" : "PA166169881", "name" : "deutetrabenazine", - "version" : 7 + "version" : 13 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329562", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Deutetrabenazine - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { "id" : 1452216567, "html" : "

"Results in higher systemic concentrations and adverse reaction risk (QT prolongation). The maximum recommended dosage should not exceed 36 mg (maximum single dose of 18 mg)."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 } ], "url" : "https://www.pharmgkb.org/fdaPgxAssociations#PA166329562" @@ -179326,7 +182417,7 @@ "citations" : [ { "id" : 15155142, - "title" : "Table of Pharmacogenetic Associations", + "title" : "FDA Table of Pharmacogenetic Associations", "_sameAs" : "https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations", "authors" : [], "crossReferences" : [ @@ -179349,7 +182440,7 @@ "pgkbPublication" : false, "terms" : [], "type" : "Literature", - "version" : 0, + "version" : 2, "year" : -1 } ], @@ -179364,11 +182455,11 @@ "dosingInformation" : false, "history" : [], "literature" : [ - {"id":15155142,"title":"Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} + {"id":15155142,"title":"FDA Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} ], "originalDrugText" : "Dronabinol", "originalGeneText" : "CYP2C9", - "otherPrescribingGuidance" : false, + "otherPrescribingGuidance" : true, "pediatric" : false, "relatedAlleles" : [], "relatedChemicals" : [ @@ -179376,7 +182467,7 @@ "objCls" : "Chemical", "id" : "PA449421", "name" : "dronabinol", - "version" : 8 + "version" : 27 } ], "relatedGenes" : [ @@ -179385,7 +182476,7 @@ "id" : "PA126", "symbol" : "CYP2C9", "name" : "cytochrome P450 family 2 subfamily C member 9", - "version" : 7877 + "version" : 7952 } ], "removed" : false, @@ -179398,18 +182489,18 @@ }, "terms" : [], "userId" : "pharmgkb", - "version" : 0, + "version" : 2, "versionDate" : "10/26/2022" }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166312022", - "name" : "Recommendation Annotation PA166312022", + "id" : "PA166312021", + "name" : "Recommendation Annotation PA166312021", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2C9": "1.0"}, + "lookupKey" : {"CYP2C9": "0.5"}, "otherPrescribingGuidance" : true, "population" : "Affected subgroup: CYP2C9 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -179417,30 +182508,30 @@ "objCls" : "Chemical", "id" : "PA449421", "name" : "dronabinol", - "version" : 8 + "version" : 27 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329563", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Dronabinol - CYP2C9", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452216221, + "id" : 1452216220, "html" : "

"May result in higher systemic concentrations and higher adverse reaction risk. Monitor for adverse reactions."

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312001", - "name" : "Recommendation Annotation PA166312001", + "id" : "PA166312023", + "name" : "Recommendation Annotation PA166312023", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2C9": "0.0"}, + "lookupKey" : {"CYP2C9": "1.5"}, "otherPrescribingGuidance" : true, "population" : "Affected subgroup: CYP2C9 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -179448,30 +182539,30 @@ "objCls" : "Chemical", "id" : "PA449421", "name" : "dronabinol", - "version" : 8 + "version" : 27 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329563", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Dronabinol - CYP2C9", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452216200, + "id" : 1452216222, "html" : "

"May result in higher systemic concentrations and higher adverse reaction risk. Monitor for adverse reactions."

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312021", - "name" : "Recommendation Annotation PA166312021", + "id" : "PA166312022", + "name" : "Recommendation Annotation PA166312022", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2C9": "0.5"}, + "lookupKey" : {"CYP2C9": "1.0"}, "otherPrescribingGuidance" : true, "population" : "Affected subgroup: CYP2C9 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -179479,30 +182570,30 @@ "objCls" : "Chemical", "id" : "PA449421", "name" : "dronabinol", - "version" : 8 + "version" : 27 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329563", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Dronabinol - CYP2C9", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452216220, + "id" : 1452216221, "html" : "

"May result in higher systemic concentrations and higher adverse reaction risk. Monitor for adverse reactions."

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312023", - "name" : "Recommendation Annotation PA166312023", + "id" : "PA166312001", + "name" : "Recommendation Annotation PA166312001", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2C9": "1.5"}, + "lookupKey" : {"CYP2C9": "0.0"}, "otherPrescribingGuidance" : true, "population" : "Affected subgroup: CYP2C9 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -179510,21 +182601,21 @@ "objCls" : "Chemical", "id" : "PA449421", "name" : "dronabinol", - "version" : 8 + "version" : 27 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329563", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Dronabinol - CYP2C9", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452216222, + "id" : 1452216200, "html" : "

"May result in higher systemic concentrations and higher adverse reaction risk. Monitor for adverse reactions."

\n", "version" : 0 }, - "version" : 0 + "version" : 3 } ], "url" : "https://www.pharmgkb.org/fdaPgxAssociations#PA166329563" @@ -179533,7 +182624,7 @@ "citations" : [ { "id" : 15155142, - "title" : "Table of Pharmacogenetic Associations", + "title" : "FDA Table of Pharmacogenetic Associations", "_sameAs" : "https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations", "authors" : [], "crossReferences" : [ @@ -179556,7 +182647,7 @@ "pgkbPublication" : false, "terms" : [], "type" : "Literature", - "version" : 0, + "version" : 2, "year" : -1 } ], @@ -179571,11 +182662,11 @@ "dosingInformation" : false, "history" : [], "literature" : [ - {"id":15155142,"title":"Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} + {"id":15155142,"title":"FDA Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} ], "originalDrugText" : "Eliglustat", "originalGeneText" : "CYP2D6", - "otherPrescribingGuidance" : false, + "otherPrescribingGuidance" : true, "pediatric" : false, "relatedAlleles" : [], "relatedChemicals" : [ @@ -179583,7 +182674,7 @@ "objCls" : "Chemical", "id" : "PA166123486", "name" : "eliglustat", - "version" : 5 + "version" : 6 } ], "relatedGenes" : [ @@ -179592,7 +182683,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "removed" : false, @@ -179605,18 +182696,18 @@ }, "terms" : [], "userId" : "pharmgkb", - "version" : 0, + "version" : 2, "versionDate" : "10/26/2022" }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166312389", - "name" : "Recommendation Annotation PA166312389", + "id" : "PA166312409", + "name" : "Recommendation Annotation PA166312409", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "2.0"}, + "lookupKey" : {"CYP2D6": "≥3.25"}, "otherPrescribingGuidance" : true, "population" : "Affected subgroup: CYP2D6 ultrarapid, normal, intermediate, or poor metabolizers", "relatedChemicals" : [ @@ -179624,30 +182715,30 @@ "objCls" : "Chemical", "id" : "PA166123486", "name" : "eliglustat", - "version" : 5 + "version" : 6 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329564", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Eliglustat - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452216669, + "id" : 1452216708, "html" : "

"Alters systemic concentrations, effectiveness, and adverse reaction risk (QT prolongation). Indicated for normal, intermediate, and poor metabolizer patients. Ultrarapid metabolizers may not achieve adequate concentrations to achieve a therapeutic effect. The recommended dosages are based on CYP2D6 metabolizer status. Coadministration with strong CYP3A inhibitors is contraindicated in intermediate and poor CYP2D6 metabolizers. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312407", - "name" : "Recommendation Annotation PA166312407", + "id" : "PA166312422", + "name" : "Recommendation Annotation PA166312422", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "3.0"}, + "lookupKey" : {"CYP2D6": "0.25"}, "otherPrescribingGuidance" : true, "population" : "Affected subgroup: CYP2D6 ultrarapid, normal, intermediate, or poor metabolizers", "relatedChemicals" : [ @@ -179655,30 +182746,30 @@ "objCls" : "Chemical", "id" : "PA166123486", "name" : "eliglustat", - "version" : 5 + "version" : 6 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329564", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Eliglustat - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452216706, - "html" : "

"Alters systemic concentrations, effectiveness, and adverse reaction risk (QT prolongation). Indicated for normal, intermediate, and poor metabolizer patients. Ultrarapid metabolizers may not achieve adequate concentrations to achieve a therapeutic effect. The recommended dosages are based on CYP2D6 metabolizer status. Coadministration with strong CYP3A inhibitors is contraindicated in intermediate and poor CYP2D6 metabolizers. Refer to FDA labeling for specific dosing recommendations."

\n", + "id" : 1452216721, + "html" : "

Alters systemic concentrations, effectiveness, and adverse reaction risk (QT prolongation). Indicated for normal, intermediate, and poor metabolizer patients. Ultrarapid metabolizers may not achieve adequate concentrations to achieve a therapeutic effect. The recommended dosages are based on CYP2D6 metabolizer status. Coadministration with strong CYP3A inhibitors is contraindicated in intermediate and poor CYP2D6 metabolizers. Refer to FDA labeling for specific dosing recommendations.

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312409", - "name" : "Recommendation Annotation PA166312409", + "id" : "PA166312389", + "name" : "Recommendation Annotation PA166312389", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "≥3.25"}, + "lookupKey" : {"CYP2D6": "2.0"}, "otherPrescribingGuidance" : true, "population" : "Affected subgroup: CYP2D6 ultrarapid, normal, intermediate, or poor metabolizers", "relatedChemicals" : [ @@ -179686,30 +182777,30 @@ "objCls" : "Chemical", "id" : "PA166123486", "name" : "eliglustat", - "version" : 5 + "version" : 6 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329564", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Eliglustat - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452216708, + "id" : 1452216669, "html" : "

"Alters systemic concentrations, effectiveness, and adverse reaction risk (QT prolongation). Indicated for normal, intermediate, and poor metabolizer patients. Ultrarapid metabolizers may not achieve adequate concentrations to achieve a therapeutic effect. The recommended dosages are based on CYP2D6 metabolizer status. Coadministration with strong CYP3A inhibitors is contraindicated in intermediate and poor CYP2D6 metabolizers. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312396", - "name" : "Recommendation Annotation PA166312396", + "id" : "PA166312388", + "name" : "Recommendation Annotation PA166312388", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "≥5.0"}, + "lookupKey" : {"CYP2D6": "1.5"}, "otherPrescribingGuidance" : true, "population" : "Affected subgroup: CYP2D6 ultrarapid, normal, intermediate, or poor metabolizers", "relatedChemicals" : [ @@ -179717,30 +182808,30 @@ "objCls" : "Chemical", "id" : "PA166123486", "name" : "eliglustat", - "version" : 5 + "version" : 6 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329564", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Eliglustat - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452216676, + "id" : 1452216668, "html" : "

"Alters systemic concentrations, effectiveness, and adverse reaction risk (QT prolongation). Indicated for normal, intermediate, and poor metabolizer patients. Ultrarapid metabolizers may not achieve adequate concentrations to achieve a therapeutic effect. The recommended dosages are based on CYP2D6 metabolizer status. Coadministration with strong CYP3A inhibitors is contraindicated in intermediate and poor CYP2D6 metabolizers. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312403", - "name" : "Recommendation Annotation PA166312403", + "id" : "PA166312404", + "name" : "Recommendation Annotation PA166312404", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "0.0"}, + "lookupKey" : {"CYP2D6": "0.5"}, "otherPrescribingGuidance" : true, "population" : "Affected subgroup: CYP2D6 ultrarapid, normal, intermediate, or poor metabolizers", "relatedChemicals" : [ @@ -179748,30 +182839,30 @@ "objCls" : "Chemical", "id" : "PA166123486", "name" : "eliglustat", - "version" : 5 + "version" : 6 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329564", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Eliglustat - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452216702, + "id" : 1452216703, "html" : "

"Alters systemic concentrations, effectiveness, and adverse reaction risk (QT prolongation). Indicated for normal, intermediate, and poor metabolizer patients. Ultrarapid metabolizers may not achieve adequate concentrations to achieve a therapeutic effect. The recommended dosages are based on CYP2D6 metabolizer status. Coadministration with strong CYP3A inhibitors is contraindicated in intermediate and poor CYP2D6 metabolizers. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312387", - "name" : "Recommendation Annotation PA166312387", + "id" : "PA166312403", + "name" : "Recommendation Annotation PA166312403", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "0.75"}, + "lookupKey" : {"CYP2D6": "0.0"}, "otherPrescribingGuidance" : true, "population" : "Affected subgroup: CYP2D6 ultrarapid, normal, intermediate, or poor metabolizers", "relatedChemicals" : [ @@ -179779,30 +182870,30 @@ "objCls" : "Chemical", "id" : "PA166123486", "name" : "eliglustat", - "version" : 5 + "version" : 6 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329564", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Eliglustat - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452216667, + "id" : 1452216702, "html" : "

"Alters systemic concentrations, effectiveness, and adverse reaction risk (QT prolongation). Indicated for normal, intermediate, and poor metabolizer patients. Ultrarapid metabolizers may not achieve adequate concentrations to achieve a therapeutic effect. The recommended dosages are based on CYP2D6 metabolizer status. Coadministration with strong CYP3A inhibitors is contraindicated in intermediate and poor CYP2D6 metabolizers. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 5 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312405", - "name" : "Recommendation Annotation PA166312405", + "id" : "PA166312412", + "name" : "Recommendation Annotation PA166312412", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "1.0"}, + "lookupKey" : {"CYP2D6": "≥4.0"}, "otherPrescribingGuidance" : true, "population" : "Affected subgroup: CYP2D6 ultrarapid, normal, intermediate, or poor metabolizers", "relatedChemicals" : [ @@ -179810,30 +182901,30 @@ "objCls" : "Chemical", "id" : "PA166123486", "name" : "eliglustat", - "version" : 5 + "version" : 6 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329564", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Eliglustat - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452216704, + "id" : 1452216711, "html" : "

"Alters systemic concentrations, effectiveness, and adverse reaction risk (QT prolongation). Indicated for normal, intermediate, and poor metabolizer patients. Ultrarapid metabolizers may not achieve adequate concentrations to achieve a therapeutic effect. The recommended dosages are based on CYP2D6 metabolizer status. Coadministration with strong CYP3A inhibitors is contraindicated in intermediate and poor CYP2D6 metabolizers. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312392", - "name" : "Recommendation Annotation PA166312392", + "id" : "PA166312411", + "name" : "Recommendation Annotation PA166312411", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "2.75"}, + "lookupKey" : {"CYP2D6": "≥3.75"}, "otherPrescribingGuidance" : true, "population" : "Affected subgroup: CYP2D6 ultrarapid, normal, intermediate, or poor metabolizers", "relatedChemicals" : [ @@ -179841,21 +182932,21 @@ "objCls" : "Chemical", "id" : "PA166123486", "name" : "eliglustat", - "version" : 5 + "version" : 6 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329564", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Eliglustat - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452216672, + "id" : 1452216710, "html" : "

"Alters systemic concentrations, effectiveness, and adverse reaction risk (QT prolongation). Indicated for normal, intermediate, and poor metabolizer patients. Ultrarapid metabolizers may not achieve adequate concentrations to achieve a therapeutic effect. The recommended dosages are based on CYP2D6 metabolizer status. Coadministration with strong CYP3A inhibitors is contraindicated in intermediate and poor CYP2D6 metabolizers. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", @@ -179872,30 +182963,30 @@ "objCls" : "Chemical", "id" : "PA166123486", "name" : "eliglustat", - "version" : 5 + "version" : 6 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329564", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Eliglustat - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { "id" : 1452216709, "html" : "

"Alters systemic concentrations, effectiveness, and adverse reaction risk (QT prolongation). Indicated for normal, intermediate, and poor metabolizer patients. Ultrarapid metabolizers may not achieve adequate concentrations to achieve a therapeutic effect. The recommended dosages are based on CYP2D6 metabolizer status. Coadministration with strong CYP3A inhibitors is contraindicated in intermediate and poor CYP2D6 metabolizers. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312423", - "name" : "Recommendation Annotation PA166312423", + "id" : "PA166312408", + "name" : "Recommendation Annotation PA166312408", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "1.25"}, + "lookupKey" : {"CYP2D6": "≥3.0"}, "otherPrescribingGuidance" : true, "population" : "Affected subgroup: CYP2D6 ultrarapid, normal, intermediate, or poor metabolizers", "relatedChemicals" : [ @@ -179903,30 +182994,30 @@ "objCls" : "Chemical", "id" : "PA166123486", "name" : "eliglustat", - "version" : 5 + "version" : 6 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329564", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Eliglustat - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452216722, + "id" : 1452216707, "html" : "

"Alters systemic concentrations, effectiveness, and adverse reaction risk (QT prolongation). Indicated for normal, intermediate, and poor metabolizer patients. Ultrarapid metabolizers may not achieve adequate concentrations to achieve a therapeutic effect. The recommended dosages are based on CYP2D6 metabolizer status. Coadministration with strong CYP3A inhibitors is contraindicated in intermediate and poor CYP2D6 metabolizers. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312412", - "name" : "Recommendation Annotation PA166312412", + "id" : "PA166312407", + "name" : "Recommendation Annotation PA166312407", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "≥4.0"}, + "lookupKey" : {"CYP2D6": "3.0"}, "otherPrescribingGuidance" : true, "population" : "Affected subgroup: CYP2D6 ultrarapid, normal, intermediate, or poor metabolizers", "relatedChemicals" : [ @@ -179934,30 +183025,30 @@ "objCls" : "Chemical", "id" : "PA166123486", "name" : "eliglustat", - "version" : 5 + "version" : 6 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329564", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Eliglustat - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452216711, + "id" : 1452216706, "html" : "

"Alters systemic concentrations, effectiveness, and adverse reaction risk (QT prolongation). Indicated for normal, intermediate, and poor metabolizer patients. Ultrarapid metabolizers may not achieve adequate concentrations to achieve a therapeutic effect. The recommended dosages are based on CYP2D6 metabolizer status. Coadministration with strong CYP3A inhibitors is contraindicated in intermediate and poor CYP2D6 metabolizers. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312390", - "name" : "Recommendation Annotation PA166312390", + "id" : "PA166312391", + "name" : "Recommendation Annotation PA166312391", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "2.25"}, + "lookupKey" : {"CYP2D6": "2.5"}, "otherPrescribingGuidance" : true, "population" : "Affected subgroup: CYP2D6 ultrarapid, normal, intermediate, or poor metabolizers", "relatedChemicals" : [ @@ -179965,30 +183056,30 @@ "objCls" : "Chemical", "id" : "PA166123486", "name" : "eliglustat", - "version" : 5 + "version" : 6 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329564", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Eliglustat - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452216670, + "id" : 1452216671, "html" : "

"Alters systemic concentrations, effectiveness, and adverse reaction risk (QT prolongation). Indicated for normal, intermediate, and poor metabolizer patients. Ultrarapid metabolizers may not achieve adequate concentrations to achieve a therapeutic effect. The recommended dosages are based on CYP2D6 metabolizer status. Coadministration with strong CYP3A inhibitors is contraindicated in intermediate and poor CYP2D6 metabolizers. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312388", - "name" : "Recommendation Annotation PA166312388", + "id" : "PA166312406", + "name" : "Recommendation Annotation PA166312406", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "1.5"}, + "lookupKey" : {"CYP2D6": "1.75"}, "otherPrescribingGuidance" : true, "population" : "Affected subgroup: CYP2D6 ultrarapid, normal, intermediate, or poor metabolizers", "relatedChemicals" : [ @@ -179996,30 +183087,30 @@ "objCls" : "Chemical", "id" : "PA166123486", "name" : "eliglustat", - "version" : 5 + "version" : 6 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329564", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Eliglustat - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452216668, + "id" : 1452216705, "html" : "

"Alters systemic concentrations, effectiveness, and adverse reaction risk (QT prolongation). Indicated for normal, intermediate, and poor metabolizer patients. Ultrarapid metabolizers may not achieve adequate concentrations to achieve a therapeutic effect. The recommended dosages are based on CYP2D6 metabolizer status. Coadministration with strong CYP3A inhibitors is contraindicated in intermediate and poor CYP2D6 metabolizers. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312406", - "name" : "Recommendation Annotation PA166312406", + "id" : "PA166312405", + "name" : "Recommendation Annotation PA166312405", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "1.75"}, + "lookupKey" : {"CYP2D6": "1.0"}, "otherPrescribingGuidance" : true, "population" : "Affected subgroup: CYP2D6 ultrarapid, normal, intermediate, or poor metabolizers", "relatedChemicals" : [ @@ -180027,30 +183118,30 @@ "objCls" : "Chemical", "id" : "PA166123486", "name" : "eliglustat", - "version" : 5 + "version" : 6 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329564", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Eliglustat - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452216705, + "id" : 1452216704, "html" : "

"Alters systemic concentrations, effectiveness, and adverse reaction risk (QT prolongation). Indicated for normal, intermediate, and poor metabolizer patients. Ultrarapid metabolizers may not achieve adequate concentrations to achieve a therapeutic effect. The recommended dosages are based on CYP2D6 metabolizer status. Coadministration with strong CYP3A inhibitors is contraindicated in intermediate and poor CYP2D6 metabolizers. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312408", - "name" : "Recommendation Annotation PA166312408", + "id" : "PA166312387", + "name" : "Recommendation Annotation PA166312387", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "≥3.0"}, + "lookupKey" : {"CYP2D6": "0.75"}, "otherPrescribingGuidance" : true, "population" : "Affected subgroup: CYP2D6 ultrarapid, normal, intermediate, or poor metabolizers", "relatedChemicals" : [ @@ -180058,30 +183149,30 @@ "objCls" : "Chemical", "id" : "PA166123486", "name" : "eliglustat", - "version" : 5 + "version" : 6 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329564", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Eliglustat - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452216707, + "id" : 1452216667, "html" : "

"Alters systemic concentrations, effectiveness, and adverse reaction risk (QT prolongation). Indicated for normal, intermediate, and poor metabolizer patients. Ultrarapid metabolizers may not achieve adequate concentrations to achieve a therapeutic effect. The recommended dosages are based on CYP2D6 metabolizer status. Coadministration with strong CYP3A inhibitors is contraindicated in intermediate and poor CYP2D6 metabolizers. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312404", - "name" : "Recommendation Annotation PA166312404", + "id" : "PA166312423", + "name" : "Recommendation Annotation PA166312423", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "0.5"}, + "lookupKey" : {"CYP2D6": "1.25"}, "otherPrescribingGuidance" : true, "population" : "Affected subgroup: CYP2D6 ultrarapid, normal, intermediate, or poor metabolizers", "relatedChemicals" : [ @@ -180089,30 +183180,30 @@ "objCls" : "Chemical", "id" : "PA166123486", "name" : "eliglustat", - "version" : 5 + "version" : 6 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329564", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Eliglustat - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452216703, + "id" : 1452216722, "html" : "

"Alters systemic concentrations, effectiveness, and adverse reaction risk (QT prolongation). Indicated for normal, intermediate, and poor metabolizer patients. Ultrarapid metabolizers may not achieve adequate concentrations to achieve a therapeutic effect. The recommended dosages are based on CYP2D6 metabolizer status. Coadministration with strong CYP3A inhibitors is contraindicated in intermediate and poor CYP2D6 metabolizers. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312422", - "name" : "Recommendation Annotation PA166312422", + "id" : "PA166312393", + "name" : "Recommendation Annotation PA166312393", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "0.25"}, + "lookupKey" : {"CYP2D6": "4.0"}, "otherPrescribingGuidance" : true, "population" : "Affected subgroup: CYP2D6 ultrarapid, normal, intermediate, or poor metabolizers", "relatedChemicals" : [ @@ -180120,30 +183211,30 @@ "objCls" : "Chemical", "id" : "PA166123486", "name" : "eliglustat", - "version" : 5 + "version" : 6 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329564", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Eliglustat - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452216721, - "html" : "

Alters systemic concentrations, effectiveness, and adverse reaction risk (QT prolongation). Indicated for normal, intermediate, and poor metabolizer patients. Ultrarapid metabolizers may not achieve adequate concentrations to achieve a therapeutic effect. The recommended dosages are based on CYP2D6 metabolizer status. Coadministration with strong CYP3A inhibitors is contraindicated in intermediate and poor CYP2D6 metabolizers. Refer to FDA labeling for specific dosing recommendations.

\n", + "id" : 1452216673, + "html" : "

"Alters systemic concentrations, effectiveness, and adverse reaction risk (QT prolongation). Indicated for normal, intermediate, and poor metabolizer patients. Ultrarapid metabolizers may not achieve adequate concentrations to achieve a therapeutic effect. The recommended dosages are based on CYP2D6 metabolizer status. Coadministration with strong CYP3A inhibitors is contraindicated in intermediate and poor CYP2D6 metabolizers. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312393", - "name" : "Recommendation Annotation PA166312393", + "id" : "PA166312392", + "name" : "Recommendation Annotation PA166312392", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "4.0"}, + "lookupKey" : {"CYP2D6": "2.75"}, "otherPrescribingGuidance" : true, "population" : "Affected subgroup: CYP2D6 ultrarapid, normal, intermediate, or poor metabolizers", "relatedChemicals" : [ @@ -180151,30 +183242,30 @@ "objCls" : "Chemical", "id" : "PA166123486", "name" : "eliglustat", - "version" : 5 + "version" : 6 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329564", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Eliglustat - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452216673, + "id" : 1452216672, "html" : "

"Alters systemic concentrations, effectiveness, and adverse reaction risk (QT prolongation). Indicated for normal, intermediate, and poor metabolizer patients. Ultrarapid metabolizers may not achieve adequate concentrations to achieve a therapeutic effect. The recommended dosages are based on CYP2D6 metabolizer status. Coadministration with strong CYP3A inhibitors is contraindicated in intermediate and poor CYP2D6 metabolizers. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312411", - "name" : "Recommendation Annotation PA166312411", + "id" : "PA166312390", + "name" : "Recommendation Annotation PA166312390", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "≥3.75"}, + "lookupKey" : {"CYP2D6": "2.25"}, "otherPrescribingGuidance" : true, "population" : "Affected subgroup: CYP2D6 ultrarapid, normal, intermediate, or poor metabolizers", "relatedChemicals" : [ @@ -180182,21 +183273,21 @@ "objCls" : "Chemical", "id" : "PA166123486", "name" : "eliglustat", - "version" : 5 + "version" : 6 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329564", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Eliglustat - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452216710, + "id" : 1452216670, "html" : "

"Alters systemic concentrations, effectiveness, and adverse reaction risk (QT prolongation). Indicated for normal, intermediate, and poor metabolizer patients. Ultrarapid metabolizers may not achieve adequate concentrations to achieve a therapeutic effect. The recommended dosages are based on CYP2D6 metabolizer status. Coadministration with strong CYP3A inhibitors is contraindicated in intermediate and poor CYP2D6 metabolizers. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", @@ -180213,30 +183304,30 @@ "objCls" : "Chemical", "id" : "PA166123486", "name" : "eliglustat", - "version" : 5 + "version" : 6 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329564", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Eliglustat - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { "id" : 1452216712, "html" : "

"Alters systemic concentrations, effectiveness, and adverse reaction risk (QT prolongation). Indicated for normal, intermediate, and poor metabolizer patients. Ultrarapid metabolizers may not achieve adequate concentrations to achieve a therapeutic effect. The recommended dosages are based on CYP2D6 metabolizer status. Coadministration with strong CYP3A inhibitors is contraindicated in intermediate and poor CYP2D6 metabolizers. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312391", - "name" : "Recommendation Annotation PA166312391", + "id" : "PA166312396", + "name" : "Recommendation Annotation PA166312396", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "2.5"}, + "lookupKey" : {"CYP2D6": "≥5.0"}, "otherPrescribingGuidance" : true, "population" : "Affected subgroup: CYP2D6 ultrarapid, normal, intermediate, or poor metabolizers", "relatedChemicals" : [ @@ -180244,21 +183335,21 @@ "objCls" : "Chemical", "id" : "PA166123486", "name" : "eliglustat", - "version" : 5 + "version" : 6 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329564", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Eliglustat - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452216671, + "id" : 1452216676, "html" : "

"Alters systemic concentrations, effectiveness, and adverse reaction risk (QT prolongation). Indicated for normal, intermediate, and poor metabolizer patients. Ultrarapid metabolizers may not achieve adequate concentrations to achieve a therapeutic effect. The recommended dosages are based on CYP2D6 metabolizer status. Coadministration with strong CYP3A inhibitors is contraindicated in intermediate and poor CYP2D6 metabolizers. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 } ], "url" : "https://www.pharmgkb.org/fdaPgxAssociations#PA166329564" @@ -180267,7 +183358,7 @@ "citations" : [ { "id" : 15155142, - "title" : "Table of Pharmacogenetic Associations", + "title" : "FDA Table of Pharmacogenetic Associations", "_sameAs" : "https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations", "authors" : [], "crossReferences" : [ @@ -180290,7 +183381,7 @@ "pgkbPublication" : false, "terms" : [], "type" : "Literature", - "version" : 0, + "version" : 2, "year" : -1 } ], @@ -180305,11 +183396,11 @@ "dosingInformation" : false, "history" : [], "literature" : [ - {"id":15155142,"title":"Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} + {"id":15155142,"title":"FDA Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} ], "originalDrugText" : "Erdafitinib", "originalGeneText" : "CYP2C9", - "otherPrescribingGuidance" : false, + "otherPrescribingGuidance" : true, "pediatric" : false, "relatedAlleles" : [], "relatedChemicals" : [ @@ -180317,7 +183408,7 @@ "objCls" : "Chemical", "id" : "PA166182720", "name" : "erdafitinib", - "version" : 5 + "version" : 6 } ], "relatedGenes" : [ @@ -180326,7 +183417,7 @@ "id" : "PA126", "symbol" : "CYP2C9", "name" : "cytochrome P450 family 2 subfamily C member 9", - "version" : 7877 + "version" : 7952 } ], "removed" : false, @@ -180339,7 +183430,7 @@ }, "terms" : [], "userId" : "pharmgkb", - "version" : 0, + "version" : 2, "versionDate" : "10/26/2022" }, "recommendations" : [ @@ -180358,21 +183449,21 @@ "objCls" : "Chemical", "id" : "PA166182720", "name" : "erdafitinib", - "version" : 5 + "version" : 6 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329565", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Erdafitinib - CYP2C9", - "version" : 0 + "version" : 2 }, "text" : { "id" : 1452219000, "html" : "

"May result in higher systemic concentrations and higher adverse reaction risk. Monitor for adverse reactions."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", @@ -180389,21 +183480,21 @@ "objCls" : "Chemical", "id" : "PA166182720", "name" : "erdafitinib", - "version" : 5 + "version" : 6 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329565", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Erdafitinib - CYP2C9", - "version" : 0 + "version" : 2 }, "text" : { "id" : 1452218980, "html" : "

"May result in higher systemic concentrations and higher adverse reaction risk. Monitor for adverse reactions."

\n", "version" : 0 }, - "version" : 0 + "version" : 3 } ], "url" : "https://www.pharmgkb.org/fdaPgxAssociations#PA166329565" @@ -180412,7 +183503,7 @@ "citations" : [ { "id" : 15155142, - "title" : "Table of Pharmacogenetic Associations", + "title" : "FDA Table of Pharmacogenetic Associations", "_sameAs" : "https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations", "authors" : [], "crossReferences" : [ @@ -180435,7 +183526,7 @@ "pgkbPublication" : false, "terms" : [], "type" : "Literature", - "version" : 0, + "version" : 2, "year" : -1 } ], @@ -180450,11 +183541,11 @@ "dosingInformation" : false, "history" : [], "literature" : [ - {"id":15155142,"title":"Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} + {"id":15155142,"title":"FDA Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} ], "originalDrugText" : "Flibanserin", "originalGeneText" : "CYP2C19", - "otherPrescribingGuidance" : false, + "otherPrescribingGuidance" : true, "pediatric" : false, "relatedAlleles" : [], "relatedChemicals" : [ @@ -180462,7 +183553,7 @@ "objCls" : "Chemical", "id" : "PA166153431", "name" : "flibanserin", - "version" : 5 + "version" : 6 } ], "relatedGenes" : [ @@ -180471,7 +183562,7 @@ "id" : "PA124", "symbol" : "CYP2C19", "name" : "cytochrome P450 family 2 subfamily C member 19", - "version" : 7210 + "version" : 7266 } ], "removed" : false, @@ -180484,18 +183575,18 @@ }, "terms" : [], "userId" : "pharmgkb", - "version" : 0, + "version" : 2, "versionDate" : "10/26/2022" }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166315202", - "name" : "Recommendation Annotation PA166315202", + "id" : "PA166315201", + "name" : "Recommendation Annotation PA166315201", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2C19": "Likely Poor Metabolizer"}, + "lookupKey" : {"CYP2C19": "Poor Metabolizer"}, "otherPrescribingGuidance" : true, "population" : "Affected subgroup: CYP2C19 poor metabolizers", "relatedChemicals" : [ @@ -180503,17 +183594,17 @@ "objCls" : "Chemical", "id" : "PA166153431", "name" : "flibanserin", - "version" : 5 + "version" : 6 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329566", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Flibanserin - CYP2C19", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452245881, + "id" : 1452245880, "html" : "

"May result in higher systemic concentrations and higher adverse reaction risk. Monitor patients for adverse reactions."

\n", "version" : 0 }, @@ -180521,12 +183612,12 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166315201", - "name" : "Recommendation Annotation PA166315201", + "id" : "PA166315202", + "name" : "Recommendation Annotation PA166315202", "alternateDrugAvailable" : false, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2C19": "Poor Metabolizer"}, + "lookupKey" : {"CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : true, "population" : "Affected subgroup: CYP2C19 poor metabolizers", "relatedChemicals" : [ @@ -180534,17 +183625,17 @@ "objCls" : "Chemical", "id" : "PA166153431", "name" : "flibanserin", - "version" : 5 + "version" : 6 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329566", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Flibanserin - CYP2C19", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452245880, + "id" : 1452245881, "html" : "

"May result in higher systemic concentrations and higher adverse reaction risk. Monitor patients for adverse reactions."

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"Results in higher adverse reaction risk (severe, life-threatening, or fatal toxicities). No dosage has proven safe in poor metabolizers and insufficient data are available to recommend a dosage in intermediate metabolizers. Withhold or discontinue in the presence of early-onset or unusually severe toxicity."

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"Results in higher adverse reaction risk (severe, life-threatening, or fatal toxicities). No dosage has proven safe in poor metabolizers and insufficient data are available to recommend a dosage in intermediate metabolizers. Withhold or discontinue in the presence of early-onset or unusually severe toxicity."

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"Results in higher adverse reaction risk (severe, life-threatening, or fatal toxicities). No dosage has proven safe in poor metabolizers and insufficient data are available to recommend a dosage in intermediate metabolizers. Withhold or discontinue in the presence of early-onset or unusually severe toxicity."

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"Results in higher adverse reaction risk (severe, life-threatening, or fatal toxicities). No dosage has proven safe in poor metabolizers and insufficient data are available to recommend a dosage in intermediate metabolizers. Withhold or discontinue in the presence of early-onset or unusually severe toxicity."

\n", "version" : 0 }, - "version" : 0 + "version" : 3 } ], "url" : "https://www.pharmgkb.org/fdaPgxAssociations#PA166329568" @@ -180764,7 +183855,7 @@ "citations" : [ { "id" : 15155142, - "title" : "Table of Pharmacogenetic Associations", + "title" : "FDA Table of Pharmacogenetic Associations", "_sameAs" : "https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations", "authors" : [], "crossReferences" : [ @@ -180787,7 +183878,7 @@ "pgkbPublication" : false, "terms" : [], "type" : "Literature", - "version" : 0, + "version" : 2, "year" : -1 } ], @@ -180799,10 +183890,10 @@ "alternateDrugAvailable" : false, "cancerGenome" : false, "crossReferences" : [], - "dosingInformation" : false, + "dosingInformation" : true, "history" : [], "literature" : [ - {"id":15155142,"title":"Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} + {"id":15155142,"title":"FDA Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} ], "originalDrugText" : "Flurbiprofen", "originalGeneText" : "CYP2C9", @@ -180814,7 +183905,7 @@ "objCls" : "Chemical", "id" : "PA449683", "name" : "flurbiprofen", - "version" : 12 + "version" : 35 } ], "relatedGenes" : [ @@ -180823,7 +183914,7 @@ "id" : "PA126", "symbol" : "CYP2C9", "name" : "cytochrome P450 family 2 subfamily C member 9", - "version" : 7877 + "version" : 7952 } ], "removed" : false, @@ -180836,18 +183927,18 @@ }, "terms" : [], "userId" : "pharmgkb", - "version" : 0, + "version" : 2, "versionDate" : "10/26/2022" }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166311942", - "name" : "Recommendation Annotation PA166311942", + "id" : "PA166312662", + "name" : "Recommendation Annotation PA166312662", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"CYP2C9": "0.0"}, + "lookupKey" : {"CYP2C9": {"*1": 1, "*3": 1}}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: CYP2C9 poor metabolizers or *3 carriers", "relatedChemicals" : [ @@ -180855,30 +183946,30 @@ "objCls" : "Chemical", "id" : "PA449683", "name" : "flurbiprofen", - "version" : 12 + "version" : 35 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329567", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Flurbiprofen - CYP2C9", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452216141, + "id" : 1452218961, "html" : "

"Results in higher systemic concentrations. Use a reduced dosage in poor metabolizers."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312662", - "name" : "Recommendation Annotation PA166312662", + "id" : "PA166311928", + "name" : "Recommendation Annotation PA166311928", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"CYP2C9": {"*1": 1, "*3": 1}}, + "lookupKey" : {"CYP2C9": "0.5"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: CYP2C9 poor metabolizers or *3 carriers", "relatedChemicals" : [ @@ -180886,30 +183977,30 @@ "objCls" : "Chemical", "id" : "PA449683", "name" : "flurbiprofen", - "version" : 12 + "version" : 35 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329567", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Flurbiprofen - CYP2C9", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452218961, + "id" : 1452216127, "html" : "

"Results in higher systemic concentrations. Use a reduced dosage in poor metabolizers."

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166311928", - "name" : "Recommendation Annotation PA166311928", + "id" : "PA166311942", + "name" : "Recommendation Annotation PA166311942", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"CYP2C9": "0.5"}, + "lookupKey" : {"CYP2C9": "0.0"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: CYP2C9 poor metabolizers or *3 carriers", "relatedChemicals" : [ @@ -180917,21 +184008,21 @@ "objCls" : "Chemical", "id" : "PA449683", "name" : "flurbiprofen", - "version" : 12 + "version" : 35 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329567", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Flurbiprofen - CYP2C9", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452216127, + "id" : 1452216141, "html" : "

"Results in higher systemic concentrations. Use a reduced dosage in poor metabolizers."

\n", "version" : 0 }, - "version" : 0 + "version" : 3 } ], "url" : "https://www.pharmgkb.org/fdaPgxAssociations#PA166329567" @@ -180940,7 +184031,7 @@ "citations" : [ { "id" : 15155142, - "title" : "Table of Pharmacogenetic Associations", + "title" : "FDA Table of Pharmacogenetic Associations", "_sameAs" : "https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations", "authors" : [], "crossReferences" : [ @@ -180963,7 +184054,7 @@ "pgkbPublication" : false, "terms" : [], "type" : "Literature", - "version" : 0, + "version" : 2, "year" : -1 } ], @@ -180972,13 +184063,13 @@ "id" : "PA166329569", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Fosphenytoin - CYP2C9", "affectedSubgroup" : "intermediate or poor metabolizers", - "alternateDrugAvailable" : false, + "alternateDrugAvailable" : true, "cancerGenome" : false, "crossReferences" : [], - "dosingInformation" : false, + "dosingInformation" : true, "history" : [], "literature" : [ - {"id":15155142,"title":"Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} + {"id":15155142,"title":"FDA Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} ], "originalDrugText" : "Fosphenytoin", "originalGeneText" : "CYP2C9", @@ -180990,7 +184081,7 @@ "objCls" : "Chemical", "id" : "PA164746820", "name" : "fosphenytoin", - "version" : 9 + "version" : 24 } ], "relatedGenes" : [ @@ -180999,7 +184090,7 @@ "id" : "PA126", "symbol" : "CYP2C9", "name" : "cytochrome P450 family 2 subfamily C member 9", - "version" : 7877 + "version" : 7952 } ], "removed" : false, @@ -181012,18 +184103,18 @@ }, "terms" : [], "userId" : "pharmgkb", - "version" : 0, + "version" : 2, "versionDate" : "10/26/2022" }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166324225", - "name" : "Recommendation Annotation PA166324225", + "id" : "PA166324222", + "name" : "Recommendation Annotation PA166324222", "alternateDrugAvailable" : true, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"CYP2C9": "1.5"}, + "lookupKey" : {"CYP2C9": "0.0"}, "otherPrescribingGuidance" : false, "population" : "CYP2C9 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -181031,17 +184122,17 @@ "objCls" : "Chemical", "id" : "PA164746820", "name" : "fosphenytoin", - "version" : 9 + "version" : 24 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329569", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Fosphenytoin - CYP2C9", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452337684, + "id" : 1452337681, "html" : "

"May result in higher systemic concentrations and higher adverse reaction risk (central nervous system toxicity). Consider starting at the lower end of the dosage range and monitor serum concentrations. Refer to FDA labeling for specific dosing recommendations. Carriers of CYP2C9*3 alleles may be at increased risk of severe cutaneous adverse reactions. Consider avoiding fosphenytoin as an alternative to carbamazepine in patients who are CYP2C9*3 carriers. Genotyping is not a substitute for clinical vigilance and patient management."

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"May result in higher systemic concentrations and higher adverse reaction risk (central nervous system toxicity). Consider starting at the lower end of the dosage range and monitor serum concentrations. Refer to FDA labeling for specific dosing recommendations. Carriers of CYP2C9*3 alleles may be at increased risk of severe cutaneous adverse reactions. Consider avoiding fosphenytoin as an alternative to carbamazepine in patients who are CYP2C9*3 carriers. Genotyping is not a substitute for clinical vigilance and patient management."

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"Results in higher systemic concentrations and higher adverse reaction risk. Monitor for adverse reactions."

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"Results in higher systemic concentrations and higher adverse reaction risk (QT prolongation). Reduce dosage by 50%."

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"May affect systemic concentrations. Monitor for adverse reactions and clinical effect."

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"May affect systemic concentrations. Monitor for adverse reactions and clinical effect."

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"May affect systemic concentrations. Monitor for adverse reactions and clinical effect."

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"May affect systemic concentrations. Monitor for adverse reactions and clinical effect."

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"May affect systemic concentrations. Monitor for adverse reactions and clinical effect."

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"May affect systemic concentrations. Monitor for adverse reactions and clinical effect."

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"May affect systemic concentrations. Monitor for adverse reactions and clinical effect."

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"May affect systemic concentrations. Monitor for adverse reactions and clinical effect."

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"May affect systemic concentrations. Monitor for adverse reactions and clinical effect."

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"May affect systemic concentrations. Monitor for adverse reactions and clinical effect."

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"May affect systemic concentrations. Monitor for adverse reactions and clinical effect."

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"May affect systemic concentrations. Monitor for adverse reactions and clinical effect."

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"May affect systemic concentrations. Monitor for adverse reactions and clinical effect."

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\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", @@ -182480,21 +185579,21 @@ "objCls" : "Chemical", "id" : "PA450353", "name" : "meloxicam", - "version" : 14 + "version" : 32 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329576", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Meloxicam - CYP2C9", - "version" : 0 + "version" : 2 }, "text" : { "id" : 1452216280, "html" : "

"Results in higher systemic concentrations. Consider dose reductions in poor metabolizers. Monitor patients for adverse reactions."

\n", "version" : 0 }, - "version" : 0 + "version" : 3 } ], "url" : "https://www.pharmgkb.org/fdaPgxAssociations#PA166329576" @@ -182503,7 +185602,7 @@ "citations" : [ { "id" : 15155142, - "title" : "Table of Pharmacogenetic Associations", + "title" : "FDA Table of Pharmacogenetic Associations", "_sameAs" : "https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations", "authors" : [], "crossReferences" : [ @@ -182526,7 +185625,7 @@ "pgkbPublication" : false, "terms" : [], "type" : "Literature", - "version" : 0, + "version" : 2, "year" : -1 } ], @@ -182538,10 +185637,10 @@ "alternateDrugAvailable" : false, "cancerGenome" : false, "crossReferences" : [], - "dosingInformation" : false, + "dosingInformation" : true, "history" : [], "literature" : [ - {"id":15155142,"title":"Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} + {"id":15155142,"title":"FDA Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} ], "originalDrugText" : "Mercaptopurine", "originalGeneText" : "TPMT and/or NUDT15", @@ -182553,7 +185652,7 @@ "objCls" : "Chemical", "id" : "PA450379", "name" : "mercaptopurine", - "version" : 31 + "version" : 73 } ], "relatedGenes" : [ @@ -182562,14 +185661,14 @@ "id" : "PA134963132", "symbol" : "NUDT15", "name" : "nudix hydrolase 15", - "version" : 11 + "version" : 39 }, { "objCls" : "Gene", "id" : "PA356", "symbol" : "TPMT", "name" : "thiopurine S-methyltransferase", - "version" : 7545 + "version" : 7628 } ], "removed" : false, @@ -182582,18 +185681,18 @@ }, "terms" : [], "userId" : "pharmgkb", - "version" : 0, + "version" : 2, "versionDate" : "10/26/2022" }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166311029", - "name" : "Recommendation Annotation PA166311029", + "id" : "PA166311001", + "name" : "Recommendation Annotation PA166311001", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -182601,30 +185700,30 @@ "objCls" : "Chemical", "id" : "PA450379", "name" : "mercaptopurine", - "version" : 31 + "version" : 73 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329578", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Mercaptopurine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452213628, + "id" : 1452213601, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166311126", - "name" : "Recommendation Annotation PA166311126", + "id" : "PA166311041", + "name" : "Recommendation Annotation PA166311041", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Indeterminate"}, + "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -182632,30 +185731,30 @@ "objCls" : "Chemical", "id" : "PA450379", "name" : "mercaptopurine", - "version" : 31 + "version" : 73 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329578", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Mercaptopurine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452213725, + "id" : 1452213640, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166311084", - "name" : "Recommendation Annotation PA166311084", + "id" : "PA166311026", + "name" : "Recommendation Annotation PA166311026", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "No Result"}, + "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Possible Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -182663,30 +185762,30 @@ "objCls" : "Chemical", "id" : "PA450379", "name" : "mercaptopurine", - "version" : 31 + "version" : 73 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329578", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Mercaptopurine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452213683, + "id" : 1452213625, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166311027", - "name" : "Recommendation Annotation PA166311027", + "id" : "PA166311021", + "name" : "Recommendation Annotation PA166311021", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Normal Metabolizer"}, + "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -182694,30 +185793,30 @@ "objCls" : "Chemical", "id" : "PA450379", "name" : "mercaptopurine", - "version" : 31 + "version" : 73 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329578", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Mercaptopurine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452213626, + "id" : 1452213620, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166311124", - "name" : "Recommendation Annotation PA166311124", + "id" : "PA166311027", + "name" : "Recommendation Annotation PA166311027", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Normal Metabolizer"}, + "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -182725,30 +185824,30 @@ "objCls" : "Chemical", "id" : "PA450379", "name" : "mercaptopurine", - "version" : 31 + "version" : 73 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329578", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Mercaptopurine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452213723, + "id" : 1452213626, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166311082", - "name" : "Recommendation Annotation PA166311082", + "id" : "PA166311028", + "name" : "Recommendation Annotation PA166311028", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Possible Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "No Result"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -182756,30 +185855,30 @@ "objCls" : "Chemical", "id" : "PA450379", "name" : "mercaptopurine", - "version" : 31 + "version" : 73 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329578", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Mercaptopurine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452213681, + "id" : 1452213627, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166311122", - "name" : "Recommendation Annotation PA166311122", + "id" : "PA166311029", + "name" : "Recommendation Annotation PA166311029", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "No Result", "NUDT15": "Possible Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -182787,30 +185886,30 @@ "objCls" : "Chemical", "id" : "PA450379", "name" : "mercaptopurine", - "version" : 31 + "version" : 73 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329578", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Mercaptopurine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452213721, + "id" : 1452213628, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166311001", - "name" : "Recommendation Annotation PA166311001", + "id" : "PA166311030", + "name" : "Recommendation Annotation PA166311030", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Poor Metabolizer"}, + "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -182818,30 +185917,30 @@ "objCls" : "Chemical", "id" : "PA450379", "name" : "mercaptopurine", - "version" : 31 + "version" : 73 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329578", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Mercaptopurine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452213601, + "id" : 1452213629, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 4 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166311062", - "name" : "Recommendation Annotation PA166311062", + "id" : "PA166311022", + "name" : "Recommendation Annotation PA166311022", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "No Result", "NUDT15": "Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -182849,30 +185948,30 @@ "objCls" : "Chemical", "id" : "PA450379", "name" : "mercaptopurine", - "version" : 31 + "version" : 73 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329578", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Mercaptopurine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452213661, + "id" : 1452213621, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166311121", - "name" : "Recommendation Annotation PA166311121", + "id" : "PA166311023", + "name" : "Recommendation Annotation PA166311023", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "Possible Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "No Result", "NUDT15": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -182880,21 +185979,21 @@ "objCls" : "Chemical", "id" : "PA450379", "name" : "mercaptopurine", - "version" : 31 + "version" : 73 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329578", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Mercaptopurine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452213720, + "id" : 1452213622, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", @@ -182911,30 +186010,30 @@ "objCls" : "Chemical", "id" : "PA450379", "name" : "mercaptopurine", - "version" : 31 + "version" : 73 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329578", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Mercaptopurine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { "id" : 1452213623, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166311022", - "name" : "Recommendation Annotation PA166311022", + "id" : "PA166311025", + "name" : "Recommendation Annotation PA166311025", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "Poor Metabolizer"}, + "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -182942,30 +186041,30 @@ "objCls" : "Chemical", "id" : "PA450379", "name" : "mercaptopurine", - "version" : 31 + "version" : 73 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329578", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Mercaptopurine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452213621, + "id" : 1452213624, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166311101", - "name" : "Recommendation Annotation PA166311101", + "id" : "PA166311062", + "name" : "Recommendation Annotation PA166311062", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Possible Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "No Result", "NUDT15": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -182973,30 +186072,30 @@ "objCls" : "Chemical", "id" : "PA450379", "name" : "mercaptopurine", - "version" : 31 + "version" : 73 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329578", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Mercaptopurine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452213700, + "id" : 1452213661, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166311028", - "name" : "Recommendation Annotation PA166311028", + "id" : "PA166311101", + "name" : "Recommendation Annotation PA166311101", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "No Result"}, + "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Possible Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -183004,30 +186103,30 @@ "objCls" : "Chemical", "id" : "PA450379", "name" : "mercaptopurine", - "version" : 31 + "version" : 73 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329578", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Mercaptopurine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452213627, + "id" : 1452213700, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166311125", - "name" : "Recommendation Annotation PA166311125", + "id" : "PA166311124", + "name" : "Recommendation Annotation PA166311124", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "No Result"}, + "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -183035,30 +186134,30 @@ "objCls" : "Chemical", "id" : "PA450379", "name" : "mercaptopurine", - "version" : 31 + "version" : 73 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329578", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Mercaptopurine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452213724, + "id" : 1452213723, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166311083", - "name" : "Recommendation Annotation PA166311083", + "id" : "PA166311125", + "name" : "Recommendation Annotation PA166311125", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Normal Metabolizer"}, + "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "No Result"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -183066,30 +186165,30 @@ "objCls" : "Chemical", "id" : "PA450379", "name" : "mercaptopurine", - "version" : 31 + "version" : 73 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329578", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Mercaptopurine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452213682, + "id" : 1452213724, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166311123", - "name" : "Recommendation Annotation PA166311123", + "id" : "PA166311126", + "name" : "Recommendation Annotation PA166311126", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "Possible Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -183097,30 +186196,30 @@ "objCls" : "Chemical", "id" : "PA450379", "name" : "mercaptopurine", - "version" : 31 + "version" : 73 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329578", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Mercaptopurine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452213722, + "id" : 1452213725, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166311026", - "name" : "Recommendation Annotation PA166311026", + "id" : "PA166311121", + "name" : "Recommendation Annotation PA166311121", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Possible Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "Possible Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -183128,30 +186227,30 @@ "objCls" : "Chemical", "id" : "PA450379", "name" : "mercaptopurine", - "version" : 31 + "version" : 73 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329578", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Mercaptopurine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452213625, + "id" : 1452213720, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166311081", - "name" : "Recommendation Annotation PA166311081", + "id" : "PA166311061", + "name" : "Recommendation Annotation PA166311061", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -183159,30 +186258,30 @@ "objCls" : "Chemical", "id" : "PA450379", "name" : "mercaptopurine", - "version" : 31 + "version" : 73 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329578", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Mercaptopurine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452213680, + "id" : 1452213660, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166311063", - "name" : "Recommendation Annotation PA166311063", + "id" : "PA166311122", + "name" : "Recommendation Annotation PA166311122", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "No Result", "NUDT15": "Possible Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -183190,30 +186289,30 @@ "objCls" : "Chemical", "id" : "PA450379", "name" : "mercaptopurine", - "version" : 31 + "version" : 73 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329578", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Mercaptopurine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452213662, + "id" : 1452213721, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166311061", - "name" : "Recommendation Annotation PA166311061", + "id" : "PA166311082", + "name" : "Recommendation Annotation PA166311082", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Possible Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -183221,30 +186320,30 @@ "objCls" : "Chemical", "id" : "PA450379", "name" : "mercaptopurine", - "version" : 31 + "version" : 73 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329578", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Mercaptopurine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452213660, + "id" : 1452213681, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166311085", - "name" : "Recommendation Annotation PA166311085", + "id" : "PA166311083", + "name" : "Recommendation Annotation PA166311083", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Indeterminate"}, + "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -183252,30 +186351,30 @@ "objCls" : "Chemical", "id" : "PA450379", "name" : "mercaptopurine", - "version" : 31 + "version" : 73 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329578", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Mercaptopurine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452213684, + "id" : 1452213682, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166311030", - "name" : "Recommendation Annotation PA166311030", + "id" : "PA166311084", + "name" : "Recommendation Annotation PA166311084", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Indeterminate"}, + "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "No Result"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -183283,30 +186382,30 @@ "objCls" : "Chemical", "id" : "PA450379", "name" : "mercaptopurine", - "version" : 31 + "version" : 73 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329578", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Mercaptopurine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452213629, + "id" : 1452213683, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166311041", - "name" : "Recommendation Annotation PA166311041", + "id" : "PA166311063", + "name" : "Recommendation Annotation PA166311063", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -183314,30 +186413,30 @@ "objCls" : "Chemical", "id" : "PA450379", "name" : "mercaptopurine", - "version" : 31 + "version" : 73 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329578", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Mercaptopurine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452213640, + "id" : 1452213662, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166311025", - "name" : "Recommendation Annotation PA166311025", + "id" : "PA166311085", + "name" : "Recommendation Annotation PA166311085", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "Poor Metabolizer"}, + "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -183345,30 +186444,30 @@ "objCls" : "Chemical", "id" : "PA450379", "name" : "mercaptopurine", - "version" : 31 + "version" : 73 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329578", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Mercaptopurine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452213624, + "id" : 1452213684, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166311023", - "name" : "Recommendation Annotation PA166311023", + "id" : "PA166311123", + "name" : "Recommendation Annotation PA166311123", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "No Result", "NUDT15": "Poor Metabolizer"}, + "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "Possible Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -183376,30 +186475,30 @@ "objCls" : "Chemical", "id" : "PA450379", "name" : "mercaptopurine", - "version" : 31 + "version" : 73 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329578", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Mercaptopurine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452213622, + "id" : 1452213722, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166311021", - "name" : "Recommendation Annotation PA166311021", + "id" : "PA166311081", + "name" : "Recommendation Annotation PA166311081", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Poor Metabolizer"}, + "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -183407,21 +186506,21 @@ "objCls" : "Chemical", "id" : "PA450379", "name" : "mercaptopurine", - "version" : 31 + "version" : 73 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329578", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Mercaptopurine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452213620, + "id" : 1452213680, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 } ], "url" : "https://www.pharmgkb.org/fdaPgxAssociations#PA166329578" @@ -183430,7 +186529,7 @@ "citations" : [ { "id" : 15155142, - "title" : "Table of Pharmacogenetic Associations", + "title" : "FDA Table of Pharmacogenetic Associations", "_sameAs" : "https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations", "authors" : [], "crossReferences" : [ @@ -183453,7 +186552,7 @@ "pgkbPublication" : false, "terms" : [], "type" : "Literature", - "version" : 0, + "version" : 2, "year" : -1 } ], @@ -183465,10 +186564,10 @@ "alternateDrugAvailable" : false, "cancerGenome" : false, "crossReferences" : [], - "dosingInformation" : false, + "dosingInformation" : true, "history" : [], "literature" : [ - {"id":15155142,"title":"Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} + {"id":15155142,"title":"FDA Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} ], "originalDrugText" : "Metoclopramide", "originalGeneText" : "CYP2D6", @@ -183480,7 +186579,7 @@ "objCls" : "Chemical", "id" : "PA450475", "name" : "metoclopramide", - "version" : 8 + "version" : 32 } ], "relatedGenes" : [ @@ -183489,7 +186588,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "removed" : false, @@ -183502,7 +186601,7 @@ }, "terms" : [], "userId" : "pharmgkb", - "version" : 0, + "version" : 2, "versionDate" : "10/26/2022" }, "recommendations" : [ @@ -183521,21 +186620,21 @@ "objCls" : "Chemical", "id" : "PA450475", "name" : "metoclopramide", - "version" : 8 + "version" : 32 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329577", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Metoclopramide - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { "id" : 1452216663, "html" : "

"Results in higher systemic concentrations and higher adverse reaction risk. The recommended dosage is lower. Refer to FDA labeling for specific dosing recommendations."

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"Results in higher systemic concentrations and may result in higher adverse reaction risk (hypoglycemia). Dosage reduction is recommended. Increase monitoring frequency for adverse reactions. Refer to FDA labeling for specific dosing recommendations."

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"Results in higher systemic concentrations and may result in higher adverse reaction risk (hypoglycemia). Dosage reduction is recommended. Increase monitoring frequency for adverse reactions. Refer to FDA labeling for specific dosing recommendations."

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"Results in higher systemic concentrations and higher adverse reaction risk (respiratory depression and sedation). May require less frequent dosing."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 } ], "url" : "https://www.pharmgkb.org/fdaPgxAssociations#PA166329581" @@ -183803,7 +186902,7 @@ "citations" : [ { "id" : 15155142, - "title" : "Table of Pharmacogenetic Associations", + "title" : "FDA Table of Pharmacogenetic Associations", "_sameAs" : "https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations", "authors" : [], "crossReferences" : [ @@ -183826,7 +186925,7 @@ "pgkbPublication" : false, "terms" : [], "type" : "Literature", - "version" : 0, + "version" : 2, "year" : -1 } ], @@ -183838,10 +186937,10 @@ "alternateDrugAvailable" : false, "cancerGenome" : false, "crossReferences" : [], - "dosingInformation" : false, + "dosingInformation" : true, "history" : [], "literature" : [ - {"id":15155142,"title":"Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} + {"id":15155142,"title":"FDA Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} ], "originalDrugText" : "Pantoprazole", "originalGeneText" : "CYP2C19", @@ -183853,7 +186952,7 @@ "objCls" : "Chemical", "id" : "PA450774", "name" : "pantoprazole", - "version" : 15 + "version" : 37 } ], "relatedGenes" : [ @@ -183862,7 +186961,7 @@ "id" : "PA124", "symbol" : "CYP2C19", "name" : "cytochrome P450 family 2 subfamily C member 19", - "version" : 7210 + "version" : 7266 } ], "removed" : false, @@ -183875,18 +186974,18 @@ }, "terms" : [], "userId" : "pharmgkb", - "version" : 0, + "version" : 2, "versionDate" : "10/26/2022" }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166310323", - "name" : "Recommendation Annotation PA166310323", + "id" : "PA166310322", + "name" : "Recommendation Annotation PA166310322", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"CYP2C19": "Likely Intermediate Metabolizer"}, + "lookupKey" : {"CYP2C19": "Likely Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Pediatrics; Affected subgroup: CYP2C19 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -183894,30 +186993,30 @@ "objCls" : "Chemical", "id" : "PA450774", "name" : "pantoprazole", - "version" : 15 + "version" : 37 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329582", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Pantoprazole - CYP2C19", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452211502, + "id" : 1452211501, "html" : "

"Results in higher systemic concentrations. Consider dosage reduction in children who are poor metabolizers. No dosage adjustment is needed for adult patients who are intermediate or poor metabolizers."

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"Results in higher systemic concentrations. Consider dosage reduction in children who are poor metabolizers. No dosage adjustment is needed for adult patients who are intermediate or poor metabolizers."

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"Results in higher systemic concentrations. Consider dosage reduction in children who are poor metabolizers. No dosage adjustment is needed for adult patients who are intermediate or poor metabolizers."

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"Results in higher systemic concentrations. Consider dosage reduction in children who are poor metabolizers. No dosage adjustment is needed for adult patients who are intermediate or poor metabolizers."

\n", "version" : 0 }, - "version" : 0 + "version" : 3 } ], "url" : "https://www.pharmgkb.org/fdaPgxAssociations#PA166329582" @@ -184010,7 +187109,7 @@ "citations" : [ { "id" : 15155142, - "title" : "Table of Pharmacogenetic Associations", + "title" : "FDA Table of Pharmacogenetic Associations", "_sameAs" : "https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations", "authors" : [], "crossReferences" : [ @@ -184033,7 +187132,7 @@ "pgkbPublication" : false, "terms" : [], "type" : "Literature", - "version" : 0, + "version" : 2, "year" : -1 } ], @@ -184042,13 +187141,13 @@ "id" : "PA166329583", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Phenytoin - CYP2C9", "affectedSubgroup" : "intermediate or poor metabolizers", - "alternateDrugAvailable" : false, + "alternateDrugAvailable" : true, "cancerGenome" : false, "crossReferences" : [], - "dosingInformation" : false, + "dosingInformation" : true, "history" : [], "literature" : [ - {"id":15155142,"title":"Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} + {"id":15155142,"title":"FDA Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} ], "originalDrugText" : "Phenytoin", "originalGeneText" : "CYP2C9", @@ -184060,7 +187159,7 @@ "objCls" : "Chemical", "id" : "PA450947", "name" : "phenytoin", - "version" : 14 + "version" : 49 } ], "relatedGenes" : [ @@ -184069,7 +187168,7 @@ "id" : "PA126", "symbol" : "CYP2C9", "name" : "cytochrome P450 family 2 subfamily C member 9", - "version" : 7877 + "version" : 7952 } ], "removed" : false, @@ -184082,18 +187181,18 @@ }, "terms" : [], "userId" : "pharmgkb", - "version" : 0, + "version" : 2, "versionDate" : "10/26/2022" }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166324201", - "name" : "Recommendation Annotation PA166324201", + "id" : "PA166324202", + "name" : "Recommendation Annotation PA166324202", "alternateDrugAvailable" : true, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"CYP2C9": "0.0"}, + "lookupKey" : {"CYP2C9": "0.5"}, "otherPrescribingGuidance" : false, "population" : "CYP2C9 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -184101,17 +187200,17 @@ "objCls" : "Chemical", "id" : "PA450947", "name" : "phenytoin", - "version" : 14 + "version" : 49 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329583", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Phenytoin - CYP2C9", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452337660, + "id" : 1452337661, "html" : "

"May result in higher systemic concentrations and higher adverse reaction risk (central nervous system toxicity). Refer to FDA labeling for specific dosing recommendations. Carriers of CYP2C9*3 alleles may be at increased risk of severe cutaneous adverse reactions. Consider avoiding phenytoin as an alternative to carbamazepine in patients who are CYP2C9*3 carriers. Genotyping is not a substitute for clinical vigilance and patient management."

\n", "version" : 0 }, @@ -184119,12 +187218,12 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166324204", - "name" : "Recommendation Annotation PA166324204", + "id" : "PA166324201", + "name" : "Recommendation Annotation PA166324201", "alternateDrugAvailable" : true, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"CYP2C9": "1.5"}, + "lookupKey" : {"CYP2C9": "0.0"}, "otherPrescribingGuidance" : false, "population" : "CYP2C9 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -184132,30 +187231,30 @@ "objCls" : "Chemical", "id" : "PA450947", "name" : "phenytoin", - "version" : 14 + "version" : 49 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329583", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Phenytoin - CYP2C9", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452337663, + "id" : 1452337660, "html" : "

"May result in higher systemic concentrations and higher adverse reaction risk (central nervous system toxicity). Refer to FDA labeling for specific dosing recommendations. Carriers of CYP2C9*3 alleles may be at increased risk of severe cutaneous adverse reactions. Consider avoiding phenytoin as an alternative to carbamazepine in patients who are CYP2C9*3 carriers. Genotyping is not a substitute for clinical vigilance and patient management."

\n", "version" : 0 }, - "version" : 0 + "version" : 1 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166324202", - "name" : "Recommendation Annotation PA166324202", + "id" : "PA166324203", + "name" : "Recommendation Annotation PA166324203", "alternateDrugAvailable" : true, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"CYP2C9": "0.5"}, + "lookupKey" : {"CYP2C9": "1.0"}, "otherPrescribingGuidance" : false, "population" : "CYP2C9 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -184163,17 +187262,17 @@ "objCls" : "Chemical", "id" : "PA450947", "name" : "phenytoin", - "version" : 14 + "version" : 49 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329583", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Phenytoin - CYP2C9", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452337661, + "id" : 1452337662, "html" : "

"May result in higher systemic concentrations and higher adverse reaction risk (central nervous system toxicity). Refer to FDA labeling for specific dosing recommendations. Carriers of CYP2C9*3 alleles may be at increased risk of severe cutaneous adverse reactions. Consider avoiding phenytoin as an alternative to carbamazepine in patients who are CYP2C9*3 carriers. Genotyping is not a substitute for clinical vigilance and patient management."

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"May result in higher systemic concentrations and higher adverse reaction risk (central nervous system toxicity). Refer to FDA labeling for specific dosing recommendations. Carriers of CYP2C9*3 alleles may be at increased risk of severe cutaneous adverse reactions. Consider avoiding phenytoin as an alternative to carbamazepine in patients who are CYP2C9*3 carriers. Genotyping is not a substitute for clinical vigilance and patient management."

\n", "version" : 0 }, @@ -184217,7 +187316,7 @@ "citations" : [ { "id" : 15155142, - "title" : "Table of Pharmacogenetic Associations", + "title" : "FDA Table of Pharmacogenetic Associations", "_sameAs" : "https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations", "authors" : [], "crossReferences" : [ @@ -184240,7 +187339,7 @@ "pgkbPublication" : false, "terms" : [], "type" : "Literature", - "version" : 0, + "version" : 2, "year" : -1 } ], @@ -184249,25 +187348,33 @@ "id" : "PA166329584", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Phenytoin - HLA-B", "affectedSubgroup" : "*15:02 allele positive", - "alternateDrugAvailable" : false, + "alternateDrugAvailable" : true, "cancerGenome" : false, "crossReferences" : [], "dosingInformation" : false, "history" : [], "literature" : [ - {"id":15155142,"title":"Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} + {"id":15155142,"title":"FDA Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} ], "originalDrugText" : "Phenytoin", "originalGeneText" : "HLA-B", "otherPrescribingGuidance" : false, "pediatric" : false, - "relatedAlleles" : [], + "relatedAlleles" : [ + { + "objCls" : "Haplotype", + "id" : "PA165954769", + "symbol" : "HLA-B*15:02", + "name" : "*15:02", + "version" : 21 + } + ], "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450947", "name" : "phenytoin", - "version" : 14 + "version" : 49 } ], "relatedGenes" : [ @@ -184276,7 +187383,7 @@ "id" : "PA35056", "symbol" : "HLA-B", "name" : "major histocompatibility complex, class I, B", - "version" : 40 + "version" : 2920 } ], "removed" : false, @@ -184289,7 +187396,7 @@ }, "terms" : [], "userId" : "pharmgkb", - "version" : 0, + "version" : 4, "versionDate" : "10/26/2022" }, "recommendations" : [ @@ -184308,14 +187415,14 @@ "objCls" : "Chemical", "id" : "PA450947", "name" : "phenytoin", - "version" : 14 + "version" : 49 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329584", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Phenytoin - HLA-B", - "version" : 0 + "version" : 4 }, "text" : { "id" : 1452337620, @@ -184331,7 +187438,7 @@ "citations" : [ { "id" : 15155142, - "title" : "Table of Pharmacogenetic Associations", + "title" : "FDA Table of Pharmacogenetic Associations", "_sameAs" : "https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations", "authors" : [], "crossReferences" : [ @@ -184354,7 +187461,7 @@ "pgkbPublication" : false, "terms" : [], "type" : "Literature", - "version" : 0, + "version" : 2, "year" : -1 } ], @@ -184366,10 +187473,10 @@ "alternateDrugAvailable" : false, "cancerGenome" : false, "crossReferences" : [], - "dosingInformation" : false, + "dosingInformation" : true, "history" : [], "literature" : [ - {"id":15155142,"title":"Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} + {"id":15155142,"title":"FDA Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} ], "originalDrugText" : "Pimozide", "originalGeneText" : "CYP2D6", @@ -184381,7 +187488,7 @@ "objCls" : "Chemical", "id" : "PA450965", "name" : "pimozide", - "version" : 12 + "version" : 33 } ], "relatedGenes" : [ @@ -184390,7 +187497,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "removed" : false, @@ -184403,71 +187510,71 @@ }, "terms" : [], "userId" : "pharmgkb", - "version" : 0, + "version" : 2, "versionDate" : "10/26/2022" }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166312149", - "name" : "Recommendation Annotation PA166312149", + "id" : "PA166312150", + "name" : "Recommendation Annotation PA166312150", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], "lookupKey" : {"CYP2D6": "0.0"}, "otherPrescribingGuidance" : false, - "population" : "Affected subgroup: CYP2D6 poor metabolizers", + "population" : "Pediatrics; Affected subgroup: CYP2D6 poor metabolizers", "relatedChemicals" : [ { "objCls" : "Chemical", "id" : "PA450965", "name" : "pimozide", - "version" : 12 + "version" : 33 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329585", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Pimozide - 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"Results in higher systemic concentrations. Dosages should not exceed 0.05 mg/kg in children or 4 mg/day in adults who are poor metabolizers and dosages should not be increased earlier than 14 days."

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"Results in higher systemic concentrations. Dosages should not exceed 0.05 mg/kg in children or 4 mg/day in adults who are poor metabolizers and dosages should not be increased earlier than 14 days."

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"Results in higher systemic concentrations. Consider reducing dosage in poor metabolizers."

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"Results in higher systemic concentrations. Consider reducing dosage in poor metabolizers."

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"Results in higher systemic concentrations. Consider reducing dosage in poor metabolizers."

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166311931", - "name" : "Recommendation Annotation PA166311931", + "id" : "PA166311930", + "name" : "Recommendation Annotation PA166311930", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"CYP2C9": "0.5"}, + "lookupKey" : {"CYP2C9": "0.0"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: CYP2C9 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -184660,21 +187767,21 @@ "objCls" : "Chemical", "id" : "PA450985", "name" : "piroxicam", - "version" : 13 + "version" : 31 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329586", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Piroxicam - CYP2C9", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452216130, + "id" : 1452216129, "html" : "

"Results in higher systemic concentrations. Consider reducing dosage in poor metabolizers."

\n", "version" : 0 }, - "version" : 0 + "version" : 3 } ], "url" : "https://www.pharmgkb.org/fdaPgxAssociations#PA166329586" @@ -184683,7 +187790,7 @@ "citations" : [ { "id" : 15155142, - "title" : "Table of Pharmacogenetic Associations", + "title" : "FDA Table of Pharmacogenetic Associations", "_sameAs" : "https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations", "authors" : [], "crossReferences" : [ @@ -184706,7 +187813,7 @@ "pgkbPublication" : false, "terms" : [], "type" : "Literature", - "version" : 0, + "version" : 2, "year" : -1 } ], @@ -184718,10 +187825,10 @@ "alternateDrugAvailable" : false, "cancerGenome" : false, "crossReferences" : [], - "dosingInformation" : false, + "dosingInformation" : true, "history" : [], "literature" : [ - {"id":15155142,"title":"Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} + {"id":15155142,"title":"FDA Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} ], "originalDrugText" : "Pitolisant", "originalGeneText" : "CYP2D6", @@ -184733,7 +187840,7 @@ "objCls" : "Chemical", "id" : "PA166185163", "name" : "pitolisant", - "version" : 4 + "version" : 5 } ], "relatedGenes" : [ @@ -184742,7 +187849,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "removed" : false, @@ -184755,7 +187862,7 @@ }, "terms" : [], "userId" : "pharmgkb", - "version" : 0, + "version" : 2, "versionDate" : "10/26/2022" }, "recommendations" : [ @@ -184774,21 +187881,21 @@ "objCls" : "Chemical", "id" : "PA166185163", "name" : "pitolisant", - "version" : 4 + "version" : 5 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329587", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Pitolisant - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { "id" : 1452216723, "html" : "

"Results in higher systemic concentrations. Use lowest recommended starting dosage. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 } ], "url" : "https://www.pharmgkb.org/fdaPgxAssociations#PA166329587" @@ -184797,7 +187904,7 @@ "citations" : [ { "id" : 15155142, - "title" : "Table of Pharmacogenetic Associations", + "title" : "FDA Table of Pharmacogenetic Associations", "_sameAs" : "https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations", "authors" : [], "crossReferences" : [ @@ -184820,7 +187927,7 @@ "pgkbPublication" : false, "terms" : [], "type" : "Literature", - "version" : 0, + "version" : 2, "year" : -1 } ], @@ -184829,13 +187936,13 @@ "id" : "PA166329588", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Propafenone - CYP2D6", "affectedSubgroup" : "poor metabolizers", - "alternateDrugAvailable" : false, + "alternateDrugAvailable" : true, "cancerGenome" : false, "crossReferences" : [], "dosingInformation" : false, "history" : [], "literature" : [ - {"id":15155142,"title":"Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} + {"id":15155142,"title":"FDA Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} ], "originalDrugText" : "Propafenone", "originalGeneText" : "CYP2D6", @@ -184847,7 +187954,7 @@ "objCls" : "Chemical", "id" : "PA451131", "name" : "propafenone", - "version" : 11 + "version" : 28 } ], "relatedGenes" : [ @@ -184856,7 +187963,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "removed" : false, @@ -184869,7 +187976,7 @@ }, "terms" : [], "userId" : "pharmgkb", - "version" : 0, + "version" : 2, "versionDate" : "10/26/2022" }, "recommendations" : [ @@ -184888,21 +187995,21 @@ "objCls" : "Chemical", "id" : "PA451131", "name" : "propafenone", - "version" : 11 + "version" : 28 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329588", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Propafenone - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { "id" : 1452216420, "html" : "

"Results in higher systemic concentrations and higher adverse reaction risk (arrhythmia). Avoid use in poor metabolizers taking a CYP3A4 inhibitor."

\n", "version" : 0 }, - "version" : 0 + "version" : 3 } ], "url" : "https://www.pharmgkb.org/fdaPgxAssociations#PA166329588" @@ -184911,7 +188018,7 @@ "citations" : [ { "id" : 15155142, - "title" : "Table of Pharmacogenetic Associations", + "title" : "FDA Table of Pharmacogenetic Associations", "_sameAs" : "https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations", "authors" : [], "crossReferences" : [ @@ -184934,7 +188041,7 @@ "pgkbPublication" : false, "terms" : [], "type" : "Literature", - "version" : 0, + "version" : 2, "year" : -1 } ], @@ -184949,11 +188056,11 @@ "dosingInformation" : false, "history" : [], "literature" : [ - {"id":15155142,"title":"Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} + {"id":15155142,"title":"FDA Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} ], "originalDrugText" : "Sacituzumab Govitecan-hziy", "originalGeneText" : "UGT1A1", - "otherPrescribingGuidance" : false, + "otherPrescribingGuidance" : true, "pediatric" : false, "relatedAlleles" : [], "relatedChemicals" : [ @@ -184961,7 +188068,7 @@ "objCls" : "Chemical", "id" : "PA166225061", "name" : "sacituzumab govitecan", - "version" : 4 + "version" : 8 } ], "relatedGenes" : [ @@ -184970,7 +188077,7 @@ "id" : "PA420", "symbol" : "UGT1A1", "name" : "UDP glucuronosyltransferase 1 family, polypeptide A1", - "version" : 6110 + "version" : 6350 } ], "removed" : false, @@ -184983,7 +188090,7 @@ }, "terms" : [], "userId" : "pharmgkb", - "version" : 0, + "version" : 2, "versionDate" : "10/26/2022" }, "recommendations" : [ @@ -185002,21 +188109,21 @@ "objCls" : "Chemical", "id" : "PA166225061", "name" : "sacituzumab govitecan", - "version" : 4 + "version" : 8 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329589", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Sacituzumab Govitecan-hziy - UGT1A1", - "version" : 0 + "version" : 2 }, "text" : { "id" : 1452269120, "html" : "

"May result in higher systemic concentrations and adverse reaction risk (neutropenia). Monitor for adverse reactions and tolerance to treatment."

\n", - "version" : 0 + "version" : 1 }, - "version" : 0 + "version" : 1 } ], "url" : "https://www.pharmgkb.org/fdaPgxAssociations#PA166329589" @@ -185025,7 +188132,7 @@ "citations" : [ { "id" : 15155142, - "title" : "Table of Pharmacogenetic Associations", + "title" : "FDA Table of Pharmacogenetic Associations", "_sameAs" : "https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations", "authors" : [], "crossReferences" : [ @@ -185048,7 +188155,7 @@ "pgkbPublication" : false, "terms" : [], "type" : "Literature", - "version" : 0, + "version" : 2, "year" : -1 } ], @@ -185057,13 +188164,13 @@ "id" : "PA166329590", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Siponimod - CYP2C9", "affectedSubgroup" : "intermediate or poor metabolizers", - "alternateDrugAvailable" : false, + "alternateDrugAvailable" : true, "cancerGenome" : false, "crossReferences" : [], - "dosingInformation" : false, + "dosingInformation" : true, "history" : [], "literature" : [ - {"id":15155142,"title":"Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} + {"id":15155142,"title":"FDA Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} ], "originalDrugText" : "Siponimod", "originalGeneText" : "CYP2C9", @@ -185075,7 +188182,7 @@ "objCls" : "Chemical", "id" : "PA166182736", "name" : "siponimod", - "version" : 7 + "version" : 9 } ], "relatedGenes" : [ @@ -185084,7 +188191,7 @@ "id" : "PA126", "symbol" : "CYP2C9", "name" : "cytochrome P450 family 2 subfamily C member 9", - "version" : 7877 + "version" : 7952 } ], "removed" : false, @@ -185097,18 +188204,18 @@ }, "terms" : [], "userId" : "pharmgkb", - "version" : 0, + "version" : 2, "versionDate" : "10/26/2022" }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166312703", - "name" : "Recommendation Annotation PA166312703", + "id" : "PA166312704", + "name" : "Recommendation Annotation PA166312704", "alternateDrugAvailable" : true, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"CYP2C9": "0.5"}, + "lookupKey" : {"CYP2C9": "1.0"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: CYP2C9 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -185116,21 +188223,21 @@ "objCls" : "Chemical", "id" : "PA166182736", "name" : "siponimod", - "version" : 7 + "version" : 9 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329590", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Siponimod - CYP2C9", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452219002, + "id" : 1452219003, "html" : "

"Results in higher systemic concentrations. Adjust dosage based on genotype. Do not use in patients with CYP2C9 *3/*3 genotype. Refer to FDA labeling for specific dosing recommendations."

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"Results in higher systemic concentrations. Adjust dosage based on genotype. Do not use in patients with CYP2C9 *3/*3 genotype. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312721", - "name" : "Recommendation Annotation PA166312721", + "id" : "PA166312703", + "name" : "Recommendation Annotation PA166312703", "alternateDrugAvailable" : true, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"CYP2C9": "0.0"}, + "lookupKey" : {"CYP2C9": "0.5"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: CYP2C9 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -185178,30 +188285,30 @@ "objCls" : "Chemical", "id" : "PA166182736", "name" : "siponimod", - "version" : 7 + "version" : 9 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329590", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Siponimod - CYP2C9", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452219020, + "id" : 1452219002, "html" : "

"Results in higher systemic concentrations. Adjust dosage based on genotype. Do not use in patients with CYP2C9 *3/*3 genotype. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312704", - "name" : "Recommendation Annotation PA166312704", + "id" : "PA166312721", + "name" : "Recommendation Annotation PA166312721", "alternateDrugAvailable" : true, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"CYP2C9": "1.0"}, + "lookupKey" : {"CYP2C9": "0.0"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: CYP2C9 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -185209,21 +188316,21 @@ "objCls" : "Chemical", "id" : "PA166182736", "name" : "siponimod", - "version" : 7 + "version" : 9 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329590", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Siponimod - CYP2C9", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452219003, + "id" : 1452219020, "html" : "

"Results in higher systemic concentrations. Adjust dosage based on genotype. Do not use in patients with CYP2C9 *3/*3 genotype. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 } ], "url" : "https://www.pharmgkb.org/fdaPgxAssociations#PA166329590" @@ -185232,7 +188339,7 @@ "citations" : [ { "id" : 15155142, - "title" : "Table of Pharmacogenetic Associations", + "title" : "FDA Table of Pharmacogenetic Associations", "_sameAs" : "https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations", "authors" : [], "crossReferences" : [ @@ -185255,7 +188362,7 @@ "pgkbPublication" : false, "terms" : [], "type" : "Literature", - "version" : 0, + "version" : 2, "year" : -1 } ], @@ -185267,10 +188374,10 @@ "alternateDrugAvailable" : false, "cancerGenome" : false, "crossReferences" : [], - "dosingInformation" : false, + "dosingInformation" : true, "history" : [], "literature" : [ - {"id":15155142,"title":"Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} + {"id":15155142,"title":"FDA Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} ], "originalDrugText" : "Tacrolimus", "originalGeneText" : "CYP3A5", @@ -185282,7 +188389,7 @@ "objCls" : "Chemical", "id" : "PA451578", "name" : "tacrolimus", - "version" : 25 + "version" : 81 } ], "relatedGenes" : [ @@ -185291,7 +188398,7 @@ "id" : "PA131", "symbol" : "CYP3A5", "name" : "cytochrome P450 family 3 subfamily A member 5", - "version" : 7962 + "version" : 8072 } ], "removed" : false, @@ -185304,7 +188411,7 @@ }, "terms" : [], "userId" : "pharmgkb", - "version" : 0, + "version" : 2, "versionDate" : "10/26/2022" }, "recommendations" : [ @@ -185323,14 +188430,14 @@ "objCls" : "Chemical", "id" : "PA451578", "name" : "tacrolimus", - "version" : 25 + "version" : 81 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329592", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Tacrolimus - CYP3A5", - "version" : 0 + "version" : 2 }, "text" : { "id" : 1452246020, @@ -185341,12 +188448,12 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166315263", - "name" : "Recommendation Annotation PA166315263", + "id" : "PA166315262", + "name" : "Recommendation Annotation PA166315262", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"CYP3A5": "Possible Intermediate Metabolizer"}, + "lookupKey" : {"CYP3A5": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: CYP3A5 intermediate or normal metabolizers", "relatedChemicals" : [ @@ -185354,17 +188461,17 @@ "objCls" : "Chemical", "id" : "PA451578", "name" : "tacrolimus", - "version" : 25 + "version" : 81 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329592", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Tacrolimus - CYP3A5", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452246022, + "id" : 1452246021, "html" : "

"Results in lower systemic concentrations, lower probability of achieving target concentrations and may result in higher rejection risk. Measure drug concentrations and adjust dosage based on trough whole blood tacrolimus concentrations."

\n", "version" : 0 }, @@ -185372,12 +188479,12 @@ }, { "objCls" : "Recommendation Annotation", - "id" : "PA166315262", - "name" : "Recommendation Annotation PA166315262", + "id" : "PA166315263", + "name" : "Recommendation Annotation PA166315263", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"CYP3A5": "Normal Metabolizer"}, + "lookupKey" : {"CYP3A5": "Possible Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: CYP3A5 intermediate or normal metabolizers", "relatedChemicals" : [ @@ -185385,17 +188492,17 @@ "objCls" : "Chemical", "id" : "PA451578", "name" : "tacrolimus", - "version" : 25 + "version" : 81 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329592", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Tacrolimus - CYP3A5", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452246021, + "id" : 1452246022, "html" : "

"Results in lower systemic concentrations, lower probability of achieving target concentrations and may result in higher rejection risk. Measure drug concentrations and adjust dosage based on trough whole blood tacrolimus concentrations."

\n", "version" : 0 }, @@ -185408,7 +188515,7 @@ "citations" : [ { "id" : 15155142, - "title" : "Table of Pharmacogenetic Associations", + "title" : "FDA Table of Pharmacogenetic Associations", "_sameAs" : "https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations", "authors" : [], "crossReferences" : [ @@ -185431,7 +188538,7 @@ "pgkbPublication" : false, "terms" : [], "type" : "Literature", - "version" : 0, + "version" : 2, "year" : -1 } ], @@ -185443,10 +188550,10 @@ "alternateDrugAvailable" : false, "cancerGenome" : false, "crossReferences" : [], - "dosingInformation" : false, + "dosingInformation" : true, "history" : [], "literature" : [ - {"id":15155142,"title":"Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} + {"id":15155142,"title":"FDA Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} ], "originalDrugText" : "Tetrabenazine", "originalGeneText" : "CYP2D6", @@ -185458,7 +188565,7 @@ "objCls" : "Chemical", "id" : "PA140222719", "name" : "tetrabenazine", - "version" : 8 + "version" : 28 } ], "relatedGenes" : [ @@ -185467,7 +188574,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "removed" : false, @@ -185480,7 +188587,7 @@ }, "terms" : [], "userId" : "pharmgkb", - "version" : 0, + "version" : 2, "versionDate" : "10/26/2022" }, "recommendations" : [ @@ -185499,21 +188606,21 @@ "objCls" : "Chemical", "id" : "PA140222719", "name" : "tetrabenazine", - "version" : 8 + "version" : 28 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329593", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Tetrabenazine - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { "id" : 1452215586, "html" : "

"Results in higher systemic concentrations. The maximum recommended single dose is 25 mg and should not exceed 50 mg/day."

\n", "version" : 0 }, - "version" : 0 + "version" : 3 } ], "url" : "https://www.pharmgkb.org/fdaPgxAssociations#PA166329593" @@ -185522,7 +188629,7 @@ "citations" : [ { "id" : 15155142, - "title" : "Table of Pharmacogenetic Associations", + "title" : "FDA Table of Pharmacogenetic Associations", "_sameAs" : "https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations", "authors" : [], "crossReferences" : [ @@ -185545,7 +188652,7 @@ "pgkbPublication" : false, "terms" : [], "type" : "Literature", - "version" : 0, + "version" : 2, "year" : -1 } ], @@ -185557,10 +188664,10 @@ "alternateDrugAvailable" : false, "cancerGenome" : false, "crossReferences" : [], - "dosingInformation" : false, + "dosingInformation" : true, "history" : [], "literature" : [ - {"id":15155142,"title":"Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} + {"id":15155142,"title":"FDA Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} ], "originalDrugText" : "Thioguanine", "originalGeneText" : "TPMT and/or NUDT15", @@ -185572,7 +188679,7 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "relatedGenes" : [ @@ -185581,14 +188688,14 @@ "id" : "PA134963132", "symbol" : "NUDT15", "name" : "nudix hydrolase 15", - "version" : 11 + "version" : 39 }, { "objCls" : "Gene", "id" : "PA356", "symbol" : "TPMT", "name" : "thiopurine S-methyltransferase", - "version" : 7545 + "version" : 7628 } ], "removed" : false, @@ -185601,7 +188708,7 @@ }, "terms" : [], "userId" : "pharmgkb", - "version" : 0, + "version" : 2, "versionDate" : "10/26/2022" }, "recommendations" : [ @@ -185620,30 +188727,30 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329594", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Thioguanine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { "id" : 1452216309, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312081", - "name" : "Recommendation Annotation PA166312081", + "id" : "PA166312073", + "name" : "Recommendation Annotation PA166312073", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -185651,30 +188758,30 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329594", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Thioguanine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452216320, + "id" : 1452216312, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312072", - "name" : "Recommendation Annotation PA166312072", + "id" : "PA166312064", + "name" : "Recommendation Annotation PA166312064", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "No Result"}, + "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -185682,30 +188789,30 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329594", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Thioguanine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452216311, + "id" : 1452216303, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312083", - "name" : "Recommendation Annotation PA166312083", + "id" : "PA166312068", + "name" : "Recommendation Annotation PA166312068", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -185713,30 +188820,30 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329594", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Thioguanine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452216322, + "id" : 1452216307, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312101", - "name" : "Recommendation Annotation PA166312101", + "id" : "PA166312071", + "name" : "Recommendation Annotation PA166312071", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Indeterminate"}, + "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "No Result"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -185744,30 +188851,30 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329594", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Thioguanine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452216340, + "id" : 1452216310, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312033", - "name" : "Recommendation Annotation PA166312033", + "id" : "PA166312074", + "name" : "Recommendation Annotation PA166312074", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Poor Metabolizer"}, + "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -185775,30 +188882,30 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329594", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Thioguanine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452216232, + "id" : 1452216313, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312042", - "name" : "Recommendation Annotation PA166312042", + "id" : "PA166312032", + "name" : "Recommendation Annotation PA166312032", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Possible Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "Possible Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -185806,30 +188913,30 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329594", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Thioguanine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452216282, + "id" : 1452216231, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312066", - "name" : "Recommendation Annotation PA166312066", + "id" : "PA166312065", + "name" : "Recommendation Annotation PA166312065", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "No Result", "NUDT15": "Poor Metabolizer"}, + "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -185837,30 +188944,30 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329594", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Thioguanine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452216305, + "id" : 1452216304, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312068", - "name" : "Recommendation Annotation PA166312068", + "id" : "PA166312042", + "name" : "Recommendation Annotation PA166312042", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Normal Metabolizer"}, + "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Possible Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -185868,30 +188975,30 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329594", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Thioguanine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452216307, + "id" : 1452216282, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312044", - "name" : "Recommendation Annotation PA166312044", + "id" : "PA166312061", + "name" : "Recommendation Annotation PA166312061", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Normal Metabolizer"}, + "lookupKey" : {"TPMT": "No Result", "NUDT15": "Possible Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -185899,30 +189006,30 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329594", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Thioguanine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452216284, + "id" : 1452216300, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312031", - "name" : "Recommendation Annotation PA166312031", + "id" : "PA166312066", + "name" : "Recommendation Annotation PA166312066", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Possible Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "No Result", "NUDT15": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -185930,21 +189037,21 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329594", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Thioguanine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452216230, + "id" : 1452216305, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", @@ -185961,30 +189068,30 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329594", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Thioguanine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { "id" : 1452216301, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312102", - "name" : "Recommendation Annotation PA166312102", + "id" : "PA166312033", + "name" : "Recommendation Annotation PA166312033", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -185992,30 +189099,30 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329594", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Thioguanine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452216341, + "id" : 1452216232, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312104", - "name" : "Recommendation Annotation PA166312104", + "id" : "PA166312069", + "name" : "Recommendation Annotation PA166312069", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Indeterminate"}, + "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -186023,30 +189130,30 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329594", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Thioguanine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452216343, + "id" : 1452216308, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312073", - "name" : "Recommendation Annotation PA166312073", + "id" : "PA166312072", + "name" : "Recommendation Annotation PA166312072", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "No Result"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -186054,30 +189161,30 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329594", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Thioguanine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452216312, + "id" : 1452216311, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312064", - "name" : "Recommendation Annotation PA166312064", + "id" : "PA166312063", + "name" : "Recommendation Annotation PA166312063", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Poor Metabolizer"}, + "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "Possible Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -186085,30 +189192,30 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329594", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Thioguanine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452216303, + "id" : 1452216302, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312082", - "name" : "Recommendation Annotation PA166312082", + "id" : "PA166312081", + "name" : "Recommendation Annotation PA166312081", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "No Result", "NUDT15": "Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -186116,30 +189223,30 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329594", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Thioguanine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452216321, + "id" : 1452216320, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312071", - "name" : "Recommendation Annotation PA166312071", + "id" : "PA166312082", + "name" : "Recommendation Annotation PA166312082", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "No Result"}, + "lookupKey" : {"TPMT": "No Result", "NUDT15": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -186147,30 +189254,30 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329594", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Thioguanine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452216310, + "id" : 1452216321, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312069", - "name" : "Recommendation Annotation PA166312069", + "id" : "PA166312083", + "name" : "Recommendation Annotation PA166312083", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Normal Metabolizer"}, + "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -186178,30 +189285,30 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329594", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Thioguanine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452216308, + "id" : 1452216322, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312065", - "name" : "Recommendation Annotation PA166312065", + "id" : "PA166312102", + "name" : "Recommendation Annotation PA166312102", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "Poor Metabolizer"}, + "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -186209,30 +189316,30 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329594", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Thioguanine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452216304, + "id" : 1452216341, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312032", - "name" : "Recommendation Annotation PA166312032", + "id" : "PA166312031", + "name" : "Recommendation Annotation PA166312031", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Normal Metabolizer", "NUDT15": "Possible Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Possible Intermediate Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -186240,30 +189347,30 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329594", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Thioguanine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452216231, + "id" : 1452216230, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312043", - "name" : "Recommendation Annotation PA166312043", + "id" : "PA166312044", + "name" : "Recommendation Annotation PA166312044", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Poor Metabolizer"}, + "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Normal Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -186271,30 +189378,30 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329594", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Thioguanine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452216283, + "id" : 1452216284, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312067", - "name" : "Recommendation Annotation PA166312067", + "id" : "PA166312101", + "name" : "Recommendation Annotation PA166312101", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "Poor Metabolizer"}, + "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -186302,21 +189409,21 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329594", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Thioguanine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452216306, + "id" : 1452216340, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", @@ -186333,30 +189440,30 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329594", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Thioguanine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { "id" : 1452216342, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312074", - "name" : "Recommendation Annotation PA166312074", + "id" : "PA166312104", + "name" : "Recommendation Annotation PA166312104", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Poor Metabolizer", "NUDT15": "Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Intermediate Metabolizer", "NUDT15": "Indeterminate"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -186364,30 +189471,30 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329594", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Thioguanine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452216313, + "id" : 1452216343, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312061", - "name" : "Recommendation Annotation PA166312061", + "id" : "PA166312067", + "name" : "Recommendation Annotation PA166312067", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "No Result", "NUDT15": "Possible Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -186395,30 +189502,30 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329594", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Thioguanine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452216300, + "id" : 1452216306, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166312063", - "name" : "Recommendation Annotation PA166312063", + "id" : "PA166312043", + "name" : "Recommendation Annotation PA166312043", "alternateDrugAvailable" : false, "dosingInformation" : true, "implications" : [], - "lookupKey" : {"TPMT": "Indeterminate", "NUDT15": "Possible Intermediate Metabolizer"}, + "lookupKey" : {"TPMT": "Possible Intermediate Metabolizer", "NUDT15": "Poor Metabolizer"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: TPMT and/or NUDT15 intermediate or poor metabolizers", "relatedChemicals" : [ @@ -186426,21 +189533,21 @@ "objCls" : "Chemical", "id" : "PA451663", "name" : "thioguanine", - "version" : 14 + "version" : 41 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329594", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Thioguanine - TPMT and/or NUDT15", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452216302, + "id" : 1452216283, "html" : "

"Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 } ], "url" : "https://www.pharmgkb.org/fdaPgxAssociations#PA166329594" @@ -186449,7 +189556,7 @@ "citations" : [ { "id" : 15155142, - "title" : "Table of Pharmacogenetic Associations", + "title" : "FDA Table of Pharmacogenetic Associations", "_sameAs" : "https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations", "authors" : [], "crossReferences" : [ @@ -186472,7 +189579,7 @@ "pgkbPublication" : false, "terms" : [], "type" : "Literature", - "version" : 0, + "version" : 2, "year" : -1 } ], @@ -186481,13 +189588,13 @@ "id" : "PA166329595", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Thioridazine - CYP2D6", "affectedSubgroup" : "poor metabolizers", - "alternateDrugAvailable" : false, + "alternateDrugAvailable" : true, "cancerGenome" : false, "crossReferences" : [], "dosingInformation" : false, "history" : [], "literature" : [ - {"id":15155142,"title":"Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} + {"id":15155142,"title":"FDA Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} ], "originalDrugText" : "Thioridazine", "originalGeneText" : "CYP2D6", @@ -186499,7 +189606,7 @@ "objCls" : "Chemical", "id" : "PA451666", "name" : "thioridazine", - "version" : 12 + "version" : 30 } ], "relatedGenes" : [ @@ -186508,7 +189615,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "removed" : false, @@ -186521,7 +189628,7 @@ }, "terms" : [], "userId" : "pharmgkb", - "version" : 0, + "version" : 2, "versionDate" : "10/26/2022" }, "recommendations" : [ @@ -186540,21 +189647,21 @@ "objCls" : "Chemical", "id" : "PA451666", "name" : "thioridazine", - "version" : 12 + "version" : 30 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329595", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Thioridazine - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { "id" : 1452216701, "html" : "

"Results in higher systemic concentrations and higher adverse reaction risk (QT prolongation). Predicted effect based on experience with CYP2D6 inhibitors. Contraindicated in poor metabolizers."

\n", "version" : 0 }, - "version" : 0 + "version" : 3 } ], "url" : "https://www.pharmgkb.org/fdaPgxAssociations#PA166329595" @@ -186563,7 +189670,7 @@ "citations" : [ { "id" : 15155142, - "title" : "Table of Pharmacogenetic Associations", + "title" : "FDA Table of Pharmacogenetic Associations", "_sameAs" : "https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations", "authors" : [], "crossReferences" : [ @@ -186586,7 +189693,7 @@ "pgkbPublication" : false, "terms" : [], "type" : "Literature", - "version" : 0, + "version" : 2, "year" : -1 } ], @@ -186595,13 +189702,13 @@ "id" : "PA166329596", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Tramadol - CYP2D6", "affectedSubgroup" : "Ultrarapid metabolizers", - "alternateDrugAvailable" : false, + "alternateDrugAvailable" : true, "cancerGenome" : false, "crossReferences" : [], "dosingInformation" : false, "history" : [], "literature" : [ - {"id":15155142,"title":"Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} + {"id":15155142,"title":"FDA Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} ], "originalDrugText" : "Tramadol", "originalGeneText" : "CYP2D6", @@ -186613,7 +189720,7 @@ "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "relatedGenes" : [ @@ -186622,7 +189729,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "removed" : false, @@ -186635,18 +189742,18 @@ }, "terms" : [], "userId" : "pharmgkb", - "version" : 0, + "version" : 2, "versionDate" : "10/26/2022" }, "recommendations" : [ { "objCls" : "Recommendation Annotation", - "id" : "PA166311223", - "name" : "Recommendation Annotation PA166311223", + "id" : "PA166311228", + "name" : "Recommendation Annotation PA166311228", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "2.75"}, + "lookupKey" : {"CYP2D6": "≥5.0"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: CYP2D6 ultrarapid metabolizers", "relatedChemicals" : [ @@ -186654,30 +189761,30 @@ "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329596", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Tramadol - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452214462, + "id" : 1452214468, "html" : "

"Results in higher systemic and breast milk active metabolite concentrations, which may result in respiratory depression and death. Contraindicated in children under 12 and in adolescents following tonsillectomy/adenoidectomy. Breastfeeding is not recommended during treatment."

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166311243", - "name" : "Recommendation Annotation PA166311243", + "id" : "PA166311223", + "name" : "Recommendation Annotation PA166311223", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "≥4.0"}, + "lookupKey" : {"CYP2D6": "2.75"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: CYP2D6 ultrarapid metabolizers", "relatedChemicals" : [ @@ -186685,30 +189792,30 @@ "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329596", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Tramadol - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452214482, + "id" : 1452214462, "html" : "

"Results in higher systemic and breast milk active metabolite concentrations, which may result in respiratory depression and death. Contraindicated in children under 12 and in adolescents following tonsillectomy/adenoidectomy. Breastfeeding is not recommended during treatment."

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166311227", - "name" : "Recommendation Annotation PA166311227", + "id" : "PA166311242", + "name" : "Recommendation Annotation PA166311242", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "≥3.5"}, + "lookupKey" : {"CYP2D6": "≥3.75"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: CYP2D6 ultrarapid metabolizers", "relatedChemicals" : [ @@ -186716,30 +189823,30 @@ "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329596", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Tramadol - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452214467, + "id" : 1452214481, "html" : "

"Results in higher systemic and breast milk active metabolite concentrations, which may result in respiratory depression and death. Contraindicated in children under 12 and in adolescents following tonsillectomy/adenoidectomy. Breastfeeding is not recommended during treatment."

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166311225", - "name" : "Recommendation Annotation PA166311225", + "id" : "PA166311241", + "name" : "Recommendation Annotation PA166311241", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "4.0"}, + "lookupKey" : {"CYP2D6": "≥3.25"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: CYP2D6 ultrarapid metabolizers", "relatedChemicals" : [ @@ -186747,30 +189854,30 @@ "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329596", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Tramadol - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452214464, + "id" : 1452214480, "html" : "

"Results in higher systemic and breast milk active metabolite concentrations, which may result in respiratory depression and death. Contraindicated in children under 12 and in adolescents following tonsillectomy/adenoidectomy. Breastfeeding is not recommended during treatment."

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166311242", - "name" : "Recommendation Annotation PA166311242", + "id" : "PA166311226", + "name" : "Recommendation Annotation PA166311226", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "≥3.75"}, + "lookupKey" : {"CYP2D6": "≥3.0"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: CYP2D6 ultrarapid metabolizers", "relatedChemicals" : [ @@ -186778,30 +189885,30 @@ "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329596", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Tramadol - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452214481, + "id" : 1452214465, "html" : "

"Results in higher systemic and breast milk active metabolite concentrations, which may result in respiratory depression and death. Contraindicated in children under 12 and in adolescents following tonsillectomy/adenoidectomy. Breastfeeding is not recommended during treatment."

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"Results in higher systemic and breast milk active metabolite concentrations, which may result in respiratory depression and death. Contraindicated in children under 12 and in adolescents following tonsillectomy/adenoidectomy. Breastfeeding is not recommended during treatment."

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"Results in higher systemic and breast milk active metabolite concentrations, which may result in respiratory depression and death. Contraindicated in children under 12 and in adolescents following tonsillectomy/adenoidectomy. Breastfeeding is not recommended during treatment."

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"Results in higher systemic and breast milk active metabolite concentrations, which may result in respiratory depression and death. Contraindicated in children under 12 and in adolescents following tonsillectomy/adenoidectomy. Breastfeeding is not recommended during treatment."

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"Results in higher systemic and breast milk active metabolite concentrations, which may result in respiratory depression and death. Contraindicated in children under 12 and in adolescents following tonsillectomy/adenoidectomy. Breastfeeding is not recommended during treatment."

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"Results in higher systemic and breast milk active metabolite concentrations, which may result in respiratory depression and death. Contraindicated in children under 12 and in adolescents following tonsillectomy/adenoidectomy. Breastfeeding is not recommended during treatment."

\n", "version" : 0 }, - "version" : 0 + "version" : 3 }, { "objCls" : "Recommendation Annotation", - "id" : "PA166311241", - "name" : "Recommendation Annotation PA166311241", + "id" : "PA166311222", + "name" : "Recommendation Annotation PA166311222", "alternateDrugAvailable" : true, "dosingInformation" : false, "implications" : [], - "lookupKey" : {"CYP2D6": "≥3.25"}, + "lookupKey" : {"CYP2D6": "2.5"}, "otherPrescribingGuidance" : false, "population" : "Affected subgroup: CYP2D6 ultrarapid metabolizers", "relatedChemicals" : [ @@ -186964,21 +190071,21 @@ "objCls" : "Chemical", "id" : "PA451735", "name" : "tramadol", - "version" : 12 + "version" : 40 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329596", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Tramadol - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { - "id" : 1452214480, + "id" : 1452214461, "html" : "

"Results in higher systemic and breast milk active metabolite concentrations, which may result in respiratory depression and death. Contraindicated in children under 12 and in adolescents following tonsillectomy/adenoidectomy. Breastfeeding is not recommended during treatment."

\n", "version" : 0 }, - "version" : 0 + "version" : 3 } ], "url" : "https://www.pharmgkb.org/fdaPgxAssociations#PA166329596" @@ -186987,7 +190094,7 @@ "citations" : [ { "id" : 15155142, - "title" : "Table of Pharmacogenetic Associations", + "title" : "FDA Table of Pharmacogenetic Associations", "_sameAs" : "https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations", "authors" : [], "crossReferences" : [ @@ -187010,7 +190117,7 @@ "pgkbPublication" : false, "terms" : [], "type" : "Literature", - "version" : 0, + "version" : 2, "year" : -1 } ], @@ -187022,10 +190129,10 @@ "alternateDrugAvailable" : false, "cancerGenome" : false, "crossReferences" : [], - "dosingInformation" : false, + "dosingInformation" : true, "history" : [], "literature" : [ - {"id":15155142,"title":"Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} + {"id":15155142,"title":"FDA Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} ], "originalDrugText" : "Valbenazine", "originalGeneText" : "CYP2D6", @@ -187037,7 +190144,7 @@ "objCls" : "Chemical", "id" : "PA166170051", "name" : "valbenazine", - "version" : 4 + "version" : 6 } ], "relatedGenes" : [ @@ -187046,7 +190153,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "removed" : false, @@ -187059,7 +190166,7 @@ }, "terms" : [], "userId" : "pharmgkb", - "version" : 0, + "version" : 2, "versionDate" : "10/26/2022" }, "recommendations" : [ @@ -187078,21 +190185,21 @@ "objCls" : "Chemical", "id" : "PA166170051", "name" : "valbenazine", - "version" : 4 + "version" : 6 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329597", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Valbenazine - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { "id" : 1452216568, "html" : "

"Results in higher systemic active metabolite concentrations and higher adverse reaction risk (QT prolongation). Dosage reductions may be necessary."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 } ], "url" : "https://www.pharmgkb.org/fdaPgxAssociations#PA166329597" @@ -187101,7 +190208,7 @@ "citations" : [ { "id" : 15155142, - "title" : "Table of Pharmacogenetic Associations", + "title" : "FDA Table of Pharmacogenetic Associations", "_sameAs" : "https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations", "authors" : [], "crossReferences" : [ @@ -187124,7 +190231,7 @@ "pgkbPublication" : false, "terms" : [], "type" : "Literature", - "version" : 0, + "version" : 2, "year" : -1 } ], @@ -187136,10 +190243,10 @@ "alternateDrugAvailable" : false, "cancerGenome" : false, "crossReferences" : [], - "dosingInformation" : false, + "dosingInformation" : true, "history" : [], "literature" : [ - {"id":15155142,"title":"Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} + {"id":15155142,"title":"FDA Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} ], "originalDrugText" : "Venlafaxine", "originalGeneText" : "CYP2D6", @@ -187151,7 +190258,7 @@ "objCls" : "Chemical", "id" : "PA451866", "name" : "venlafaxine", - "version" : 8 + "version" : 40 } ], "relatedGenes" : [ @@ -187160,7 +190267,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "removed" : false, @@ -187173,7 +190280,7 @@ }, "terms" : [], "userId" : "pharmgkb", - "version" : 0, + "version" : 2, "versionDate" : "10/26/2022" }, "recommendations" : [ @@ -187192,14 +190299,14 @@ "objCls" : "Chemical", "id" : "PA451866", "name" : "venlafaxine", - "version" : 8 + "version" : 40 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329598", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Venlafaxine - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { "id" : 1452246120, @@ -187215,7 +190322,7 @@ "citations" : [ { "id" : 15155142, - "title" : "Table of Pharmacogenetic Associations", + "title" : "FDA Table of Pharmacogenetic Associations", "_sameAs" : "https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations", "authors" : [], "crossReferences" : [ @@ -187238,7 +190345,7 @@ "pgkbPublication" : false, "terms" : [], "type" : "Literature", - "version" : 0, + "version" : 2, "year" : -1 } ], @@ -187250,10 +190357,10 @@ "alternateDrugAvailable" : false, "cancerGenome" : false, "crossReferences" : [], - "dosingInformation" : false, + "dosingInformation" : true, "history" : [], "literature" : [ - {"id":15155142,"title":"Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} + {"id":15155142,"title":"FDA Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} ], "originalDrugText" : "Vortioxetine", "originalGeneText" : "CYP2D6", @@ -187265,7 +190372,7 @@ "objCls" : "Chemical", "id" : "PA166122595", "name" : "vortioxetine", - "version" : 5 + "version" : 10 } ], "relatedGenes" : [ @@ -187274,7 +190381,7 @@ "id" : "PA128", "symbol" : "CYP2D6", "name" : "cytochrome P450 family 2 subfamily D member 6", - "version" : 7891 + "version" : 8001 } ], "removed" : false, @@ -187287,7 +190394,7 @@ }, "terms" : [], "userId" : "pharmgkb", - "version" : 0, + "version" : 2, "versionDate" : "10/26/2022" }, "recommendations" : [ @@ -187306,21 +190413,21 @@ "objCls" : "Chemical", "id" : "PA166122595", "name" : "vortioxetine", - "version" : 5 + "version" : 10 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329599", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Vortioxetine - CYP2D6", - "version" : 0 + "version" : 2 }, "text" : { "id" : 1452215500, "html" : "

"Results in higher systemic concentrations. The maximum recommended dose is 10 mg."

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"Alters systemic concentrations and dosage requirements. Select initial dosage, taking into account clinical and genetic factors. Monitor and adjust dosages based on INR."

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"Alters systemic concentrations and dosage requirements. Select initial dosage, taking into account clinical and genetic factors. Monitor and adjust dosages based on INR."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 }, { "objCls" : "Recommendation Annotation", @@ -187513,21 +190620,21 @@ "objCls" : "Chemical", "id" : "PA451906", "name" : "warfarin", - "version" : 17 + "version" : 70 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329600", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Warfarin - CYP2C9", - "version" : 0 + "version" : 2 }, "text" : { "id" : 1452219040, "html" : "

"Alters systemic concentrations and dosage requirements. Select initial dosage, taking into account clinical and genetic factors. Monitor and adjust dosages based on INR."

\n", "version" : 0 }, - "version" : 0 + "version" : 2 } ], "url" : "https://www.pharmgkb.org/fdaPgxAssociations#PA166329600" @@ -187536,7 +190643,7 @@ "citations" : [ { "id" : 15155142, - "title" : "Table of Pharmacogenetic Associations", + "title" : "FDA Table of Pharmacogenetic Associations", "_sameAs" : "https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations", "authors" : [], "crossReferences" : [ @@ -187559,7 +190666,7 @@ "pgkbPublication" : false, "terms" : [], "type" : "Literature", - "version" : 0, + "version" : 2, "year" : -1 } ], @@ -187571,14 +190678,14 @@ "alternateDrugAvailable" : false, "cancerGenome" : false, "crossReferences" : [], - "dosingInformation" : false, + "dosingInformation" : true, "history" : [], "literature" : [ - {"id":15155142,"title":"Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} + {"id":15155142,"title":"FDA Table of Pharmacogenetic Associations","_sameAs":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","crossReferences":[{"id":1452402460,"resource":"URL","resourceId":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations","_url":"https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations"}],"objCls":"Literature","terms":[],"type":"Literature"} ], "originalDrugText" : "Warfarin", "originalGeneText" : "VKORC1", - "otherPrescribingGuidance" : false, + "otherPrescribingGuidance" : true, "pediatric" : false, "relatedAlleles" : [], "relatedChemicals" : [ @@ -187586,7 +190693,7 @@ "objCls" : "Chemical", "id" : "PA451906", "name" : "warfarin", - "version" : 17 + "version" : 70 } ], "relatedGenes" : [ @@ -187595,7 +190702,7 @@ "id" : "PA133787052", "symbol" : "VKORC1", "name" : "vitamin K epoxide reductase complex subunit 1", - "version" : 16 + "version" : 52 } ], "removed" : false, @@ -187608,7 +190715,7 @@ }, "terms" : [], "userId" : "pharmgkb", - "version" : 0, + "version" : 2, "versionDate" : "10/26/2022" }, "recommendations" : [ @@ -187627,14 +190734,14 @@ "objCls" : "Chemical", "id" : "PA451906", "name" : "warfarin", - "version" : 17 + "version" : 70 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329602", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Warfarin - VKORC1", - "version" : 0 + "version" : 2 }, "text" : { "id" : 1452337685, @@ -187658,14 +190765,14 @@ "objCls" : "Chemical", "id" : "PA451906", "name" : "warfarin", - "version" : 17 + "version" : 70 } ], "source" : { "objCls" : "PGx Association", "id" : "PA166329602", "name" : "FDA PGx Association [Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations]: Warfarin - VKORC1", - "version" : 0 + "version" : 2 }, "text" : { "id" : 1452337686, @@ -187678,5 +190785,5 @@ "url" : "https://www.pharmgkb.org/fdaPgxAssociations#PA166329602" } ], - "version" : "2024-05-23-09-04" + "version" : "2024-07-15-21-58" } \ No newline at end of file diff --git a/src/test/java/org/pharmgkb/pharmcat/PipelineTest.java b/src/test/java/org/pharmgkb/pharmcat/PipelineTest.java index d69de84b..b2419e29 100644 --- a/src/test/java/org/pharmgkb/pharmcat/PipelineTest.java +++ b/src/test/java/org/pharmgkb/pharmcat/PipelineTest.java @@ -425,7 +425,7 @@ void testCounts(TestInfo testInfo) throws Exception { .flatMap((k) -> testWrapper.getContext().getDrugReports().get(k).values().stream() .map(DrugReport::getName)) .collect(Collectors.toCollection(TreeSet::new)); - assertEquals(175, drugs.size()); + assertEquals(177, drugs.size()); } @Test @@ -1843,7 +1843,8 @@ void testMtrnr1(TestInfo testInfo) throws Exception { testWrapper.testCalledByMatcher("CYP2C19"); testWrapper.testCalledByMatcher("CYP2C9"); testWrapper.testReportable("MT-RNR1"); - testWrapper.testMatchedAnnotations("amikacin", 1); + testWrapper.testMatchedAnnotations("amikacin", PrescribingGuidanceSource.CPIC_GUIDELINE, 1); + testWrapper.testMatchedAnnotations("amikacin", PrescribingGuidanceSource.FDA_LABEL, 1); }